Effects of large conductance Ca2+-activated K+ channels on nitroglycerin-mediated vasorelaxation in humans

Nitric oxide (NO)-induced vasorelaxation and the regulation of endothelial superoxide anion levels is partly mediated by vascular large conductance Ca2+-activated K+ (BKc) channels. Nitroglycerin acts through the release of NO and its effect is modulated by changes in endothelial superoxide levels. This study examines the effect of BKCa channel blockade on nitroglycerin-induced vasorelaxation in human arterial and venous vascular segments and whether responses to BKCa channel blockade are influenced by the development of venous nitroglycerin tolerance. Dose-relaxation curves to nitroglycerin (10(-10)-10(-4) M) were obtained in segments of the saphenous vein and the left mammary artery. Studies were performed with and without pre-incubation with the BKCa channel blocker iberiotoxin (10(-7) M) and venous tolerance to nitroglycerin were induced by a 24-h i.v. infusion (0.5 mug/kg/min). Iberiotoxin reduced the vasorelaxant effect of nitroglycerin (E-max) by 60% in endothelium-intact arteries and 13% in endothelium-denuded arteries (P<0.05). Development of nitroglycerin tolerance did not affect the response to iberiotoxin in the venous vascular segments (P>0.05) and (compared to arterial segments) veins were less sensitive to BKCa channel blockade (30% reduction in E-max) or endothelial removal. The results suggest that primarily arterial effects of nitroglycerin are significantly inhibited by changes in the activity of the endothelial BKCa channels. Although endothelial BKCa are likely regulators of mechanisms underlying arterial tolerance development to nitroglycerin, they do not appear to play a role in human venous nitroglycerin tolerance development. (C) 2002 Elsevier Science B.V. All rights reserved.