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. Additionally, we have found that AM3506 does not induce metabolic side effects including hyperglycemia/glucose intolerance. Such effects are commonly seen with other FAAH inhibitors, such as URB597, or in FAAH-/- mice, and are due to inhibition of FAH in the liver and the consequent increase in hepatic anndamide levels that result in activation of hepatic CB1 receptors. We have demonstrated that the the unique lack of such side effects with AM3506 is due to its very rapid metablism by the liver, resulting in ts inabiliity to block FAAH in the liver. These results are in press at Chemistry &Biology.
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