Our earlier studies have indicated that the endothelium-dependent vasodilator effect of anandamide and of some atypical cannabinoid ligands, such as abnormal cannabidiol (abn-cbd) is mediated by a pertussis toxin-sensitive, G protein-coupled receptor distinct from CB1 or CB2. In collaboration with Mechoulam's group we have earlier identified a novel, endocannabinoid-like brain lipid, arachidonoyl L-serine (ARA-S). Contrary to anandamide, ARA-S has no affinity for CB1, CB2 or vanilloid TRPV1 receptors, and it produces partially endothelium-dependent vasodilation in rat isolated mesenteric artery and aorta preparations. We have analyzed the effect of ARA-S on Ca2+-activated K+ currents in human embryonic kidney cells stably transfected with the alpha-subunit of the human, large conductance Ca2+-activated K+ (BKCa) channel (HEK293hSlo cells). ARA-S caused relaxation of isolated, intact and denuded, small mesenteric arteries (pEC50: 5.49 and 5.14, respectively) of the rat. In both preparations the response was inhibited by 100 nM iberiotoxin. In HEK293hSlo cells, ARA-S and its enantiomer N-arachidonoyl-D-serine enhanced the whole cell outward K+ current with similar potency (pEC50: 5.63 and 5.32, respectively). The potentiation was not mediated by ARA-S metabolites, stimulation of known cannabinoid receptors, G proteins, protein kinases or Ca2+-dependent processes, and it was lost after patch excision or following membrane cholesterol depletion, but was restored after cholesterol reconstitution. BKCa currents were also enhanced by anandamide (AEA, pEC50: 5.27) but inhibited by another endocannabinoid, virodhamine (pIC50: 6.35), or by the synthetic cannabinoid O-1918, which blocks ARA-S-induced vasodilation (pIC50: 6.59). These findings indicate that (i) endocannabinoids directly modulate the activity of BKCa channels or a channel-associated component. (ii) This interaction does not involve cytosolic factors but is dependent on the presence of membrane cholesterol (iii) Direct BKCa channel activation likely contributes to the endothelium-independent component of ARA-S-induced mesenteric vasorelaxation. (iv) Depending on the structure of the head group, the effect on BKCa currents is either stimulatory or inhibitory. (v) O-1918 is a potent BKCa channel inhibitor. These findings have been published in 2009. Inhibition of fatty acid amidohydrolase (FAAH), the enzyme responsible for the selective in vivo degradation of the endocannabinoid anandamide, elicits CB1 receptor-mediated anxiolytic, analgesic and cardiovascular depressor effects, without inducing behavioral effects predictive of addictive potential. We have recently demonstrated that a novel, highly potent, in vivo effective FAAH inhibitor, AM3506, normalizes the elevated blood pressure and inappropriately increased cardiac contractility of both anesthetized and conscious spontaneously hypertensive rats (SHR) without affecting these parameters in normotensive animals. The cardiovascular depressor effects in SHR were maintained following ganglionic blockade and restoration of blood pressure by vasopressin infusion, and thus could be attributed to a reduction in sympathetic tone elicited via activation of CB1 receptors in the central nervous system by endogenous anandamide. We further showed that the greater sensitivity of hypertensive relative to normotensive animals to CB1R-mediated cardiovascular depressor effects is related to increased efficiency of coupling of CB1R to G proteins. These findings suggest that targeting the endocannabinoid system may have therapeutic value in hypertension. These findings have been written up for submission for publication. Ongoing studies in spontaneously hypertensive rats are aimed to test whether chronic treatment with the FAAH antagonist can delay/prevent the development of cardiac hypertrophy.