ANTIHYPERTENSIVE EFFECT OF THE NOVEL FAAH INHIBITOR AM3506

Abstract

The endocannabinoid system (ES) has been implicated in the regulation of blood pressure. We have previously shown that inhibition of fatty acid amide hydrolase (FAAH), the enzyme that degrades endogenous anandamide, transiently normalizes the elevated blood pressure and cardiac contractility in different experimental models of hypertension. Here we tested the effects of a novel, selective, highly potent and in vivo effective FAAH inhibitor, AM3506, in SHR and WKY rats. AM3506 has a Ki of 31 nM for FAAH, with much lower affinity for other ES targets. At a dose of 0.1 mg/kg i.p., AM3506 caused >85% inhibition of brain FAAH with no appreciable inhibition of other serine hydrolase targets. In anesthetized SHR, basal mean arterial pressure (MAP, 179.8±7.6 mmHg) was reduced to 113.7±20.4 mmHg by 1mg/kg AM3506 with no sign of recovery for over an hour. Left ventricular (LV) function was analyzed using pressure‐volume catheter system. LVESP, dP/dt, SV, CO and TPR were elevated in SHR compared to WKY and were markedly reduced by 1 mg/kg AM3506. In awake, freely moving SHR, AM3506 caused a dose‐dependent and long lasting reduction in MAP (173.0±3.8 to 126.0±2.2 mmHg). The effects of AM3506 in both anesthetized and conscious SHR could be prevented by CB1 antagonist pretreatment, suggesting that they are triggered by the rise in endogenous anandamide acting via CB1 receptors. Because inhibition of FAAH does not elicit behavioral effects predictive of addictive potential, FAAH inhibitors such as AM3506 may be considered for the treatment of hypertension.