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 Ca(2+)-activated K(+) channels had no effect on ANG versus blunting relaxation in NORM (log EC(50): -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 H(2)O(2) 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 H(2)O(2) production (ACh: 2.8+/-0.2 micromol/mg; N(omega)-nitro-l-arginine methyl ester hydrochloride+ACh: 1.8+/-0.1 micromol/mg) in small arteries from ANG. H(2)O(2) induced vasorelaxation and catalase blunted ACh-mediated vasorelaxation. In conclusion, Ca(2+)-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 H(2)O(2) production.
Kang
Kyu-Tae
KT
Vascular Biology Center, Medical College of Georgia, Augusta, GA 30912, USA.
Sullivan
Jennifer C
JC
Sasser
Jennifer M
JM
Imig
John D
JD
Pollock
Jennifer S
JS
D000109:Acetylcholine / Q000494:pharmacology; D000804:Angiotensin II; D000818:Animals; D000975:Antioxidants / Q000378:metabolism / Q000494:pharmacology; D001011:Aorta / Q000378:metabolism; D001158:Arteries / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology*; D001794:Blood Pressure; D006152:Cyclic GMP / Q000378:metabolism; D004338:Drug Combinations; D006861:Hydrogen Peroxide / Q000378:metabolism / Q000494:pharmacology; D006973:Hypertension / Q000139:chemically induced / Q000201:enzymology / Q000503:physiopathology*; D008297:Male; D008638:Mesenteric Arteries / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D024681:Potassium Channels, Calcium-Activated / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D012965:Sodium Chloride; D014664:Vasodilation; D014665:Vasodilator Agents / Q000494:pharmacology
D000975:Antioxidants; D004338:Drug Combinations; D024681:Potassium Channels, Calcium-Activated; D014665:Vasodilator Agents; D000804:Angiotensin II; D009569:Nitric Oxide; D012965:Sodium Chloride; D006861:Hydrogen Peroxide; D019001:Nitric Oxide Synthase; D006152:Cyclic GMP; D000109:Acetylcholine