Nitroglycerin-mediated vasorelaxation is modulated by endothelial calcium-activated potassium channels

Objective: Recent in vitro data suggest, large conductance calcium-activate d K+ channels (BKCa) modulate the vascular response to nitric oxide (NO). T he in vivo implications and the characteristics of this interaction are not clear. This study firstly investigates whether modulation of BK,, affects the vascular response to nitroglycerin (NTG)-derived NO in vivo and in the isolated heart and secondly examines the influence of endothelial BK,, on N TG-mediated vasodilation in vitro, Methods: The hypotensive effect of NTG w as measured in conscious, chronically catheterized rats during i.v. infusio ns of iberiotoxin (IbTX, a selective inhibitor of BK,,) or placebo. Similar ly, NTG-induced flow-changes in the isolated perfused rat heart were examin ed before and after IbTX treatment (0.1 mu M). Concentration-relaxation cur ves to NTG in the presence of various K+ channel modulating agents were per formed in vitro on porcine coronary arteries with and without intact endoth elium. Results: I.v. infusion of IbTX reduced the in vivo hypotensive effec t of NTG by 55% (before IbTX: 32.0+/-3.0 mmHg, vs. after IbTX: 14.5+/-3.2 m mHg, P<0.05) and nearly abolished NTG-induced increase in coronary flow in the isolated perfused heart (P<0.05). In vitro, this effect depended on an intact endothelium (endothelium intact segments; NTG: pD(2)=5.8+/-0.1, E-ma x=97.6+/-3.2% vs. NTG+IbTX: pD(2) =4.9+/-0.2. E-max=49.7+/-6.2%, P<0.05; en dothelium denuded segments; NTG: pD(2)=6.9+?-0.1, E-max=104.0+/-1.4% vs. NT G+IbTX: pD(2)=6.7+/-0.1, E-max=100+/-1.2%, P>0.05). Conclusion: The results suggest, that modulation of endothelial BKCa significantly affects NTG-ind uced vasorelaxation in vitro, in the isolated perfused heart and in vivo. ( C) 1999 Elsevier Science B.V. All rights reserved.