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 (CB 1 ) 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 CB 1 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. CB 1 agonists lower blood pressure much more in SHR than in normotensive Wistar-Kyoto rats, and the expression of CB 1 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 CB 1 -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.

The cannabinoid analog abnormal cannabidiol [abn-cbd; (Ϫ)-4-(3-3,4-trans-p-menthadien-[1,8]-yl)-olivetol] does not bind to CB 1 or CB 2 receptors, yet it acts as a full agonist in relaxing rat isolated mesenteric artery segments. Vasorelaxation by abncbd is endothelium-dependent, pertussis toxin-sensitive, and is inhibited by the BK Ca channel inhibitor charybdotoxin, but not by the nitric-oxide synthase inhibitor N -nitro-L-arginine methyl ester or by the vanilloid VR1 receptor antagonist capsazepine. The cannabidiol analog O-1918 does not bind to CB 1 or CB 2 receptors and does not cause vasorelaxation at concentrations up to 30 M, but it does cause concentration-dependent (1-30 M) inhibition of the vasorelaxant effects of abn-cbd and anandamide. In anesthetized mice, O-1918 dose-dependently inhibits the hypotensive effect of abn-cbd but not the hypotensive effect of the CB 1 receptor agonist (Ϫ)-11-OH-⌬ 9 -tetrahydrocannabinol dimethylheptyl. In human umbilical vein endothelial cells, abn-cbd induces phosphorylation of p42/44 mitogenactivated protein kinase and protein kinase B/Akt, which is inhibited by O-1918, by pertussis toxin or by phosphatidylinositol 3 (PI3) kinase inhibitors. These findings indicate that abncbd is a selective agonist and that O-1918 is a selective, silent antagonist of an endothelial "anandamide receptor", which is distinct from CB 1 or CB 2 receptors and is coupled through G i /G o to the PI3 kinase/Akt signaling pathway.