Mechanical test methods of biomedical membranes such as used for otolaryngology. Biomedical membranes, such as artificial tympanic membranes, are subject to noncontact internal air pressure. To estimate mechanical characteristics of such membranes, it is necessary to carry out the noncontact pressure test and membranous contact test, in addition to the usual monotonic tensile test, by using a rectangular specimen cut from the membranes. In this paper, these mechanical test methods and results on such biomedical membranes were studied. Some of the authors have already presented the mechanical test methods of cellophane membrane for hemodialysis under applied water pressure. Herein, we are concerned with the mechanical test methods of biomedical membranes such as tympanic membrane, in which gaseous pressure was applied.


The mechanical and microscopic aspects of the deformation and fracture of a poly (ether urethane-urea) spun arterial prosthesis. The mechanical properties of a microporous, electrostatically spun poly (ether urethane-urea), used in the construction of arterial prostheses, have been examined, with particular reference to anisotropic, crack initiation processes and preconditioning. The results demonstrate considerable anisotropy in relation to samples derived from circumferential and longitudinal directions of the tube wall structure related to the spinning process. There is also a considerable difference in crack initiation on inner and outer surface of the arterial wall, again related to the processing conditions. The results provide an important contribution to an understanding of structure-property relationships in microporous arterial prosthesis.


Visual evoked potential measurement by maximum length sequence technique. The maximum length sequence (MLS) technique is applied to improve data collection of a clinically important long latency visual potential. Given a limited time for measuring the response and with low number of stimulus presentation, the MLS technique exceeded the conventional method of ensemble averaging in attaining a higher signal-to-noise ratio (SNR). The theoretical consideration of such improvement is developed along with the system implementation. Typical examples of the results obtained in a human subject are presented.


[Results of endoscopic treatment of primary vesico-ureteral reflux with a follow-up of 2-5 years]. 34 patients treated by endoscopic injection of Teflon for vesico-ureteric reflux were reviewed with a follow-up of 2 to 5 years. 45 of the 48 treated ureters showed no signs of reflux, i.e. 93.7% medium-term success rate. 3 cases of reflux recurred after two years and 2 of them were successfully reinjected. There were no upper urinary tract complications. Endoscopic injection of Teflon appears to be a reliable alternative to open surgery.


[Kidney transplantation with cutaneous continent urinary diversion (apropos of 6 cases)]. In a series of 525 renal transplantations performed between January 1987 and September 1990, 5 patients (i.e. 1%) presented with vesical, sphincteric and urethral lesions which prevented classical uretero-vesical or uretero-ureteric reimplantation and functionally satisfactory vesico-sphincteric reconstruction. Under these conditions, in which drainage of the urine into the bladder was impossible, a diversion was created using a continent intestinal reservoir constructed prior to the graft. Four Kock pouches and one Mainz pouch were created during the months preceding renal transplantation with a cadavre kidney. A sixth patient, transplanted in 1981, had to undergo continent urinary diversion in February 1988 after a non-functional bladder augmentation for problems of bladder drainage. We did not observe any mortality or major medical or surgical complications. The follow-up after transplantation in the first 5 patients is now 3, 6, 10, 37 and 40 months. Renal function is normal in all 5 cases with serum creatinine below 130 mmol/l. For the sixth patient, the follow-up is 9 years after the transplantation and 32 months after the continent urinary diversion; serum creatinine is 200 mmol/l and stable since the urinary diversion. Continence is excellent and the comfort of all of the patients is undeniable. However, all patients present with bacteriuria with no symptomatic urinary tract infection.


[Histologic identification of the afferent fibers of the pelvic plexus]. The inferior hypogastric (pelvic) plexus conveys two types of fibres: sympathetic fibres originating in the thoracolumbar sympathetic chain and parasympathetic fibers originating in the sacral anterior rami. By using a histofluorescent stain (glyoxalic acid) and a histochemical stain (thiocholine) in 17 fresh cadavres, we have demonstrated that the sympathetic fibres arise from sacral sympathetic ganglia. These fibres participate in the constitution of the pelvic splanchnic nerves. In this study, we confirm that the inferior roots of the pelvic plexus are not only parasympathetic, but also sympathetic.


[Color processing of ultrasonographic images in extracorporeal lithotripsy]. A number of technical difficulties are encountered in the ultrasonographic detection of renal stones which unfortunately limit its performance. The margin of error of firing in extracorporeal shock-wave lithotripsy (ESWL) must be reduced to a minimum. The role of the ultrasonographic monitoring during lithotripsy is also essential: continuous control of the focussing of the short-wave beamand assessment if the quality of fragmentation. The authors propose to improve ultrasonographic imaging in ESWL by means of intraoperative colour processing of the stone. Each shot must be directed to its target with an economy of vision avoiding excessive fatigue. The principle of the technique consists of digitalization of the ultrasound video images using a Macintosh Mac 2 computer. The Graphis Paint II program is interfaced directly with the Quick Capture card and recovers the images on its work surface in real time. The program is then able to attribute to each of these 256 shades of grey any one of the 16.6 million colours of the Macintosh universe with specific intensity and saturation. During fragmentation, using the principle of a palette, the stone changes colour from green to red indicating complete fragmentation. A Color Space card converts the digital image obtained into a video analogue source which is visualized on the monitor. It can be superimposed and/or juxtaposed with the source image by means of a multi-standard mixing table. Colour processing of ultrasonographic images in extracoporeal shockwave lithotripsy allows better visualization of the stones and better follow-up of fragmentation and allows the shockwave treatment to be stopped earlier. It increases the stone-free performance at 6 months. This configuration will eventually be able to integrate into the ultrasound apparatus itself.


[Testicular sarcoidosis].

[Testicular sarcoidosis]. The authors report a case of testicular sarcoidosis. This lesion may mimic cancer, but the association of germ cell tumour and systemic sarcoidosis appears to be too frequent to be simply a coincidence. It is important to diagnose combinations of these 2 diseases in the scrotum or in the mediastinum, but their pathogenesis remains hypothetical.


[Bladder substitution using the double-folded ileum technic (Goodwin's cup-patch technic)]. An internal urinary diversion after radical cystoprostatectomy has been performed in 70 male patients. The bladder substitute was made from an ileal segment, opened along its antimesenteric border and folded twice, according to Goodwin's "cup-patch technique". After an observation time of 6 months to 6 years, the results are in general good: The initial capacity of the pouch made from only 40 cm of ileum (in order to avoid metabolic disturbances) increases to a functional capacity of 500 ml within the first postoperative weeks. The increase of the bladder substitute's capacity is parallel to the improvement of urinary continence. In general, the latter is achieved after 1-3 months during the day, and after 3-6 months during the night. However, loss of a few drops of urine may occur, reason why half of our patients wear a safety pad later than 6 months after surgery, at least during the night. There was no significant difference between those patients with an antireflux nipple and those patients having an ileal tubular afferent segment.


[Cryotherapy of neovascular glaucoma in diabetics]. The authors give an account of the long-term results of cryotherapy of neovascular glaucoma in 15 eyes of 12 patients with proliferative diabetic retinopathy. The operation was repeated in three instances (20%). Cyclocryothermy was used nine times, cyclocryothermy with retinal transconjunctival cryocoagulation also nine times. Within five days after operation the intraocular pressure was compensated in all patients. Within six months after cryotherapy the intraocular pressure rose above 21 Torr (2.799 kPa) in three eyes. After repeated cryosurgery the intraocular pressure in these eyes was normal. In the remaining 12 eyes at the end of the observation period--average 14.7 months--the intraocular pressure was within the range of 4.8-20.6 Torr (0.639-2.746 kPa). The pain in the eye receded in 100% of the patients. After operation eventually in all patients rubeosis receded. Deterioration of eyesight after the operation is ascribed to the duration of the high intraocular pressure and gradual progression of the proliferative diabetic retinopathy.


[Ureteral replacement using an ileal graft of reduced diameter. A preliminary report]. Extensive or even complete loss of the ureter of a functioning kidney makes it impossible to restore the normal continuity of the urinary tract by any available surgical technique. An ileal loop of appropriate length, anastomosed to the bladder with its entire lumen, is the only tissue suitable for replacing this missing ureter; this results in the formation of a megaureter or a vesical diverticulum which, although contractile, presents dimensions and conditions of anastomosis which predispose to the development of vesico-ileal reflux and a risk of torpid infection and dangerous reabsorption of the urine. We consider that it would be useful to use the ileum to create a contractile, reduced calibre tube with properties similar to those of the ureter. This technique, which has rare indications, is feasible as illustrated by the 5 cases reported here, corresponding to 7 uretero-ileoplasties modelled according to this technique. Results were satisfactory with a follow up of 6-24 months.


[Scleroplasty surgery. I. Results in children]. The authors give an account on the results of scleroplastic operations (according Pivovarov) in 159 children (298 eyes). They describe in detail the surgical procedure, the mechanism of action of the operation, the fate of the implanted material. The most suitable material for scleroplastic operations in children is the irradiated human sclera which caused the minimal incidence of complications. Most frequently eyes with the diagnosis myopia progressiva 57.7% were operated, another large group were eyes with the diagnosis of myopia gravis -35.2%. The mean age at the time of operation was 11.3 +/- 3.3 years. In myopia progressiva the correction was three years after operation the same or lower in 53.3% of the operated patients, the vision was equal or better in 80% of the operated patients. In children with myopia progressiva who were operated at the age of 10-15 years, after three years no difference in vision was recorded as compared with the finding before operation; the correction changed on average only by 0.27 dioptres. This result is very satisfactory, as indication for operation was progression of myopia by at least 1 dioptre per year before operation. In myopia gravis the correction was three years after operation equal or lower in 68.4% of operated eyes, the vision was equal or better in 81.6% of the operated eyes. Reinforcement of the sclera--scleroplasty--is at the moment the only rational therapeutic method of progressing and severe myopia.


[Scleroplasty surgery. II. Results in adults]. The authors give an account of the results assembled in 181 patients (350 eyes) where scleroplasty in Pivovarov's modification was performed. 81.4% of the operations were indicated in myopia gravis, 91% in myopia progressiva and 5.1% in combination of myopia gravis and cataract. Of four implantation materials used the irradiated human sclera proved best. Scleroplastic operations had a favourable effect on the subsequent course of myopia gravis and myopia progressiva (followed up to four years). In both these diagnoses during the postoperative period a statistically significant improvement of visual acuity was observed, while the correction changed only slightly. Scleroplasties are a suitable surgical procedure in adults who suffer from progressing or severe myopia and give them real hope of preservation of visual functions.


[Results of keratoplasty performed at the Eye Clinic of the ILF in Ustí nad Labem]. The authors give an account of their experience and results with transplantations of the cornea in 79 eyes during a period of 44 months. They investigated the condition of the optic disk and visual acuity with optimal postoperative correction in patients after keratoplasty. In 61% of the eyes vision improved as compared with the condition prior to operation, in 61% of the eyes the disk of the donor remained clear throughout the observation period. The observation period was at least one month, the maximum being 44 months.


[Panophthalmitis as a nosocomial infection]. The submitted paper deals with an epidemic of severe postoperative panophthalmitis, its development, course, causes and sequelae incl. epidemiological characteristics. The disease developed in four patients 40 hours after operation of cataract. Despite treatment all four patients developed septicaemia and therefore the affected eyeballs were eviscerated. From smears of the conjunctival sac of the affected patients and from the contents of the eviscerated eyeball Proteus mirabilis and Enterobacter cloaceae were cultivated. The authors draw attention to the epidemiological association with the eye lotion BSS which was used from which Proteus mirabilis and E. coli were cultivated and with the Ringer solution from which Enterobacter cloaceae and Klebsiella pneumoniae were cultivated. An epidemiological analysis of the epidemic was made and provisions were defined to rule out its recurrence.


[Ophthalmic complications in general corticoid therapy]. The authors investigated in a group of 850 patients the influence of long-term general corticotherapy on the transparency of the lens and intraocular pressure in relation to the length of therapy, dosage, age and sex of the patient. The presence of posterior subcapsular cataract was revealed in 5.2% of the patient, a raised intraocular pressure in 12.8%. The authors reached the conclusion that the duration of corticotherapy did not influence in a substantial way the development of posterior subcapsular cataract nor of cortisone glaucoma. A dose of 10-15 mg per day may be considered marginal for the development of cataract; dosage has no basic effect on the development of glaucoma. The maximum incidence of complications was in advanced age groups. No predisposition as regards sex was observed. A significant role in the development of cortisone cataract and cortisone glaucoma is played by individual sensitivity to corticoids.


[Accuracy of intraocular pressure measurement using a noncontact Keeler tonometer]. Using a contactless tonometer of Keeler Co. the authors assessed the intraocular pressure in enucleated eyeballs and compared the values with the intraocular pressure assessed in the eyeballs by means of a water manometer. In the second stage the scatter of assessed values in the eyeballs was compared with the scatter of values obtained by measurements in patients.


[Analysis of patients with retinal detachment surgery performed at the Eye Clinic of the ILF of the Regional Hospital in Ustí nad Labem 1987-1989]. In a group of 104 patients operated at the Ophthalmological Clinic in Ustí nad Labem on account of retinal detachment in 1987-1989 the authors investigated the anatomical and functional results of the operation during an average period of 15 months. Anatomical attachment of the retina was achieved in 82%; 52% of the patients improved from the functional aspect. In addition to vision on admission, discharge and during the last check-up the authors evaluated the extent of retinal detachment, the site of fissures, the number of myopes and aphakic subjects in the group and the period of retinal detachment before operation. There were 37.5% myopes and 27.9% aphakic patients and artephakia was recorded in 4.8%. The duration of detachment of the retina before operation was 7.4 weeks (3 days to 2 years). An association between the development of retinal detachment and injury was proved in six patients (5.8%).


[New views on treatment of intraocular foreign bodies]. The authors evaluated the results of surgery in 130 patients operated at the Second Ophthalmological Clinic in 1983-1989 on account of intraocular foreign bodies. Extraction of the body was successful in 126 patients (96%), the function of the eye was preserved in 102 of 126 extracted foreign bodies (81%), a visual acuity of 0.5 to 1.0 was recorded in 78 eyes (60%). The authors investigated the relationship of functional results on the type, size and site of the intraocular foreign body, the way of extraction, interval between the injury and operation and previous attempted extractions. Analysis of results revealed the advantages of extraction of intraocular foreign bodies under visual control in the majority of foreign bodies. Intraocular foreign bodies are not an indication for immediate but for early operation. After careful treatment of the wound where the foreign body penetrated extraction may be delayed for several days before optimal conditions for surgery are created.


[Cryotherapy in the treatment of vitreous hemorrhage of various origin]. In 54 eyes from the same number of patients transconjunctival cryotherapy was performed (12 points and 8-10 circular ones in the outer retinal periphery) to influence the absorption of vitreous haemorrhages of different aetiology. The most frequent cause was the proliferative stage of diabetic retinopathy (53.7%) and vascular changes in atherosclerosis (39%). Haemorrhage of the vitreous persisted on average for five months. Eight months after the intervention complete or partial reabsorption led to improvement of the eyesight in 74% of the patients, no change was recorded in 16.6% and further deterioration occurred in 9.4%. No serious per- or postoperative complications were recorded, the method is unpretentious, can be used in ambulatory patients, it is repeatable and suitable also as preparation before vitreous surgery.


[Retinal detachment after perforating eye injuries. IV. Anatomic and functional results of cryosurgical procedures]. In the course of ten years the authors operated 69 patients with detachment of the retina (DR) after perforating eye injuries, using cryosurgical methods with silicone episcleral implants. In 37 patients DR developed after simple perforation (group A) and in 32 patients after perforation of the eye with an intraocular foreign body (group B). In all patients the perforation affected the vitreous space. From the total number of patients anatomical apposition of the retina was achieved in 62.3%. A significant difference is the poorer anatomical result of the operation in the group with simple perforations without a foreign body 54.0%, as compared with the group after perforation with a foreign body, 71.9%. The anatomical results were evaluated with regard to the period of DR, aphakia, the characteristic of the retinal defect, the type of LR and the extent of the operation. From the total number of successfully operated patients we recorded the same or better vision in 44.2% and in 51.2% poorer vision, as compared with that after the perforating injury of the eye. Deterioration was caused by the duration of DR, detachment of the macular region, an extensive operation and complications.


[Principles of treatment of detachment using minimal retinal surgery]. Minimization of detachment surgery became feasible by: (1) omitting drainage of subretinal fluid by using elastic plombages limited to the area of the break and (2) meticulous search for the retinal break(s). On this premise the extent of the operation is solely determined by the size of the break(s) and no longer by the extent of the detachment. There were conceived: (1) the cryosurgical detachment operation in treating detachments with several breaks by single sponges (radial buckles whenever possible) by being permanent plombages and (2) the balloon operation in treating detachments with a single break by using a temporary plombage. These operations, being extraocular, can be applied in more than 9 of 10 rhegmatogenous detachments and the retina will be reattached in more than 9 of 10 cases. -However, in the presence of a problematic break (giant tear, posterior hole) an intraocular operation by using expanding gases (SF6, Perfluorocarbons) is indicated: (3) the expanding gas operation and (4) the balloon-gas procedure. By using the balloon-gas procedure (reducing the number of gas injections for treating a giant tear to one injection by providing a sufficiently large gas plombage) and (5) the modified balloon-gas operation with a retrohyaloidal injection of gas instead, a decrease of vitreoretinal complications, otherwise the main cause of failure, seems apparent.


[Visual acuity and color sensitivity in retinal detachment]. In patients with unilateral detachment of the retina after successful operation (buckling 3x, cerclage 3x, combined operation 4x), the visual acuity was assessed on Snellen optotypes or Landolt's ring chart. Optotype charts with rings were made according to recommendations of the commission for vision of the American Academy of Sciences. Snellen's visual acuity of healthy and affected eyes was 6/9-6/6. In all patients moreover sensitivity to contrast was examined assessed by means of a VISTESCH testing table. It was revealed that sensitivity for contrast in all operated eyes is significantly lower than in healthy eyes and that the threshold visual acuity and steepness of lines is significantly lower.


[Pars plana vitrectomy in proliferative diabetic retinopathy. Long-term results and prognostic parameters in diabetics with surgery 1983-1989]. The authors evaluated the long-term results and prognostic parameters of pars plana vitrectomy (PPV) in complications of proliferative diabetic retinopathy in 235 eyes of 187 diabetics operated between Jan. 1 1983 and June 30 1989. In 117 eyes PPV was combined with implantation of silicon oil. During an average observation period of 27 months PPV improved markedly the visual acuity of 125 eyes (53.2%), however a visual acuity of 0.1 or better acuity was recorded only in 53 eyes (22.6%). The number of successfully operated eyes declined with the length of the observation period from 67.7% after three months to 50% after 60 months. Active vascular proliferation, iatrogenic fissures of the retina, implantation of silicone oil and postoperative development of rubeosis were statistically significant adverse factors from the prognostic aspect. With the development of new surgical procedures the importance of different prognostic factors changes partly.


[Treatment of choroidal melanoma using photocoagulation]. The author defines the conditions for treatment of chorioid melanomas by photocoagulation which is restricted only to a small number of tumours. The author describes different therapeutic techniques, using photocoagulation. The success rate of treatment of chorioid melanomas by xenon photocoagulation is 50-60%, similar results are obtained with laser coagulation (maily krypton or a combination of argon and krypton). Treatment with an argon laser alone is not suitable as blue light which forms 70% of the light energy does not penetrate into the chorioid. Green light of the argon laser is suited for use in the first stage of treatment, i. e. for obliteration of retinal and chorioid vessels. The authors treated six patients with melanoma of the chorioid using combined xenon-argon therapy. During the average observation period of six years only one patient developed regression of the tumour, in another patient further growth ceased, but regression was not observed. In four patients on account of progression of the tumour the eye had to be enucleated.


[Metamorphosis of vitelliform macular degeneration]. The authors describe the case of vitelliform macular degeneration of a mother and daughter whom they followed up using different examination methods incl. electrophysiological ones and fluorescent angiography. During the observation subjective deterioration of vision occurred in the daughter which was due to transformation of the typical picture of egg yolk into a further stage of pathological changes.


[New views on the immunology and classification of uveitis]. The authors characterize the special immune status of the eye. They mention those anatomical and immunological characteristics of the eye which condition this special immune status. They also evaluate different types of classification of uveitis.


[The importance of immunologic tests in endogenous uveitis]. The authors evaluate the results of immunological examination of the peripheral blood of 50 patients with endogenous uveitis hospitalized at the Ophthalmological Clinic in Plzen in 1987-1989. The authors reach the conclusion that with regard to contemporary, available methods we cannot expect a significant contribution of immunological examinations of the peripheral blood for the diagnosis of endogenous uveitis without systemic disease.


[Evaluation of the long-term therapeutic effect of bacterial vaccines administered 1960-1968 to patients with recurrent anterior uveitis]. The authors evaluate after an interval of many years the effectiveness of treatment of relapsing anterior uveitis by streptococcal vaccines administered in the sixties by L. Klenka, I. Hána, M. Koleckárová. The evaluation is based on a survey conducted by means of questionnaires. After 21 years 91% of the respondents do not report relapses. The authors discuss possible reasons why this desensitization treatment is successful.


[Ocular changes in Gardner syndrome].

[Ocular changes in Gardner syndrome]. In hereditary adenomatosis of the large bowel (familial polyposis) extraintestinal manifestations of the disease are common: hyperostosis, dental anomalies, soft tissue tumours, desmoid tumours etc. Patients with marked extracolic signs are described as patients with Gardner's syndrome. Recently a further sign is described--foci of congenital hypertrophy of the pigmented retinal epithelium. The authors examined 22 patients with confirmed hereditary adenomatosis (Gardner's syndrome). The typical finding of pigmented foci on the fundus was recorded in 18 subjects (82%) incl. 9 subjects (50%) where the finding was bilateral. The authors examined also 25 children of these patients. In those a positive finding was recorded in 11 (44%). Ophthalmological examination can contribute in a significant way to detection of an asymptomatic subject with hereditary adenomatosis, in particular when seeking risk patients in an affected family. Evaluation of ophthalmological changes can also contribute to the solution of some special genetic problems of this disease.


[Ultrasonography of the bile ducts after cholecystectomy]. The paper is concerned with the results of multiprojectional ultrasound investigation of the biliferous system in 68 patients at varying time after cholecystectomy. In most cases (77.9%) signs of dilated biliary ducts were undetectable. Dilatation of the hepaticodoch was most frequently determined by choledolithiasis, stricture or stenosing papillitis, rarely--by pancreatic head cancer. Investigation of the biliary ducts in patients after cholecystectomy should be started with ultrasound tomography; endoscopic retrograde cholangiopancreatography or i.v. cholangiography and dynamic cholescintigraphy were indicated after the detection of the signs of dilated ducts (the anteroposterior diameter of the common hepatic duct was over 6 mm).


[Radiologic diagnosis of urinary tract disorders in genital endometriosis]. The paper is concerned with the results of combined investigation of 157 women suffering from genital endometriosis, operated on for this disease. The involvement of the lower parts of the ureters in a pathological process was detected in 48 patients before operation and in 6 patients at operation. Comparison of x-ray and operative findings with histology specimens made it possible to define endogenous and exogenous forms of ureteral endometriosis and three variants of an x-ray picture in this pathology (the absence of abnormal changes of the urinary tract, hydroureter is over the narrowed part of the ureter, hydroureteronephrosis). The authors have shown a high informative value of combined x-ray investigation and the effectiveness of its use in clinical practice.


[Computed tomography in the differential diagnosis of biliary, duodenal and pancreatic diseases]. The paper is concerned with analysis of CT-investigation of 150 patients with diseases of the bilio-pancreatoduodenal area, whose diagnosis was verified histologically or by clinical observation over time, using other methods (USI, RCPG, etc.). The authors have arrived at a conclusion that for increasing the informative value of CT one should use various methods of a contrast study of the duodenum and biliary tract, electron reconstruction of CT images in different projections. They have pointed out the most significant differential-diagnostic CT signs, proposed a table to facilitate the identification of causes and a level of obturation of the bile ducts, the table playing an important role in a choice of adequate therapy.


[Magnetic resonance tomography in the diagnosis of renovascular hypertension]. MR tomography was used for investigation of 38 patients with renovascular hypertension (RVH) and 26 healthy persons. A possibility of the use and practical value of the method in the diagnosis and evaluation of renal function and renal arteries (RA) were under study. Some quantitative MRT indices were calculated both for the patients and healthy persons. They included spin-spin relaxation time, proton density, and signal intensity. These data can provide important information on renal function in RVH with relation to kidney sizes and the state of the renal parenchyma (evaluation of the cortical substance and medulla and the border between them). In some cases MRT ensures noninvasive diagnosis of PA stenosis.


[Computed tomography in the diagnosis of mechanic jaundice complicated with diseases of the distal common bile duct]. Computerized tomography (CT) is a noninvasive indirect method of instrumental investigation for imaging the liver, bile ducts and the adjacent organs. CT enables one to confirm objectively the mechanical nature of jaundice, to assess a degree and level of involvement of the biliary tract, to assess the nature and spreading of disease. CT sensitivity for the diagnosis of pancreatic head cancer was 78.8%, specificity-91.3%, that for choledocholithiasis--84.6%, specificity--96.7%. CT in jaundice made it possible to establish diagnosis at various levels of accuracy: from differentiation of mechanical and parenchymatous jaundices to preliminary assessment of malignant tumor resectability facilitating a choice of surgical tactics.


[Radiologic endovascular prosthesis of the renal arteries in patients with renovascular hypertension]. A high percentage of restenoses after roentgenovascular dilatation of the renal arteries laid the basis of a search for new therapeutic methods for these patients. Experiments on implantation of nitinol spiral endoprostheses showed their ability for long-term permeability of renal arteries, not causing their thrombosis and intimal spreading, destruction of formed elements of the blood, change in plasma proteins. Morphological investigations have shown rapid formation (during 14 days) of connective tissue neointima, covered on the side of the blood flow with the true vascular endothelium (ensuring a nonadhesive surface and laminar blood flow), around the coils of an endoprosthesis. This method after its experimental development started to be used in clinical practice. The authors reported the first experience in the clinical use of this method (12 patients with vasorenal hypertension). A 15-month follow-up revealed a stable antihypertensive effect in all patients.


[Computed tomography in the diagnosis of asymptomatic renal cysts]. The authors analyzed CT-data on 1732 patients aged 21 to 83 to detect symptom-free renal cysts which were found in 30% of the patients. The rates and prevalence of symptom-free renal cysts were studied. A high resolution was noted. A majority of cysts was detected in patients over 50. The rates and prevalence of renal cysts testified to their low clinical significance (in the authors' opinion).


[Radiologic diagnosis of malignant lymphoma of the small intestine]. The authors observed 10 patients with malignant lymphoma revealed by x-ray; 2 of them were supposed to be afflicted with heavy alpha-chain disease with malignant transformation. An x-ray picture revealed a triad of pathognomonic symptoms and a regular parallelism of intestinal changes with clinico-laboratory findings. In all the cases the diagnosis was confirmed by morphological data.


[Computed tomography in the diagnosis of malignant renal neoplasms and their dissemination]. CT, performed in 66 patients with suspected renal tumors, showed renal cell carcinoma in 36. Tumor spreading was correctly established in 80.6%. Accurate diagnosis was made in 64 of 66 cases. The authors regard CT as an effective method for the recognition of sizable processes and differential diagnosis of solid tumors. Among the visual methods of investigation, used to define a tumor stage, CT turned out to be the most effective one.


[Angiographic diagnosis of agenesia, aplasia and hypoplasia of kidneys in children]. Problems of the diagnosis of congenital renal developmental defects (CRDD) still continue to present a certain interest. Basing on their own experience in the diagnosis of CRDD in 188 of 527 children with renal pathology, the authors arrived at a conclusion that intravital diagnosis of renal aplasia was not only possible with the help of angiography, but also extremely necessary because agenesia and aplasia were two separate entities in their genesis, limiting the potentialities of reconstructive operations in aplasia. Hypoplasia in children was very frequent and was characterized by 5 types of the angiographic picture. Analyzing the state of the contralateral kidneys in CRDD, the authors considered some features of compensatory hypertrophy.


[Renography of renal function depending on the results of radiotherapy of bladder cancer]. The paper is devoted to analysis of the potentialities of radionuclide renography as a method for assessment of the effectiveness of radiotherapy of bladder cancer. The results obtained suggested close correlation between change of renal function and the results of irradiation. Normal renal function was observed in 3 patients, improvement--in 16 patients, and deterioration--in 8 patients whereas a complete effect of radiotherapy brought about the following figures: 5, 11 and 3, respectively. A conclusion was made of a high significance of renography parameters in objective assessment of the results of radiotherapy of bladder cancer in conjunction with other therapeutic modalities.


[Ultrasonographic and radiographic diagnosis of breast nodules in young women]. Mammography as a priority method of diagnosis of breast nodules in young women is of low efficacy as a result of a dense background of the breast as distinct from echography permitting the detection of abnormal lesion against this background. Altogether 126 patients with clinical manifestations of breast nodules were investigated. Apparatus methods used for investigation of 38 of them, revealed but manifestations of fibrocystic mastopathy. Assessment of the efficacy of x-ray and ultrasound diagnostic methods was performed in 88 patients with breast nodules (the patients varied in age from 14 to 40). Radiodiagnostic accuracy in benign tumors was 54.1%, that in malignant tumors--78.1%. Ultrasound investigation proved to be the most informative method for diagnosis of breast nodules in young women, and the use of a proposed algorithm would permit optimization of the diagnostic process.


[Computed tomography in the diagnosis of soft tissue neoplasms of the trunk and extremities]. Analysis of CT data on 213 patients with soft tissue and trunk tumors has shown that a majority of malignant and benign tumors have a similar picture (except lipoma). Features of the contours of a tumor and its inner structure do not permit the assessment of its nature. The only significant differential-diagnostic sign of malignant soft tissue tumors is destruction of an adjacent bone, noted in 17.6%. The majority of malignant and benign soft tissue tumors (70.9%) on CT scans look like a single node; recurrent tumors look multinodular (78.2%). Verification of soft tissue tumors, revealed by CT, should be done using morphological methods.


[Descending myelography with water-soluble contrast agents using methods of lateral puncture of the great occipital cistern]. A method of lateral puncture of the great occipital cistern for descending myelography with water soluble contrast substances was employed. It was used in 150 neurosurgical inpatients aged 4 to 70 with various diseases of the spinal marrow and its coats. A new water soluble drug iopamidol-200 (or 300) (Bracco, Italy) was used for diagnosis of spinal tumors. The drug dosage was worked out for adults as well as for children. A study was made of possible side-effects on a vast clinical material (80 patients). The new contrast substance iopamidol possesses better tolerance by patients and better roentgenocontrast properties than amipack.


[Clinical and radiologic manifestations of pleural and pulmonary complications in sepsis]. Proceeding from the investigation and therapy of 106 patients with pleuropulmonary complications of sepsis the authors described clinical and x-ray features of different types of their course, complications and outcomes. In 58% of cases pulmonary lesions were detected at the stage of pyodestruction and pleural empyema; interstitial-focal and infiltrative pneumonias of considerable spreading with the development of a respiratory type of septic shock were observed less frequently. Pulmonary lesions in 24% were the only sign of septicopyemia, in 58% they prevailed in the clinical picture of polyorganic lesions; pleural complications developed in 32% of the patients. Convalescence was observed in 88 (83%) patients; they had residual bullous-sclerotic pulmonary changes. The lethality rate was 17%.


[Cholangiography of bile ducts using selective catheterization]. The paper is concerned with the use of selective catheterization of the bile ducts during endoscopic cholangiocholecystography. This method alongside with routine ones was employed for investigation of 82 patients with pathology of the hepatoduodenopancreatic area, that helped to avoid diagnostic errors.


[Radiologic pulmonary manifestations in patients with HIV virus infection]. Altogether 155 patients with a newly detected positive reaction to HIV (a human immunodeficiency virus) were investigated in the Republic of Burundi. Chest x-ray was done in 80 of them. Pulmonary tuberculosis was diagnosed in 2 of them, pneumonia (chronic, interstitial and bronchial)--in 15. Enhancement and deformity of lung marking were detected in 45 patients (coincidence with clinical signs of acute bronchitis was found but in 5 of them). A conclusion has been made of interstitial pneumonias being typical of HIV-infected patients and of frequent enhancement of lung marking in the preclinical stage of AIDS.


[Clinical and radiologic manifestations of larval paragonimiasis in children]. Investigation of 60 children with acute types and 45 children with latent types of larval paragonimiasis (LP) has revealed various clinical and x-ray manifestations of this disease, spread in the southern Primorski Territory. Three syndromes of this disease were singled out: toxico-allergic, abdominal and pulmonary. X-ray investigation showed characteristic LP symptoms: exudate in the pleural cavity, thickening of the wall, diaphragmatic and interlobular pleura, sometimes--pneumothorax. Pathology of the bronchopulmonary system manifested itself in focal and infiltrative shadows, enhanced and deformed lung markings, and bullous inflation. Diagnosis and differential diagnosis must be based on analysis of clinical and x-ray data and the results of serological reactions.


[Radiologic diagnosis of pathologic pulmonary changes in ischemic heart disease]. Combined chest x-ray investigation was performed in 187 CHD patients. Different pulmonary changes were noted in postinfarction and atherosclerotic cardiosclerosis as a result of congested effects in lesser circulation: they depended upon a stage of disturbed circulation (the more circulatory decompensation was noticeable, the more marked were changes in lesser circulation). Pulmonary and cardiac changes in patients with postinfarction cardiosclerosis were more frequent and marked.


[Endovascular embolization of arteriovenous lung fistulas (review of literature and own results)]. The authors analyze the literature data on and their own experience in endovascular closure of arteriovenous lung fistulas: 20 fistulas were closed in 12 patients, in whom transcutaneous catheterization of the pulmonary artery was performed. Large-frame angiopulmonography made it possible to reveal 10 common arteriovenous lung fistulas (7 single and 3 multiple ones). Afterwards the diagnostic procedure was turned into a therapeutic one. Several types of spirals, spongogel fragments, pieces of felt and pools with wool were used as embolizing materials. All these measures resulted in hermetic closure of the arteries and a complete stop of pathological right-left shunting of the blood at the lung level and positive dynamics of blood gaseous indices.


[Image processing of thymus tumors].

[Image processing of thymus tumors]. Altogether 40 thymic tumor patients were investigated. Radiograms and pneumomediastinograms were subjected to processing aposteriori (increased contrast and spatial filtration). Spatial filtration improved selective analysis of spatial frequencies of imaging. Processing of images specified diagnosis of thymomas by underlining the shapes of normal and abnormal mediastinal formations and signs of invasion of the pericardium and pleura.


[Magnetic resonance tomography in the diagnosis of aneurysm and coarctation of the thoracic aorta]. MR-tomography (MRT) was performed in 25 patients with aneurysms and in 11 with coarctation of the thoracic aorta. For investigations a device with a resistive magnet (the force of a field--0.23 T) was used simultaneously with ECG. MRT revealed all cases of aortic dissection (10 patients) and one case with a false-positive result. Oblique sections in the direction of the thoracic aorta were used to assess the state of the aortic arch branches. Comparison of MRT and x-ray computerized tomography has shown that the diagnostic value of both methods was almost equal, however MRT was a safer method and easier to use. MRT was shown to be a method of choice for diagnosis of aneurysms and coarctations of the thoracic aorta but cannot be a substitution for aortography.


[Comprehensive radionuclide lung imaging in preventive mass screening of industrial workers]. The results of a combined roentgenoradionuclide investigation of the lungs were studied in 45 persons at risk of developing chronic nonspecific pulmonary diseases, diagnosed in a mass screening of 3000 workers at an industrial enterprise. The results of fluorographic, roentgenoscopic and roentgenographic investigations of the lungs, roentgenopneumopolygraphy and radionuclide investigation of lung perfusion (pulmoscintigraphy with 99mTc-labeled albumin macroaggregates) were compared. During this combined investigation the signs of nonspecific pulmonary diseases were diagnosed in 40% of the patients, changes of the pulmonary blood flow--in 71%, changes of ventilation--in all the examinees. A conclusion was made of the necessity of additional combined investigation of patients belonging to risk groups, identified during mass screenings.


[Ultrasound diagnosis of gallbladder and bile duct diseases]. The paper is concerned with analysis of the potentialities of ultrasound introscopy in the diagnosis of various diseases of the gall bladder and biliferous ducts in 174 patients aged 19 to 76. The accuracy of the detection of calcium containing concrements of the gall bladder was 98.8%, that of choledocholithiasis--75%, noncalculous cholecystitis--88.4%, choledochodilatation--71.4%. In the absence of pathological changes in the gall bladder and biliferous ducts the reliability of echography was 27.7 and 93.1%, respectively. Causes of diagnostic errors in ultrasound tomography of the biliary system were discussed, methods of their prevention were proposed. A diagnostic algorithm of the sequence of use of ultrasound introscopy and other diagnostic methods to be employed in clinical practice was devised.


Cellulitis after axillary lymph node dissection for carcinoma of the breast. We present a series of patients who developed cellulitis following axillary lymph node dissection for carcinoma of the breast. Bacterial cultures were not helpful in making a diagnosis for the majority of the cases. The clinical scenario of upper extremity cellulitis after axillary dissection mimics the presentation of cellulitis in the lower extremity. Until diagnostic methods or treatment advances can eliminate the indications for axillary lymphadenectomy, many women treated for breast cancer will be at long-term risk for the development of cellulitis due to localized immune impairment. Patient and physician awareness of this syndrome is the best available tool to prevent secondary exacerbation of lymphedema. Prompt treatment with appropriate antibiotics appears universally successful. Antistreptococcal antibiotics should not be withheld pending results of blood or tissue cultures, since in only a few cases will a pathogen be isolated. Although there are no studies confirming the concept, it is likely that appropriate treatment for lymphedema may reduce the risk of infection.


Epidemiology of invasive childhood pneumococcal infections in Israel. The Israeli Pediatric Bacteremia and Meningitis Group. To study the epidemiology of childhood pneumococcal invasive infections in Israel as a background for immunization programs. A 2-year (October 1988 through September 1990) prospective, nationwide surveillance of all invasive pediatric pneumococcal infections. All 25 medical centers hospitalizing children in Israel, including all laboratories performing blood cultures from pediatric patients. Infants and children aged 0 to 12 years visiting the pediatric emergency department or hospitalized in pediatric departments were included if Streptococcus pneumoniae was isolated from blood or cerebrospinal fluid. Four hundred sixty-nine invasive infections were diagnosed. Pneumonia, bacteremia without apparent focus, meningitis, and cellulitis were found in 39%, 37%, 17%, and 3%, respectively. The annual incidence was 42 per 100,000 for children younger than 5 years of age (104 per 100,000 for those < 12 months old). The two most common serotypes were 1 and 5, which are rare in Western Europe and North America. Eight groups comprised 82% of all invasive infections. Extrapolated to a population in which 100,000 live births occur yearly, the total annual hospitalizations for pneumococci infections was calculated to be 1928 days. The overall case-fatality rate was 2.2%, but it was 30% during the first month of life. Pneumococcal invasive infections are common in children in Israel and carry considerable morbidity.


Akathisia, suicidality, and fluoxetine.

Akathisia, suicidality, and fluoxetine. The propose link between fluoxetine and suicidal ideation is explained by fluoxetine-induced akathisia and other dysphoric extrapyramidal reactions. The following literature is reviewed: (1) the subjective response of schizophrenics to akathisia, including evidence that akathisia gives rise to suicidal ideation; (2) the subjective reports of patients taking fluoxetine; and (3) preclinical studies describing the role of serotonin in the extrapyramidal system and suggesting a mechanism whereby fluoxetine can induce extrapyramidal side effects. The literature suggests that fluoxetine-induced extrapyramidal reactions may be a mediator of de novo suicidal ideation. We propose a syndrome which we name Extrapyramidal-Induced Dysphoric Reactions, one extreme manifestation of which is the emergence of suicidal ideation. We further propose a heuristic "Four Neuron Model of the Extrapyramidal Motor System" in which increased serotonin activity, by inhibiting the nigrostriatal dopamine tract, is capable of inducing extrapyramidal side effects.


Occult sacral fractures in osteopenic patients. The presentation, diagnosis, and treatment of occult sacral fractures in seventeen osteopenic patients were reviewed. Sixteen of the seventeen patients were elderly women, and the fracture usually occurred without trauma (fourteen patients). In ten patients, the sacral fracture was associated with a fracture of the pubic ramus. The sacral fractures were difficult to diagnose because nine patients also had a history of a malignant lesion of the pelvis with or without radiation treatment. Computed tomography and bone-scanning were diagnostic in all patients, but magnetic resonance imaging was not specific. Use of crutches or a walker, a reduction in activity, and use of non-narcotic analgesics allowed for the resolution of symptoms in all twelve patients who did not have mitigating conditions and permitted these patients to walk independently.


Sequences of the envM gene and of two mutated alleles in Escherichia coli. The nucleotide sequence of the Escherichia coli envM gene was determined. It codes for a protein of 262 amino acids. The sequences of the E. coli and Salmonella typhimurium EnvM proteins are 98% identical. Gene envM is preceded in E. coli by a 43-nucleotide-long structural element, termed 'box c', which occurs in several E. coli operons between structural genes. This sequence element is totally absent in S. typhimurium. Gene envM was mapped at coordinate position 1366.8 kb of the physical map of Kohara et al. (Cell, 1987, 50, 495-508). As in S. typhimurium, a Gly for Ser exchange at position 93 of the amino acid sequence leads to a diazaborine-resistant E. coli phenotype. A Ser for Phe exchange at position 241 of the EnvM protein results in a temperature-sensitive growth phenotype. Comparison of the EnvM amino acid sequence with sequences available in databases showed significant homology with the family of short-chain alcohol dehydrogenases.


Peristalsis evoked by 5-HT and renzapride: evidence for putative 5-HT4 receptor activation. The effect of 5-hydroxytryptamine and renzapride was studied on the peristaltic reflex elicited in vitro in the guinea-pig ileum. Both agents evoked the reflex at subthreshold intraluminal pressures (50% of threshold) and were blocked by ICS 205-930 (3 microM), but not ondansetron (5 microM). This novel finding suggests strongly that the prokinetic action of renzapride and gut motility stimulating action of 5-hydroxytryptamine are mediated via agonism at the putative 5-HT4 receptor.


Coronary vasoconstriction in the conscious rabbit following intravenous infusion of L-NG-nitro-arginine. Intravenous infusion of L-NG-nitro-arginine, an inhibitor of endothelial nitric oxide (NO) synthesis, produced vasoconstriction in the coronary, cerebral, renal and duodenal vascular beds of the conscious rabbit. In this study, using radiolabelled microspheres, we provide in vivo evidence for a basal NO-dependent vasodilator tone in the coronary vascular bed.


Relaxation of sheep cerebral arteries by vasoactive intestinal polypeptide and neurogenic stimulation: inhibition by L-NG-monomethyl arginine in endothelium-denuded vessels. 1. Perivascular nerves of the sheep middle cerebral artery show immunoreactivity for both vasoactive intestinal polypeptide (VIP) and calcitonin gene-related peptide (CGRP). 2. Rings of endothelium-denuded sheep middle cerebral artery precontracted with 5-hydroxytryptamine were relaxed by CGRP (maximum relaxation = 87.8 +/- 8.1%, pD2 = 7.81 +/- 0.12, n = 12) and by VIP (maximum relaxation = 55.1 +/- 4.1%, pD2 = 7.65 +/- 0.04, n = 18). Rings of endothelium-denuded cat middle cerebral artery precontracted with U46619 were also relaxed by vasoactive intestinal polypeptide (maximum relaxation = 53.1 +/- 6.1%, pD2 = 7.82 +/- 0.11, n = 6). 3. Haemolysate (1 microliters ml-1) inhibited VIP-induced relaxation in endothelium-denuded sheep and cat middle cerebral artery (n = 6) but had no effect on the CGRP-induced relaxation of the sheep middle cerebral artery (n = 6). 4. The relaxant response to VIP in endothelium-denuded sheep middle cerebral artery was inhibited by methylene blue (10 microM) and augmented by either M&B 22948 (10 microM) or superoxide dismutase (150 units ml-1). Indomethacin (1 microM) had no effect. 5. The addition of L-NG-monomethyl arginine (100 microM) inhibited both neurogenic and VIP-induced relaxation of endothelium-denuded sheep MCA by 56 +/- 6% and 60 +/- 6% (n = 5) respectively. The CGRP-induced relaxation was unaffected. 6. It is concluded that neurally mediated vasodilatation in the sheep middle cerebral artery is mediated largely by VIP through a direct action on smooth muscle through a cyclic-GMP-mediated mechanism that appears to involve synthesis of nitric oxide from L-arginine. Vasodilatation by CGRP, which is also contained in perivascular nerves, does not utilize this pathway.


Prejunctional prostanoid receptors on cardiac adrenergic terminals belong to the EP3 subtype. 1. The effects of prostaglandin E2 (PGE2) and of several synthetic prostanoids on the cardiac response to sympathetic nerve stimulation in guinea-pig atria have been evaluated. 2. PGE2 (0.01-100 nM), sulprostone (0.01-100 nM) and misoprostol (0.1-100 nM), but not butaprost (0.1-100 nM), dose-dependently reduced the increase in cardiac contractility induced by electrical field stimulation of sympathetic terminals. 3. The EP1 antagonist AH6809 (1 microM) did not modify the inhibition of cardiac response induced by PGE2, sulprostone and misoprostol. 4. In preparations preloaded with [3H]-noradrenaline, tritium overflow induced by electrical field stimulation was greatly and significantly reduced by 100 nM PGE2 and by 100 nM sulprostone. 5. These results indicate that PGE2 and other synthetic prostanoids reduce noradrenaline release from cardiac adrenergic nerve terminals acting on prejunctional inhibitory receptors belonging to the EP3 subtype.


Relationship between lipolysis and cyclic AMP generation mediated by atypical beta-adrenoceptors in rat adipocytes. 1. The nature of the beta-adrenoceptor(s) mediating adenylyl cyclase activation in rat adipocyte ghosts by (-)-isoprenaline and the lipolytically selective beta-adrenoceptor agonist, BRL 37344, was investigated by use of the beta 1-selective antagonist, CGP 20712A. The results were compared with lipolysis in adipocytes. 2. While in lipolysis BRL 37344 was a full and 10 times more potent agonist than (-)-isoprenaline, in adenylyl cyclase activation similar pD2 values for both agonists were found. BRL 37344 was only a partial agonist on rat adipocyte adenylyl cyclase, with an intrinsic activity of 0.62. 3. With CGP 20712A small rightward shifts of the (-)-isoprenaline concentration-response curve (CRC) were observed at concentrations up to 10 microM, while at 100 microM and 1 mM clear rightward shifts occurred. The BRL 37344 CRC was not shifted with antagonist concentrations up to 10 microM. Only at 100 microM and 1 mM CGP 20712A were rightward shifts observed. 4. CGP 20712A concentrations of 10 microM and 100 microM depressed the maximum of the (-)-isoprenaline CRC to 89 and 60%, while the BRL 37344 CRCs retained the control maximum effect (62% of (-)-isoprenaline). Only at 1 mM CGP 20712A, was the CRC of BRL 37344 depressed, while the (-)-isoprenaline maximum was diminished further. 5. It was concluded that as with lipolysis, (-)-isoprenaline acts both through typical beta 1- and atypical beta 3-adrenoceptors for activation of adenylyl cyclase, while BRL 37344 acts solely through atypical beta 3-adrenoceptors. 6. The results also demonstrate that the relationship between adenosine 3':5'-cyclic monophosphate (cyclic AMP) and lipolysis is different for BRL 37344 and (-)-isoprenaline. Although the maximum activation of adenylyl cyclase by BRL 37344 is only 62% of that by (-)-isoprenaline, the distance between the lipolysis and adenylyl cyclase CRCs is much larger in the case of BRL 37344, indicating a larger transduction reserve for this agonist.


Selective and competitive antagonism by suramin of ATP-stimulated catecholamine-secretion from PC12 phaeochromocytoma cells. 1. Suramin, a putative P2-antagonist, (10 to 300 microM) inhibited the adenosine 5'-triphosphate (ATP)-stimulated secretion of [3H]-noradrenaline or endogenous dopamine from phaeochromocytoma PC12 cells in a concentration-dependent manner. Suramin (300 microM) did not affect the dopamine-secretion stimulated by high K+ or nicotine. 2. Suramin shifted the concentration-response curve for ATP to the right. The antagonism was competitive with a pA2 value of 4.52. 3. ATP also stimulated an increase in intracellular Ca2+ concentration as determined by fura-2 methods. Suramin antagonized this effect over the same concentration range that antagonized the ATP-stimulated catecholamine secretion. 4. These results suggest that suramin can be used as a selective and competitive antagonist of ATP in experiments concerning mechanisms of catecholamine-secretion.


Local application of drugs to sympathetic nerve terminals: an electrophysiological analysis of the role of prejunctional alpha-adrenoceptors in the guinea-pig vas deferens. 1. Focal extracellular recording techniques were used to study the effects of clonidine, yohimbine and tyramine on the intermittent transmitter release mechanism in the guinea-pig vas deferens in vitro. Drugs were applied locally to the varicosities located within the recording electrode. Statistical methods were used to determine whether noradrenaline (NA) acts locally to inhibit secretion from the same or a closely related release site (local regulation) on an impulse-to-impulse basis. 2. The alpha-adrenoceptor agonist, clonidine, inhibited transmitter release, an effect reversed by the alpha-adrenoceptor antagonist, yohimbine. Yohimbine alone increased action potential-evoked transmitter release, findings consistent with the idea that transmitter release is regulated through prejunctional alpha-adrenoceptors. 3. The indirectly acting sympathomimetic, tyramine, powerfully inhibited evoked transmitter release, an effect reversed by both yohimbine and phentolamine. The inhibitory effects of tyramine were greatly reduced in tissues taken from animals pretreated with reserpine. Clonidine powerfully inhibited transmitter release in reserpinized tissues showing that prejunctional alpha-adrenoceptors were functionally intact. The inhibitory effects of tyramine on transmitter release are therefore mediated indirectly through the release of endogenous NA. 4. Paradoxically, when transmitter release from a small population of variscosities on a single nerve fibre was studied in the absence of alpha-adrenoceptor antagonists, no evidence was found for local regulation of transmitter release. 5. The intermittent character of the transmitter release process makes it difficult to envisage how impulse-to-impulse regulation could occur. Furthermore, it is unlikely that NA will accumulate to any appreciable extent in the vicinity of the secreting varicosity. 6. The pharmacological evidence clearly supports the view that NA released from sympathetic nerve terminals by nerve impulses modulates subsequent transmitter release. However, the evidence does not support the view that released NA acts locally to inhibit secretion from recently activated varicosities.


Beneficial effects of N-acetylcysteine and cysteine in stunned myocardium in perfused rat heart. 1. The objective of this study was to evaluate the effects of three sulphydryl (SH) compounds, N-acetylcysteine (NAC), cysteine (Cys) and cystamine, on functional recovery and ventricular arrhythmias (VF) in stunned myocardium in the isolated perfused heart of the rat. 2. Hearts (n = 7-8 per group) were perfused by the Langendorff procedure for 20 min to stabilize and then assigned to one of five groups: saline, sham, NAC, Cys and cystamine. After the stabilizing period, the drugs (at 3.6 microM min-1) or their vehicle (saline) were infused into coronary vessels throughout the experimental period. Ten min after administration of drugs, the left anterior descending coronary artery (LAD) was ligatured for 20 min and then untied to reperfuse for 30 min. In the sham group, a ligature was placed around the LAD but not tied. 3. NAC and Cys had a significant effect in attenuating myocardial stunning: the percentage recovery of rate-pressure product measured 30 min after reperfusion as an index of heart function, was improved with the NAC (98.3 +/- 4.5) and Cys groups (104.0 +/- 6.5) compared with the saline (only 73.6 +/- 3.8, P < 0.01) group. Cystamine did not show these beneficial effects. This may be due to the difference in chemical structure between NAC, Cys and cystamine since the latter does not have a free SH group with a disulphide bond formed. This phenomenon suggests that a free SH group is essential for the protective effects of compounds like NAC and Cys in myocardial injury. 4. NAC and Cys prevented the fall in coronary flow during the LAD occlusion and enhanced coronary flow during reperfusion but cystamine did not have such a beneficial effect. 5. The incidence of VF in the saline, cystamine, Cys and NAC groups was 6/8 (75.0%), 4/7 (57.1%), 3/8 (37.5%) and 2/7 (28.6%), respectively, and no significant differences (P > 0.05) were noted between the saline- and drug-treated groups. 6. An in vitro study with electron spin resonance indicated that Cys effectively scavenged the hydroxyl radical (-OH) generated by Fenton's reaction but did not scavenge superoxide generated in an irradiated riboflavin system. NAC and cystamine showed a scavenging effect on -OH to a certain extent but this effect did not reach statistical significance (P > 0.05 vs saline). 7. Our results demonstrate that NAC and Cys treatment before ischaemia and reperfusion can reduce myocardial stunning. This beneficial effect may be mainly due to their ability to preserve and enhance coronary flow during coronary occlusion and reperfusion and in part due to scavenging -OH and/or replenishing intracellular glutathione. The results also indicate that the condition of coronary perfusion can produce a great impact on postischaemic ventricular performance.


Heterogeneity of thromboxane A2 (TP-) receptors: evidence from antagonist but not agonist potency measurements. 1. Thromboxane A2 (TP-) receptors in human, rat and rabbit platelets and in smooth muscle of guinea-pig trachea, rat aorta and rabbit aorta have been characterized by measurement of the potencies of agonists and antagonists having considerable variations in chemical structure. 2. On each washed platelet system, eight prostanoids induced maximal irreversible aggregation (full agonists) and the potency ranking was EP 171 > STA2 > 9,11-azo PGH2 > 9,11-endoxy-10a-homo PGH2 > U-46619 (standard) > PGH2 = 16-p-fluorophenoxy-omega-tetranor PGF2 alpha > 16,16-dimethyl PGF2 alpha. Correlations between the three platelet preparations for both absolute and relative potencies were good. On human platelets, STA2, at concentrations above that required for maximum aggregation, exerted an inhibitory effect which was independent of its interaction with the TP-receptor. 3. Five prostanoids, EP 109, EP 167, EP 204, PTA2 and 16,20-methano PTA2, exhibited partial agonist activity on the platelet and smooth muscle preparations. There was good agreement between absolute potencies on the six preparations; on platelets potency was assessed from shape change measurements, since aggregation, when present, always showed a very shallow concentration-response relationship. The magnitude of the maximum response induced by each compound decreased in the order listed above, to the extent that 16,20-methano PTA2 could be treated as a pure antagonist. 4. With U-46619 as agonist, the pA2 values of seven antagonists were found to be very similar on human and rat platelets. The potency ranking was EP 169 > AH 23848 > EP 092 > ONO 11120 > EP 115 = 16,20-methano PTA2 > BM 13177. There was a similar trend on rabbit platelets but pA2 values were 1.0-1.5 log units smaller; the exception was BM 13177 which had similar affinities. The antagonism produced by EP 169 and AH 23848 was surmountable on rabbit platelets but not on human and rat platelets. 5. None of the antagonists was highly potent on the rabbit aorta (pA2 values < 7.5 by Schild analysis). Affinities on the guinea-pig trachea and the rat aorta were higher and in the same range as those obtained for human and rat platelets. However the correlations of pA2 values between any pair of smooth muscle preparations and between any pair of platelet/smooth muscle preparations were either weak or not significant(P > 0.05). 6. The excellent agreement for both full and partial agonist potencies between the six preparations provides no evidence for TP-receptor subtypes and further suggests that the agonist recognition sites of the TP-receptors could be very similar, if not identical, in nature. In contrast, the different antagonist affinities found in this and other published studies indicate heterogeneity of TP-receptors. However, classification into TP,-, TP2-receptors, etc. on the basis of the limited antagonist data available does not appear appropriate at this time.


Evidence that the 5-HT3 receptors of the rat, mouse and guinea-pig superior cervical ganglion may be different. 1. Using grease-gap recordings from the isolated superior cervical ganglion of mouse, rat and guinea-pig, we have compared the depolarization evoked by 5-hydroxytryptamine (5-HT) with that evoked by the selective 5-HT3 receptor agonist 2-methyl-5-HT (2-Me-5-HT). 2. The maximum depolarization induced by 2-Me-5-HT was smaller than that induced by 5-HT in all three species, and particularly in the guinea-pig. 3. The 5-HT2 receptor antagonist ketanserin (1 microM) caused a clear rightward shift of the dose-response curve to 5-HT on the guinea-pig ganglion, but not on the mouse or rat ganglion. Spiperone (0.03 microM) had a quantitatively similar action to ketanserin (0.1 microM) on the 5-HT dose-response curve of the guinea-pig ganglion. Ketanserin had no significant effect on the dose-response curve to 2-Me-5-HT on any of these ganglia. 4. Using 2-Me-5-HT as the agonist, we determined the pA2 values for two 5-HT3 receptor antagonists. The potency of ICS 205-930 varied by approximately 100 fold between the species and that of (+)-tubocurarine varied by over 1000 fold. The differences in the pA2 values of these compounds varied independently among the species. 5. We conclude that 5-HT3 receptors are present on the superior cervical ganglion from the rat, mouse and guinea-pig, but these receptors may be pharmacologically distinct from each other. In addition, the depolarization of the guinea-pig superior cervical ganglion by low concentrations of 5-HT is largely mediated by ketanserin-sensitive receptors.


Effects of vasoactive intestinal peptide (VIP) on contractile responses of smooth muscle in rat stomach. 1. The effects of vasoactive intestinal peptide (VIP) on contractile responses to carbachol (CCh), KCl and caffeine of the circular smooth muscle in rat stomach were examined by the isometric tension recording method and by measurement of the intracellular Ca level, [Ca]i, with fura 2. 2. Removal of extracellular Ca or nifedipine (0.1 microM) inhibited contractions induced by KCl (40 mM) and a low concentration (1 microM) of CCh but not that induced by caffeine (3 mM). After these treatments, the contraction induced by a high concentration of CCh (100 microM) changed to a phasic response. 3. VIP dose-dependently inhibited the contraction induced by 1 microM CCh, but not those caused by 40 mM KCl or 3 mM caffeine. 4. In Ca-free solution containing 2 mM EGTA, VIP inhibited the phasic contraction induced by 100 microM CCh, but not that induced by 30 mM caffeine. 5. CCh caused dose-dependent tension development concomitant with the increase in [Ca]i. VIP reduced both responses and thus did not affect the [Ca]i-force relation for CCh. In the chemically skinned muscle fibres, VIP had no effect on the pCa-tension relation. 6. It is suggested that the inhibitory effects of VIP on CCh-induced contractions are due to the inhibition of the processes of signal transduction from muscarinic receptors to voltage-dependent Ca channels and to intracellular Ca stores.


Adenosine-5'-O-(2-thiodiphosphate) is a potent agonist at P2 purinoceptors mediating insulin secretion from perfused rat pancreas. 1. The effects of a P2 purinoceptor agonist, adenosine 5'-O-(2-thiodiphosphate) (ADP-beta-S) have been studied on insulin secretion and flow rate of the isolated perfused pancreas of the rat. 2. In the presence of a moderately stimulating glucose concentration (8.3 mM), ADP-beta-S (4.95-495 nM) evoked a biphasic insulin response in a concentration-dependent manner. A comparison of relative potency between ADP-beta-S and adenosine 5'-triphosphate (ATP) showed that ADP-beta-S was 100 times more potent than ATP. On the other hand, in the presence of a non stimulatory glucose concentration (4.2 mM), ADP-beta-S (165 nM) did not modify the basal insulin secretion. 3. ADP-beta-S, at concentrations effective on insulin secretion and also at higher concentrations (1.65 and 16.5 microM), provoked an increase of the pancreatic flow rate in a concentration-dependent manner. 4. Our results show that ADP-beta-S is a potent insulin secretory P2 purinoceptor agonist. As it is resistant to hydrolysis it might be useful in studying the effect of activation of the P2 purinoceptor of beta cells on insulin secretion in vivo.


A comparison of the relative activities of a number of GABAB antagonists in the isolated vas deferens of the rat. 1. A series of GABAB receptor antagonists were tested against (+/-)-baclofen for activity on the presynaptic GABAB receptor in the rat vas deferens. 2. All the antagonists tested caused a rightward shift in the concentration-response curve to (+/-)-baclofen. 3. pA2 values calculated from full Schild analysis were as follows: phaclofen, pA2 = 4.3; delta-amino valeric acid, pA2 = 4.4; 3-aminopropyl(diethoxymethyl)phosphinic acid (CGP 35348), pA2 = 5.0; 3-amino-propyl(n-hexyl)phosphinic acid (3-APHPA), pA2 = 4.5. 4. These results show that none of the above compounds possess potent antagonist activity at the GABAB receptor (i.e. pA2 > 6) in this peripheral tissue. In addition, the more recently available phosphinic acid antagonists, appear to offer no great advance over the GABAB antagonists previously available.


Pharmacology of a cholecystokinin receptor on 5-hydroxytryptamine neurones in the dorsal raphe of the rat brain. 1. The effect of bath application of sulphated cholecystokinin octapeptide (CCK-8) was studied on neurones in slices containing rat raphe nucleus. 2. Intracellular recordings were made from neurones in the dorsal raphe nucleus. Some of the neurones with the characteristics of 5-hydroxytryptamine (5-HT)-containing cells which were inhibited by 5-HT and excited by noradrenaline were excited by cholecystokinin. The response to cholecystokinin was dose-dependent over the range 10 to 1000 nM. 3. The response to CCK-8 persisted in the presence of tetrodotoxin. Either reduction of extracellular calcium or addition of 25 mM magnesium did not block the CCK response, suggesting it was mediated by receptors located on the membrane of the raphe neurones. 4. The agonist and antagonist specificity of the CCK response was determined. The CCKB selective agonist, pentagastrin, was inactive when applied at concentrations up to 10 microM. the CCKA receptor antagonist L-364,718 (1 to 100 nM) blocked the response to cholecystokinin. Much higher (1-10 microM) concentrations of the CCKB receptor antagonist L-365,260 were required for inhibition of the CCK response. 5. These data support the existence of a CCK receptor, located on raphe neurones in the rat, with a pharmacological profile very similar to that described for the CCKA type.


The pressor response to central administration of beta-endorphin results from a centrally mediated increase in noradrenaline release and adrenaline secretion. 1. The effects of intracerebroventricular (i.c.v.) and intracisternal (i.c.) administration of beta-endorphin (0.01, 0.1 and 1.0 nmol kg-1) were examined in conscious rabbits. 2. After i.c.v. beta-endorphin, mean arterial pressure (MAP) increased, heart rate (HR) fell, plasma noradrenaline, adrenaline and glucose increased and there was a rise in PaCO2 and fall in PaO2; these effects were reversed by intravenous (i.v.) naloxone (300 nmol kg-1). 3. A combination of prazosin (2 mg kg-1) and yohimbine (1 mg kg-1), given i.v., prevented the rise in MAP induced by i.c.v. beta-endorphin. 4. After i.c. beta-endorphin, MAP, HR and plasma catecholamines were not significantly altered but there was a similar degree of respiratory depression. 5. Clonidine (1.0 micrograms kg-1, i.c.) reduced MAP and HR; these effects were not blocked by i.v. naloxone (6 mumol kg-1). 6. These results demonstrate that beta-endorphin acts centrally, probably mainly on periventricular mu-opioid receptors, to increase adrenaline secretion and sympathetic nerve activity leading to alpha-adrenoceptor-mediated vasoconstriction. The respiratory depression is probably mediated by brainstem mu-receptors. 7. A role for beta-endorphin in the central hypotensive action of alpha 2-adrenoceptor agonists was opposed by finding that opioid receptor antagonism with naloxone did not block the effects of clonidine.


The effects of adenosine triphosphate (ATP) and related purines on human isolated subcutaneous and omental resistance arteries. 1. Human resistance arteries were obtained from specimens of omentum and subcutaneous fat removed at surgery. They were studied in vitro by use of a myograph technique to determine the effects of purines on the arteries. 2. In preparations where tone had been raised with noradrenaline, low concentrations (1 nM-1 microM) of adenosine triphosphate (ATP) and 2-methylthioATP, but not alpha,beta-methyleneATP, produced concentration-dependent relaxation. There was a lack of relationship between the relaxation response to acetylcholine and that to ATP. 3. In preparations under basal tone, high concentrations (1 microM-1 mM) of ATP, 2-methylthioATP and alpha,beta-methyleneATP produced concentration-dependent contractions. 4. The rank order of potency of the purine nucleotide analogues for the relaxation response was 2-methylthioATP > ATP > alpha,beta-methyleneATP and for the contractile response it was alpha,beta-methyleneATP > ATP = 2-methylthioATP. 5. Adenosine produced concentration-dependent relaxation in preparations under raised tone and was less potent than ATP but did not produce contraction in preparations at basal tone. Relaxation responses to adenosine, but not to ATP, were antagonized by 8-phenyltheophylline. 6. These results indicate the presence of vasodilator P2y- and P1-purinoceptors and vasoconstrictor P2x-purinoceptors on human resistance arteries isolated from omental and subcutaneous sites.


Block of cardiac sodium channels by amiodarone studied by using Vmax of action potential in single ventricular myocytes. 1. Acute effects of amiodarone on cardiac sodium channels were investigated in ventricular myocytes isolated from guinea-pig hearts, and compared with those of lignocaine. 2. Transmembrane potential was recorded and controlled by whole-cell current-clamp and voltage-clamp respectively through suction pipette electrodes. The maximum upstroke velocity (Vmax) of the action potential was used as a qualitative index of sodium channel availability. 3. In myocytes treated with amiodarone (1 microM) or lignocaine (40 microM), Vmax of reference action potential elicited at 0.03 Hz was decreased by 6-11%, indicating minimal tonic block of sodium channels. 4. Application of a single conditioning depolarization to those myocytes resulted in a significant decrease in Vmax of a subsequent test action potential. The Vmax reduction was enhanced in a single exponential function as the clamp pulse duration was prolonged. Time constants at 0 mV clamp were 25 ms for amiodarone and 122 ms for lignocaine. 5. Vmax recovery of test action potential following a 1000 ms 0 mV clamp was approximated by a dual exponential function. Time constants for the late slow component (tau R) at the resting potential level were 418 ms for amiodarone and 178 ms for lignocaine. tau R values were shortened in a voltage-dependent manner by hyperpolarization during the coupling interval. 6. These findings suggested that amiodarone, like lignocaine, blocks the sodium channel primarily when it is in the inactivated state. Both onset and offset kinetics of the block are very rapid. Such sodium channel blocking characteristics may contribute to its potent antiarrhythmic activity.


The use of 4-diphenylacetoxy-N-(2-chloroethyl)-piperidine (4-DAMP mustard) for estimating the apparent affinities of some agonists acting at muscarinic receptors in guinea-pig ileum. 1. 4-Diphenylacetoxy-N-(2-chloroethyl)-piperidine (4-DAMP mustard), which is known to block muscarinic M3 receptors in preference to muscarinic M2 receptors, was used to estimate the apparent affinity constants of some agonists acting at muscarinic receptors in guinea-pig ileum. Estimates for carbachol and n-pentyl-trimethyl ammonium iodide were similar to published values obtained in similar conditions: those for n-hexyl-trimethyl ammonium iodide were slightly lower. 2. The results for the agonists, n-pentyl- and n-hexyl-trimethyl ammonium iodides and for the partial agonist, n-heptyl-trimethyl ammonium iodide were not as regular as was suggested by Stephenson, though there is an overall increase in apparent affinity with chain length. 3. Estimates of apparent affinity may be affected by hexamethonium, usually present in experiments on ileum. Its absence had little effect on the results with carbachol but reduced the estimates obtained with n-pentyl trimethyl ammonium, which has strong nicotinic effects compared with its muscarinic effects. On ileum treated with tetrodotoxin the values for n-pentyl trimethyl ammonium were similar to those obtained in the presence of hexamethonium (0.28 mM): slightly higher estimates of affinity were obtained in the presence of indomethacin (2.8 microM). The nicotinic effects of n-pentyl ammonium may involve the release of prostaglandins. 4. The estimates of apparent affinity did not depend on the method used to calculate them as the 'null' method and the 'operational' method give similar answers. Estimates of the transducer-ratio for the partial agonist, n-heptyl-trimethyl ammonium iodide, were numerically the same as those of its efficacy. 5. This work illustrates the use of 4-DAMP mustard as a tool for measuring the apparent affinity of agonists acting at muscarinic M3 receptors.


Pharmacokinetic-pharmacodynamic modelling of the EEG effects of midazolam in individual rats: influence of rate and route of administration. 1. The purpose of the present investigation was to quantify the concentration-pharmacological effect relationship of midazolam in individual rats by use of effect parameters derived from aperiodic EEG analysis. By varying the rate and route of administration the role of (inter)active metabolites and development of acute tolerance was evaluated. 2. The pharmacokinetics and pharmacodynamics of midazolam were determined after intravenous administration of 10 mg kg-1 during 5, 30 and 60 min and oral administration of 15 mg kg-1. Following intravenous administration the pharmacokinetics were most adequately described by a bi-exponential equation. The values (mean +/- s.e. mean, n = 20) of clearance, volume of distribution at steady-state and terminal half-life were 67 +/- 2 ml min-1 kg-1, 1.61 +/- 0.071 kg-1 and 27 +/- 1 min, respectively. Following oral administration midazolam was rapidly absorbed with a systemic availability of 45 +/- 9%. 3. The averaged amplitudes in the 11.5-30 Hz (beta) frequency band of the fronto-central lead on the left-hemisphere, as derived by aperiodic EEG analysis, was selected as a measure of the pharmacological effect of midazolam. By pharmacokinetic-pharmacodynamic modelling the individual concentration-EEG effect relationships of midazolam were derived, which were successfully quantified by the sigmoidal Emax model. No marked and systematic differences in pharmacodynamic parameters were found between the rates and routes of administration. The averaged pharmacodynamic parameters of midazolam obtained after combining the results of all rates and routes of administration were (mean + s.e.mean, n = 27): Eo = 61 + 3puV s 1, Emax = 85 + 3 Vs 1, EC50 = 40 + 3 ngmlP-1 and N = 0.84 + 0.04. 4. The results of the present study show that the concentration-EEG effect relationship of midazolam can be characterized in individual animals using the amplitudes in the 11.5-30 (beta) frequency band as a measure of pharmacological response. Acute tolerance did not develop and (inter)active metabolites did not contribute to this effect parameter within the time span of the experiments.


The effects of the stereoisomers of propafenone and diprafenone in guinea-pig heart. 1. Optically pure enantiomers of propafenone and diprafenone were prepared from their racemic mixtures and tested for their ability to block beta-adrenoceptors and to prolong functional refractory period in the guinea-pig heart. beta-Adrenoceptor affinity of the enantiomers was determined by the radioligand binding technique and in functional experiments. 2. Propafenone and diprafenone inhibited specific binding of the beta-adrenoceptor antagonist (-)-[3H]-CGP-12177 to guinea-pig myocardial membranes. beta-Adrenoceptor affinities of diprafenone enantiomers exceeded those of corresponding propafenone enantiomers by one order of magnitude. Displacement of (-)-[3H]-CGP-12177 by both antiarrhythmics was highly stereoselective, in that the (S)-enantiomers were 40-60 fold, i.e. 1.6-1.8 log units more potent than the (R)-enantiomers. 3. Propafenone and diprafenone antagonized the positive inotropic action of isoprenaline in isolated atria. beta-Adrenoceptor antagonist potencies of diprafenone enantiomers were about one order of magnitude higher than those of corresponding propafenone enantiomers. For both drugs the (S)-enantiomer was found to be considerably more potent (14-40 fold) than the (R)-enantiomer. 4. Propafenone and diprafenone prolonged functional refractory period of isolated auricles with equal potency and no difference in the antiarrhythmic activity of purified enantiomers was found. 5. It is concluded that the enantiomers of propafenone and diprafenone exert comparable antiarrhythmic activity, whereas only (S)-enantiomers block cardiac beta-adrenoceptors with high affinity, which explains the beta-adrenoceptor antagonist effects of the racemic drugs.


Differential effect of R 56865 on ouabain binding to isolated sarcolemma and intact atrial tissue of guinea-pig. 1. R 56865 (N-[1-[4-(4-fluorophenoxy)-butyl]-4-piperidinyl]-N-methyl- 2-benzothiazolamine) is a compound known to antagonize cardiac glycoside intoxication. Therefore, the effect of the compound on ouabain binding to intact cardiac tissue as well as cardiac membrane preparations was investigated. 2. The binding of ouabain to highly purified sarcolemmal membranes was not influenced by R 56865 1 x 10(-6) mol l-1 (ouabain: KD = 1.3 x 10(-7) mol l-1, Bmax = 160 pmol mg-1; ouabain + R 56865: KD = 1.4 x 10(-7) mol l-1, Bmax = 168 pmol mg-1). 3. In contrast to the results in purified membranes, the binding of ouabain (10(-8) mol l-1 to 5 x 10(-7) mol l-1) to intact atria was significantly reduced. 4. Ouabain, 5 x 10(-7) mol l-1, led to a transient positive inotropic effect of about 220% followed by a developing negative inotropic effect after 3 h. R 56865, 10(-7) mol l-1, led to a maximal positive inotropic effect of about 290% also followed by a delayed decline of contractile force. A tenfold higher concentration of R 56865 led to sustained positive inotropic effect of about 250% in the same time interval. 5. The different effects of R 56865 on ouabain binding in subcellular preparations and intact tissue do not support the view that R 56865 interferes directly with the action of ouabain on Na/K-ATPase. An indirect effect, which may be mediated by a lowered intracellular sodium load is discussed.


Comparison of the effects of several potassium-channel openers on rat bladder and rat portal vein in vitro. 1. The ability of several K-channel openers to inhibit KCl-induced contractions of rat bladder detrusor and spontaneous mechanical activity in rat portal vein was examined. 2. Lemakalim, pinacidil, Ro 31-6930, RP 49356, P1060 and S 0121 dose-dependently relaxed rat detrusor, precontracted with 20 mM KCl. With the exception of pinacidil, concentrations of these agents below 30 microM did not inhibit 80 mM KCl-included contractions. Pinacidil (10 microM) produced a small, but significant (P < 0.05) relaxation of 80 mM KCl-induced mechanical activity. Minoxidil sulphate and BRL 38226 produced some relaxation of 20 mM but not 80 mM KCl-induced contractions. 3. Glibenclamide (0.3-3 microM) antagonized the relaxant effects of lemakalim, pinacidil, Ro 31-6930, RP 49356, P1060 and S 0121 in a competitive manner (pA2 values 6.3-6.6). The effects of minoxidil sulphate and BRL 38226 were fully antagonized by 3 microM glibenclamide. 4. Lemakalim, pinacidil, S 0121, BRL 38226 and minoxidil sulphate were each approximately 8 times more potent as inhibitors of the spontaneous contractions of rat portal vein than KCl-induced contractions of the rat detrusor. Minoxidil sulphate was approximately 30 times more potent in the rat portal vein than in the bladder. This may indicate that either minoxidil sulphate is acting at different recognition sites in these two tissues, or that this compound has an additional mechanism of action in the portal vein. 5. With the exception of minoxidil sulphate, all the compounds tested stimulated 86Rb efflux and 42K efflux from preloaded rat detrusor strips. The stimulated 86Rb efflux was qualitatively but not quantitatively similar to the stimulated 42K efflux. Minoxidil sulphate stimulated 42K efflux from rat portal vein but not from rat bladder. 6. It is concluded that all the compounds tested cause relaxation of rat detrusor predominantly by Kchannel opening. Selectivity for bladder rather than vascular smooth muscle was not shown by any compound.


Anti-arrhythmic activities of opioid agonists and antagonists and their stereoisomers. 1. A series of opioid agonists, antagonists and their (+)-stereoisomers were tested for antiarrhythmic activity in the rat coronary artery occlusion model. 2. Naloxone (0.01-2 mg kg-1) significantly reduced the incidence and severity of cardiac arrhythmias, in accordance with previous published studies. 3. The non-opioid stereoisomer, (+)-naloxone, was equipotent with naloxone against occlusion-induced arrhythmia. 4. Similar non-stereospecific antiarrhythmic effects were induced by another opioid antagonist, Win 44,441-3 and its stereoisomer Win 44,441-2. 5. The opioid agonists, morphine and levorphanol, protected against occlusion-induced arrhythmia as did the opioid antagonists, and the (+)-stereoisomer, dextrorphan, was equipotent to levorphanol. 6. It is concluded that the antiarrhythmic effects of opioid drugs are not mediated by opioid receptors. A direct effect on ionic currents in cardiac muscle is suggested as the mechanism of opioid antiarrhythmic activity.


Effects of antagonists on quisqualate and nicotinic receptor-mediated currents of midbrain neurones in culture. 1. The action of non-N-methyl-D-aspartate (non-NMDA) and nicotinic antagonists on excitatory postsynaptic currents (e.p.s.cs) and on quisqualate (Quis)- and nicotine-gated currents was studied by use of whole-cell recording in dissociated culture of the rat midbrain. 2. 6-Cyano-7-nitroquinoxaline-2,3-dione (CNQX; 0.1 microM) and kynurenic acid (0.1 mM) attenuated network-generated and miniature e.p.s.cs while mecamylamine (100 microM) and hexamethonium (400 microM) had no effect. Acetylcholine (ACh) enhanced or suppressed e.p.s.cs. The suppressing effect of ACh was blocked by atropine (0.1-10 microM). 3. ACh (50-1000 microM) and quisqualate (Quis, 0.1-20 microM) induced inward currents with the same reversal potential as e.p.s.cs. 4. Application of Quis and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) in a low concentration (0.5 and 5 microM, respectively) evoked a maintained current which was attenuated by CNQX (1 microM) and kynurenic acid (0.5 mM) but not by mecamylamine (100 microM). 5. Higher concentrations of Quis (5-20 microM) and AMPA (50-100 microM) evoked a transient and a maintained current component. Kynurenic acid (1 mM) reduced the transient but not the maintained component. CNQX (5-10 microM) increased the maintained component without reducing the transient one; 20 microM CNQX reduced both components. 6. ACh-induced transient current was mimicked by nicotine and reversibly and dose-dependently blocked by mecamylamine. Atropine (10 microM), hexamethonium (400 microM) as well as CNQX (100 microM) and kynurenic acid (1 mM) did not affect the current. 7. Hexamethonium (50-400 microM) voltage-dependently depressed the maintained current elicited by both Quis and ACh. 8. In conclusion, although the antagonists examined here seem to discriminate between non-NMDA and nicotinic receptor-mediated e.p.s.cs, they vary considerably in respect of their mode of action when tested on Quis, AMPA and ACh-induced currents.


Pharmacological evidence for the possible involvement of repetitive action potentials in facilitation by GABA of catecholamine secretion in bovine adrenal chromaffin cells. 1. gamma-Aminobutyric acid (GABA) evokes catecholamine (CA) secretion and enhances the stimulation-evoked CA secretion via facilitation of Ca2+ entry in a Cl(-)-dependent manner. The present study was designed to investigate further the ionic mechanism of modulation by GABA of CA secretion from adrenal medulla, using a primary culture of bovine chromaffin cells. 2. Tetrodotoxin (TTX), a voltage-sensitive Na+ channel blocker, reduced GABA-evoked CA secretion. 3. Inhibition of the sodium pump by ouabain or removal of extracellular K+ enhanced GABA-evoked CA secretion in a TTX-sensitive manner. 4. Tetraethylammonium (TEA) and cesium, which are known to block some types of K+ channels, markedly enhanced GABA-evoked CA secretion in a concentration-related fashion. TEA-induced enhancement of the GABA-evoked CA secretion was attenuated by TTX or replacement of extracellular Na+ by choline. On the other hand, ouabain accelerated the effect of TEA. 5. TEA and ouabain also enhanced GABA-induced Ca2+ influx and accumulation of cytosolic Ca2+, assessed with 45Ca2+ uptake and quin2 fluorescence. 6. Veratridine increased accumulation of cytosolic Ca2+ in a TTX-sensitive manner. GABA facilitated the veratridine-induced elevation of cytosolic Ca2+ even when the GABA-induced rise of cytosolic Ca2+ levelled off. 7. These results suggest the involvement of repetitive action potentials in modulation of GABA by Ca2+ mobilization and, as a consequence, of the CA secretion in chromaffin cells.


Changes in neurotransmitter sensitivity in the mouse neocortical slice following propranolol and theophylline administration. 1. The mouse neocortical slice has been used to examine the sensitivity of neurones to isoprenaline, 5-hydroxytryptamine (5-HT) and adenosine acutely and following chronic treatment of animals with propranolol or theophylline. 2. While having little effect alone, all three agonists enhanced the d.c. depolarizing potential produced by N-methyl-D-aspartate (NMDA). The effect of (-)-isoprenaline (0.2 microM) was shared by (+)-isoprenaline at the much higher concentration of 10 microM. 3. Superfusion of slices with theophylline or 8-phenyltheophylline blocked responses to adenosine with evidence of selectivity. A single injection of theophylline 24 h before slice preparation did not alter agonist sensitivity, but when administered daily at 100 mg kg-1 for 14 days, the xanthine caused a loss of sensitivity to adenosine and (-)-isoprenaline but not 5-HT. The lower dose of theophylline, 10 mg kg-1 daily, also led to a loss of adenosine responses but no change of sensitivity to the amines. 4. Following the 14 day treatment with theophylline at 100 mg kg-1 daily in two groups of mice, responses to adenosine recovered to control levels after 20 days. 5. Propranolol superfusion blocked responses to both isomers of isoprenaline and 5-HT but did not affect sensitivity to adenosine. 6. Chronic treatment with propranolol at 25 mg kg-1 daily for 14 days induced a loss of sensitivity to (-)-isoprenaline and 5-HT but not adenosine. A lower dose of 5 mg kg-1 daily caused no change in responses to adenosine or 5-HT, but yielded an increased sensitivity to (-)-isoprenaline. 7. The results are discussed with respect to reports of receptor up-regulation in binding studies; caution is clearly required in extrapolating from such work to receptor activity in a functional system, especially in the case of theophylline and adenosine.


Alkylation with beta-funaltrexamine suggests differences between mu-opioid receptor systems in guinea-pig brain and myenteric-plexus. 1. The effects of pre-incubation with beta-funaltrexamine (beta-FNA) on the binding of [3H]-[D-Ala2, MePhe4, Gly-ol5]enkephalin ([3H]-DAMGO) to homogenates of guinea-pig brain and myenteric-plexus longitudinal muscle have been studied. 2. beta-FNA pretreatment of brain homogenates in Tris-HCl buffer reduced the amount of [3H]-DAMGO binding. This was principally due to a reduction in the maximal number of binding sites measurable. However, approximately 30% of sites labelled by 1 nM [3H]-DAMGO were insensitive to 1 microM beta-FNA. Similar findings were obtained when the alkylation was performed in brain homogenates prepared in Krebs solution buffered with HEPES. 3. beta-FNA pretreatment of whole myenteric-plexus longitudinal muscle strips caused an increase in the IC50 values of mu-agonists, but not of kappa-agonists. However, the binding of [3H]-DAMGO to homogenates of myenteric-plexus longitudinal muscle was not altered by pre-incubation with beta-FNA in Tris-HCl buffer. On the other hand when the pretreatment was carried out in whole tissue in Krebs solution, or in homogenates in the presence of NaCl and Gpp(NH)p, a marked reduction in [3H]-DAMGO binding was observed. 4. These results suggest that a low affinity form of the mu-opioid receptor is the physiologically relevant site for beta-FNA alkylation in the myenteric-plexus and that differences exist between mu-receptor systems in guinea-pig myenteric plexus and brain.


Dissociation of a ferric maltol complex and its subsequent metabolism during absorption across the small intestine of the rat. 1. The fate and disposition of [59Fe]-ferric [3H]-maltol after intravenous administration were investigated in anaesthetized rats. Immediate dissociation of ferric iron from maltol took place in the circulation even with high doses of ferric maltol (containing 1 mg elemental iron). In plasma samples withdrawn within 1 min of injection and subjected to gel filtration, 59Fe eluted with the high molecular weight proteins whilst the tritium was associated with low molecular weight material. 2. The rates of elimination of 59Fe and of tritium from the plasma and their ultimate fate were very different. The half life for 59Fe in the plasma was around 70 min and 59Fe appeared mainly in the bone marrow and liver. There was an initial rapid exit of tritium from the plasma with a half life of around 12 min. This was followed either by a plateau or by a rise in tritium levels, involving entry of maltol metabolites into the circulation. These metabolites could be recovered in the urine. 3. Entry of 59Fe and of tritium into the blood plasma after intraduodenal administration of [59Fe]-ferric [3H]-maltol was also very different. At low doses of ferric maltol (containing 100 micrograms elemental iron), the tritium appeared in the plasma in highest amounts within seconds and then decreased whilst there was a slow rise in 59Fe levels. At higher doses of ferric maltol (containing 7 mg elemental iron), levels of 59Fe in the plasma were highest at 5 min and then fell whereas tritium levels rose steadily. Mucosal processing of 59Fe prevented further entry of iron at high dose into the circulation. 4. Initial rates of uptake of [3H]-maltol into isolatcd intestinal fragments were measured over a range of concentrations and revealed that maltol alone could diffuse freely into the tissues whereas maltol complexed to iron showed saturable uptake kinetics similar to those seen with the iron itself. 5. After intestinal uptake, 59Fe and tritium were associated with different subcellular fractions, maltol itself being metabolized to the glucuronide conjugate within the intestinal mucosa. 6. It is concluded that dissociation of metal and ligand takes place before entry into the intestinal mucosa. Iron is then taken up on the endogenous carrier and processed in the normal way whilst maltol enters by diffusion, its rate of entry being limited by the degree of dissociation. It is subsequently metabolized by conjugation and eliminated rapidly from the body in the urine.