Novel nitric oxide synthase-dependent mechanism of vasorelaxation in small arteries from hypertensive rats

To determine the mechanism(s) involved in vasorelaxation of small arteries from hypertensive rats, normotensive (NORM), angiotensin II-infused (ANG), high-salt (HS), ANG high-salt (ANG/HS), placebo, and deoxycorticosterone acetate-salt rats were studied. Third-order mesenteric arteries from ANG or ANG/HS displayed decreased sensitivity to acetylcholine (ACh)-induced vasorelaxation compared with NORM or HS, respectively. Maximal relaxations were comparable between groups. Blockade of Ca2+-activated K+ channels had no effect on ANG versus blunting relaxation in NORM (log EC50: -6.8 +/- 0.1 versus -7.2 +/- 0.1 mol/L). NO synthase (NOS) inhibition abolished ACh-mediated relaxation in small arteries from ANG, ANG/HS, and deoxycorticosterone acetate-salt versus blunting relaxation in NORM, HS, and placebo (% maximal relaxation: ANG: 2.7 +/- 1.8; ANG/HS: 7.2 +/- 3.2; NORM: 91 +/- 3.1; HS: 82.1 +/- 13.3; deoxycorticosterone acetate-salt: 35.2 +/- 17.7; placebo: 79.3 +/- 10.3), indicating that NOS is the primary vasorelaxation pathway in these arteries from hypertensive rats. We hypothesized that NO/cGMP signaling and NOS-dependent H2O2 maintains vasorelaxation in small arteries from ANG. ACh increased NOS-dependent cGMP production, indicating that NO/cGMP signaling is present in small arteries from ANG (55.7 +/- 6.9 versus 30.5 +/- 5.1 pmol/mg), and ACh stimulated NOS-dependent H2O2 production (ACh: 2.8 +/- 0.2 mu mol/mg; N-omega-nitro-L-arginine methyl ester hydrochloride + ACh: 1.8 +/- 0.1 mu mol/mg) in small arteries from ANG. H2O2 induced vasorelaxation and catalase blunted ACh-mediated vasorelaxation. In conclusion, Ca2+-activated K+ channel-mediated relaxation is dysfunctional in small mesenteric arteries from hypertensive rats, and the NOS pathway compensates to maintain vasorelaxation in these arteries through NOS-mediated cGMP and H2O2 production.