title: Effects of large conductance Ca(2+)-activated K(+) channels on nitroglycerin-mediated vasorelaxation in humans.
abstract: Nitric oxide (NO)-induced vasorelaxation and the regulation of endothelial superoxide anion levels is partly mediated by vascular large conductance Ca(2+)-activated K(+) (BK(Ca)) 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 BK(Ca) channel blockade on nitroglycerin-induced vasorelaxation in human arterial and venous vascular segments and whether responses to BK(Ca) 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 BK(Ca) channel blocker iberiotoxin (10(-7) M) and venous tolerance to nitroglycerin were induced by a 24-h i.v. infusion (0.5 microg/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 BK(Ca) 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 BK(Ca) channels. Although endothelial BK(Ca) 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.
authors.affiliation: Medical Department B 2142, Division of Cardiology, University of Copenhagen, Rigshospitalet Blegdamsvej 9, DK-2100, Copenhagen, Denmark.
authors.forename: Nicolai
authors.initials: N
authors.lastname: Gruhn
authors.forename: Søren
authors.initials: S
authors.lastname: Boesgaard
authors.forename: Jonas
authors.initials: J
authors.lastname: Eiberg
authors.forename: Lone
authors.initials: L
authors.lastname: Bang
authors.forename: Jens
authors.initials: J
authors.lastname: Thiis
authors.forename: Torben V
authors.initials: TV
authors.lastname: Schroeder
authors.forename: Jan
authors.initials: J
authors.lastname: Aldershvile
mesh_terms: D002118:Calcium / Q000378:metabolism*; D004361:Drug Tolerance; D004730:Endothelium, Vascular / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D051036:Large-Conductance Calcium-Activated Potassium Channels; D008323:Mammary Arteries / Q000187:drug effects / Q000502:physiology; D005996:Nitroglycerin / Q000494:pharmacology*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D024681:Potassium Channels, Calcium-Activated / Q000037:antagonists & inhibitors / Q000502:physiology*; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*; D014680:Veins / Q000187:drug effects / Q000502:physiology
chemical_list: D051036:Large-Conductance Calcium-Activated Potassium Channels; D026902:Potassium Channel Blockers; D024681:Potassium Channels, Calcium-Activated; D014665:Vasodilator Agents; D005996:Nitroglycerin; D002118:Calcium