Background— Endocannabinoids are novel lipid mediators with hypotensive and cardiodepressor activity. Here, we examined the possible role of the endocannabinergic system in cardiovascular regulation in hypertension.

Methods and Results— In spontaneously hypertensive rats (SHR), cannabinoid-1 receptor (CB₁) antagonists increase blood pressure and left ventricular contractile performance. Conversely, preventing the degradation of the endocannabinoid anandamide by an inhibitor of fatty acid amidohydrolase reduces blood pressure, cardiac contractility, and vascular resistance to levels in normotensive rats, and these effects are prevented by CB₁ antagonists. Similar changes are observed in 2 additional models of hypertension, whereas in normotensive control rats, the same parameters remain unaffected by any of these treatments. CB₁ agonists lower blood pressure much more in SHR than in normotensive Wistar-Kyoto rats, and the expression of CB₁ is increased in heart and aortic endothelium of SHR compared with Wistar-Kyoto rats.

Conclusions— We conclude that endocannabinoids tonically suppress cardiac contractility in hypertension and that enhancing the CB₁-mediated cardiodepressor and vasodilator effects of endogenous anandamide by blocking its hydrolysis can normalize blood pressure. Targeting the endocannabinoid system offers novel therapeutic strategies in the treatment of hypertension.