Effects of hypertension on vasorelaxation to endocannabinoids in vitro.
ABSTRACT The hypotensive actions of methanandamide are enhanced in anaesthetised spontaneously hypertensive rats (SHR), which may be due to increased sensory nerve activity. We have now investigated in vitro the role of sensory nerves and other vasorelaxant mechanisms of anandamide in this model of hypertension, and in rats made hypertensive by chronic inhibition of nitric oxide (NO) synthase. Male SHR and Sprague-Dawley rats (given approximately 10 mg/kg/day N(G) nitro-L-arginine methyl ester (L-NAME) to drink for 4 weeks) were used. Vasorelaxant responses to anandamide and capsaicin were determined in perfused mesenteric arterial beds and thoracic aortic rings. The contributions of sensory nerves, NO, prostanoids, cannabinoid receptors and the endothelium in these responses were investigated. In mesenteric arterial beds from SHR, anandamide was less potent as a vasorelaxant, but in aortae caused greater maximal relaxations compared to controls. The reduced potency in the mesenteric arterial bed was accompanied by impaired NO-dependent relaxation. Pre-treatment with capsaicin prevented the enhancement of vasorelaxation by anandamide in mesenteric arterial beds from rats with L-NAME-induced hypertension. The reduced potency of anandamide in mesenteric arterial beds from SHR was due to reduced NO-dependent vasorelaxation, and provides no evidence for increased sensory nerve activity. The enhanced responses in the SHR aortae were endothelium-dependent. However, in L-NAME-induced hypertension the enhanced vasorelaxation to anandamide in the mesenteric vasculature was due to increased sensory nerve-mediated activity. In conclusion, the alterations in responses to anandamide in hypertension are dependent on the vessels studied and the model of hypertension.