Nitroglycerin-mediated vasorelaxation is modulated by endothelial calcium-activated potassium channels.
OBJECTIVE
Recent in vitro data suggest, large conductance calcium-activated K+ channels (BKCa) modulate the vascular response to nitric oxide (NO). The in vivo implications and the characteristics of this interaction are not clear. This study firstly investigates whether modulation of BKCa affects the vascular response to nitroglycerin (NTG)-derived NO in vivo and in the isolated heart and secondly examines the influence of endothelial BKCa on NTG-mediated vasodilation in vitro.


METHODS
The hypotensive effect of NTG was measured in conscious, chronically catheterized rats during i.v. infusions of iberiotoxin (IbTX, a selective inhibitor of BKCa) or placebo. Similarly, NTG-induced flow-changes in the isolated perfused rat heart were examined before and after IbTX treatment (0.1 microM). Concentration-relaxation curves to NTG in the presence of various K+ channel modulating agents were performed in vitro on porcine coronary arteries with and without intact endothelium.


RESULTS
I.v. infusion of IbTX reduced the in vivo hypotensive effect of NTG by 55% (before IbTX: 32.0 +/- 3.0 mmHg, vs. after IbTX: 14.5 +/- 3.2 mmHg, 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: pD2 = 5.8 +/- 0.1, Emax = 97.6 +/- 3.2% vs. NTG + IbTX: pD2 = 4.9 +/- 0.2, Emax = 49.7 +/- 6.2%, P < 0.05; endothelium denuded segments; NTG: pD2 = 6.9 +/- 0.1, Emax = 104.0 +/- 1.4% vs. NTG + IbTX: pD2 = 6.7 +/- 0.1, Emax = 100 +/- 1.2%, P > 0.05).


CONCLUSIONS
The results suggest, that modulation of endothelial BKCa significantly affects NTG-induced vasorelaxation in vitro, in the isolated perfused heart and in vivo.
Bang
L
L
Medical Department B, Rigshospitalet, University of Copenhagen, Denmark.
Boesgaard
S
S
Nielsen-Kudsk
J E
JE
Vejlstrup
N G
NG
Aldershvile
J
J
D000818:Animals; D002118:Calcium / Q000378:metabolism; D003331:Coronary Vessels / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D066298:In Vitro Techniques; D015640:Ion Channel Gating / Q000187:drug effects*; D008297:Male; D005996:Nitroglycerin / Q000494:pharmacology*; D010069:Oxadiazoles / Q000494:pharmacology; D010078:Oxazines / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology*; D010477:Perfusion; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012039:Regional Blood Flow / Q000187:drug effects; D012044:Regression Analysis; D013552:Swine; D014665:Vasodilator Agents / Q000494:pharmacology*
D004791:Enzyme Inhibitors; C111257:NS 2028; D010069:Oxadiazoles; D010078:Oxazines; D010455:Peptides; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D014665:Vasodilator Agents; C064719:iberiotoxin; D006162:Guanylate Cyclase; D005996:Nitroglycerin; D002118:Calcium