Control of myogenic tone and agonist induced contraction of intramural coronary resistance arterioles by cannabinoid type 1 receptors and endocannabinoids

It was tested whether intrinsic CB1R activation modifies myogenic and agonist induced contraction of intramural coronary resistance arteries of the rat. CB1R protein was detected by immuno-histochemistry and by Western blot, its mRNA by qRT-PCR in their wall. Microsurgically prepared cylindrical coronary segments (similar to 100-150 mu m) developed myogenic contraction (similar to 20% of relaxed luminal diameter), from which a substantial relaxation (similar to 15%) in response to WIN55212 (a specific agonist of the CB(1)Rs) has been found. CB1R-mediated relaxation was blocked by O2050 and AM251 (neutral antagonist and inverse agonist of the CB1R, respectively) and was partially blocked by the NO synthase blocker N omega-nitro-L-arginine. CB1R blockade enhanced myogenic tone and augmented AngII-induced vasoconstriction (from 17.8 +/- 1.2 to 29.1 +/- 2.9%, p < 0.05). Inhibition of diacylglycerol lipase by tetrahydrolipstatin, (inhibitor of endogenous 2-AG production) also augmented coronary vasoconstriction. These observations prove that vascular endocannabinoids are significant negative modulators of the myogenic and agonist-induced tone of intramural coronary arterioles acting through CB(1)Rs.