Enhanced role of potassium channels in relaxations to acetylcholine in hypercholesterolemic rabbit carotid artery.
The effect of hypercholesterolemia for 10 wk on endothelium-dependent relaxations to acetylcholine was studied in isolated rings of rabbit carotid artery and abdominal aorta contracted with phenylephrine or elevated potassium. In these arteries obtained from hypercholesterolemic rabbits, endothelium-dependent relaxations to acetylcholine were not significantly different from those of normal rabbits. In normal and hypercholesterolemic arteries, partial relaxation persisted in the presence of NG-nitro-L-arginine methyl ester (L-NAME), which blocked acetylcholine-induced increases in arterial guanosine 3',5'-cyclic monophosphate (cGMP). Combined treatment with L-NAME and the calcium-dependent potassium-channel inhibitor, charybdotoxin, blocked relaxations in both groups, suggesting that L-NAME-resistant relaxations are mediated by an endothelium-derived hyperpolarizing factor. Charybdotoxin alone or depolarizing potassium had no significant effect on normal carotid artery or normal and hypercholesterolemic abdominal aorta but significantly inhibited relaxations of the carotid artery from cholesterol-fed rabbits. The enhanced role of calcium-dependent potassium channels and the hyperpolarizing factor in relaxation of the hypercholesterolemic carotid artery suggested by these results was likely related to the fact that acetylcholine failed to stimulate cGMP only in that artery. These data suggest that endothelium-dependent relaxation in these rabbit arteries is mediated by nitric oxide-cGMP-dependent and -independent mechanisms. In hypercholesterolemia, the contribution of nitric oxide-cGMP in the carotid artery is reduced, but a hyperpolarizing factor and calcium-dependent potassium channels maintain normal acetylcholine-induced relaxation.
Najibi
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Robert Dawson Evans Department of Clinical Research, Boston University Medical Center, Massachusetts 02118.
Cowan
C L
CL
Palacino
J J
JJ
Cohen
R A
RA
D000109:Acetylcholine / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology; D002339:Carotid Arteries / Q000187:drug effects / Q000378:metabolism / Q000502:physiology / Q000503:physiopathology*; D018999:Charybdotoxin; D002791:Cholesterol, Dietary; D006152:Cyclic GMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006937:Hypercholesterolemia / Q000378:metabolism / Q000503:physiopathology*; D066298:In Vitro Techniques; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000502:physiology / Q000503:physiopathology; D019331:NG-Nitroarginine Methyl Ester; D011188:Potassium / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*; D011817:Rabbits; D012016:Reference Values; D012604:Scorpion Venoms / Q000494:pharmacology
D002791:Cholesterol, Dietary; D015221:Potassium Channels; D012604:Scorpion Venoms; D018999:Charybdotoxin; D001120:Arginine; D006152:Cyclic GMP; D000109:Acetylcholine; D011188:Potassium; D019331:NG-Nitroarginine Methyl Ester