Cytochrome P-450 metabolites of 2-arachidonoylglycerol play a role in [Ca.sup.2+]-induced relaxation of rat mesenteric arteries

The perivascular sensory nerve (PvN) [Ca.sup.2+]-sensing receptor (CAR) is implicated in [Ca.sup.2+]induced relaxation of isolated, phenylephrine (PE)-contracted mesenteric arteries, which involves the vascular endogenous cannabinoid system. We determined the effect of inhibition of diacylglycerol (DAG) lipase (DAGL), phospholipase [A.sub.2] (PL[A.sub.2]), and cytochrome P-450 (CYP) on [Ca.sup.2+]-induced relaxation of PE-contracted rat ruesenteric arteries. Our findings indicate that [Ca.sup.2+]-induced vasorelaxation is not dependent on the endothelium. The DAGL inhibitor RHC 802675 (1 [micro]M) and the CYP and PL[A.sub.2] inhibitors quinacrine (5 [micro] M) (E[C.sub.50]: RHC 802675 2.8 [+ or -] 0.4 mM vs. control 1.4 [+ or -] 0.3 mM; quinacrine 4.8 [+ or -] 0.4 mM vs. control 2.0 [+ or -] 0.3 mM; n = 5) and arachidonyltrifluoromethyl ketone (AACOC[F.sub.3], 1 [micro] M) reduced [Ca.sup.2+]induced relaxation of mesenteric arteries. Synthetic 2-arachidonoylglycerol (2-AG) and glycerated epoxyeicosatfienoic acids (GEETs) induced concentration-dependent relaxation of isolated arteries. 2-AG relaxations were blocked by iberiotoxin (IBTX) (E[C.sub.50]: control 0.96 [+ or -] 0.14 nM, IBTX 1.3 [+ or -] 0.5 [micro] M) and miconazole (48 [+ or -] 3%), and 11,12-GEET responses were blocked by IBTX (E[C.sub.50]: control 55 [+ or -] 9 nM, IBTX 690 [+ or -] 96 nM) and SR-141716A. The data suggest that activation of the CaR in the PvN network by [Ca.sup.2+] leads to synthesis and/or release of metabolites of the CYP epoxygenase pathway and metabolism of DAG to 2-AG and subsequently to GEETs. The findings indicate a role for 2-AG and its metabolites in [Ca.sup.2+]-induced relaxation of resistance arteries; therefore this receptor may be a potential target for the development of new vasodilator compounds for antihypertensive therapy. [Ca.sup.2+]-sensing receptor; arachidonic acid; vasorelaxation