The Mayo Autonomic Disorders PPG was the first autonomic disorders program project funded by NIH. In the 9 years since its inception, we have continued our focus on orthostatic intolerance and failure. Orthostatic intolerance can be unassociated with OH as in POTS. Over the past 10 years we have assembled a unique combination of personnel, patients, and instruments to facilitate the series of important studies we are proposing;some of which can only be done at Mayo. POTS: At the inception of this PPG, little information was available on the pathophysiology of POTS. Orthostatic intolerance without OH occurs much more commonly than OH in a ratio of approximately 5:1.46'47 Over the last 4 years of the current cycle, significant progress has been made in this and other autonomic programs. We reported that about 50% of POTS may be post-infectious suggesting an immune-mediated limited autonomic neuropathy. 'Since that time, the clinical features have been prospectively evaluated using a standardized instrument.58 Independent clinical and laboratory features that aid the diagnosis of POTS have been defined and its outcome evaluated.51 We have, for the first time, developed a validated instrument to evaluate autonomic symptoms.73 Significant advances have also been made on its pathophysiology. Peripheral denervation has been confirmed, and about 10% have ganglionic antibody.76 Norepinephrine spillover in the leg is reduced by 50% in POTS31 and there is denervation supersensitivity of the lower extremity veins.71 Sudomotor denervation is present in the distal lower extremity.26'48 Denervation results in an increase in vascular capacity manifested as increased venous pooling48'66 and a reduction in preload.47 Excessive venous pooling and/or a reduced plasma volume results in a hyperadrenergic state29 and there may be a component of p-receptor supersensitivity.69 Cerebral hypoperfusion occurs during HUT but not during supine rest, in part due to hypocapnia.53 HUT results in a large but transient fall in BP, with recovery within 30 seconds. During this interval, the depth but not rate of respiration increases53 and pCO2 falls resulting in a large fall in cerebral perfusion. Reversing hypocapnia with rebreathing CO2 will normalize cerebral perfusion.53 POTS is heterogenous in its manifestations. The term mild orthostatic intolerance is often applied to a heterogeneous group of subjects that include constitutional orthostatic intolerance, deconditioning, and mild hypovolemia. A hyperadrenegic state is typical,29'32'47'61 characterized by a heart rate increment >30 bpm, an absolute orthostatic heart rate >120 b.p.m, orthostatic plasma norepinephrine >600 pg/ml and is the most likely group to have reduced plasma volume. There is commonly some evidence of peripheral denervation and sometimes the term neuropathic POTS is used. Baroreflex vasoconstriction is often reduced or absent on the Valsalva maneuver47'61 and total systemic resistance is reduced.68 Pressor response to tyramine is reduced and response to phenylephrine increased, suggestive of postganglionic denervation.32 Symptoms suggestive of dysregulation are also seen, manifested as excessive increases in diastolic BP, excessive oscillations in BP on HUT, and spontaneous episodes of dysautonomia.48 It has been .suggested that these patients have a brain-stem disorder. One patient responded dramatically to decompression of the rostral ventrolateral medulla.46'48 Vasomotor, especially venomotor, tone can be impaired in an autonomic neuropathy.61 Excessive sequestration of labeled protein was demonstrated in the calves with standing, correctable by venous compression.48'70 An excessive fall in enddiastolic volume on head-up tilt (HUT) also suggests venous pooling.47 Venous pooling would result in a reduction in preload and excessive baroreceptor unloading in the upright position, with a resultant increase in sympathetic outflow. HUT results in excessive transcapillary efflux in POTS 7 and can be reflected in a progressive fall in plasma volume with continuation of standing.15 Venous occlusion plethysmography has been utilized to separately evaluate the venous and capillary components of fluid segregation and transfer. When the limb is occluded above venous pressure, the increase in limb volume evolves through two phases. There is an initial volume increase that corresponds to venous filling. This phase is followed by a slower phase representing net capillary filtration.22 A large increase in orthostatic norepinephrine is well documented in POTS (see above). Less well known is that orthostatic and supine epinephrine can also be increased in POTS. The vasoreactivity of (32-adrenoreceptors to epinephrine is important in orthostatic preload. Of particular interest is the relationship between certain polymorphisms of $2- adrenoreceptors and function. Significant interest has focussed on the relationship between two common polymorphisms, one at codon 16 and one at codon 27, on agonist-mediated vasodilatation and desensitization in the venous bed. Subjects who were homozygous for Argl6 had almost complete desensitization;venodilatation in response to isoproterenol in this group returned to normal much more quickly than subjects who were homozygous for Glyl6 who had more sustained venodilation.9 Subjects who were homozygous for Glu27 had higher maximal venodilatation in response to isoproterenol than those who were homozygous for Gln27. Some investigators have expanded interest from single nucleotide polymorphisms (SNPs) to chromosomally phased SNPs (haplotypes).11 The distribution of some haplotypes are quite different in Caucasian, African-American, Asian, and Hispanic-Latino ethnic groups with >20-fold differences among the frequencies of the four major haplotypes. Functional differences were shown to be more dependent on haplotype pairs than to individual SNPs. The results indicate that the unique interactions of multiple SNPs within a haplotype ultimately can affect biologic and therapeutic phenotype. Applied to POTS, and based on our preliminary data, it appears that there is an overrepresentation of a certain haplotype that results in sustained venodilatation (preliminary data). We will systematically explore the relationship among the interplay of epinephrine, polymorphic (32AR with its association with resistance to agonist-mediated desensitization leading to prolonged vasodilatation, and studies on veins and HUT indices.