Loss of endothelial KATP channel-dependent, NO-mediated dilation of endocardial resistance coronary arteries in pigs with left ventricular hypertrophy.
The influence of left ventricular hypertrophy (LVH) on the endothelial function of resistance endocardial arteries is not well established. The aim of this study was to characterise the mechanisms responsible for UK-14,304 (alpha(2)-adrenoreceptor agonist)-induced endothelium-dependent dilation in pig endocardial arteries isolated from hearts with or without LVH. LVH was induced by aortic banding 2 months before determining endothelial function. Following euthanasia, hearts were harvested and endocardial resistance arteries were isolated and pressurised to 100 mmHg in no-flow conditions. Vessels were preconstricted with acetylcholine (ACh) or high external K(+) (40 mmol l(-1) KCl). Results are expressed as mean+/-s.e.m. UK-14,304 induced a maximal dilation representing 79+/-6% (n=8) of the maximal diameter. NO synthase (l-NNA, 10 micromol l(-1), n=7) or guanylate cyclase (ODQ, 10 micromol l(-1), n=4) inhibition reduced (P<0.05) UK-14,304-dependent dilation to 35+/-6 and 18+/-7%, respectively. Apamin and charybdotoxin reduced (P<0.05) to 39+/-8% (n=4) the dilation induced by UK-14,304. In depolarised conditions, however, this dilation was prevented (P<0.05). UK-14,304-induced dilation was reduced (P<0.05) by glibenclamide (Glib, 1 micromol l(-1)), a K(ATP) channel blocker, either alone (35+/-10%, n=5) or in combination with l-NNA (34+/-9%, n=4). In LVH, UK-14,304-induced maximal dilation was markedly reduced (25+/-4%, P<0.05) compared to control; it was insensitive to l-NNA (21+/-5%) but prevented either by the combination of l-NNA, apamin and charybdotoxin, or by 40 mmol l(-1) KCl. Activation of endothelial alpha(2)-adrenoreceptor induces an endothelium-dependent dilation of pig endocardial resistance arteries. This dilation is in part dependent on NO, the release of which appears to be dependent on the activation of endothelial K(ATP) channels. This mechanism is blunted in LVH, leading to a profound reduction in UK-14,304-dependent dilation.
Department of Surgery, Research Center, Institut de Cardiologie de Montréal, 5000, rue Bélanger, Montréal, Québec, Canada H1T 1C8.
Marie-Eve
ME
Gendron
Eric
E
Thorin
Louis P
LP
Perrault
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001920:Bradykinin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000068438:Brimonidine Tartrate; D002170:Canada; D018999:Charybdotoxin / Q000494:pharmacology; D003331:Coronary Vessels / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D004699:Endocardium / Q000187:drug effects / Q000503:physiopathology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000503:physiopathology*; D005905:Glyburide / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D017379:Hypertrophy, Left Ventricular / Q000503:physiopathology*; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism* / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000494:pharmacology; D019335:Nitroarginine / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D010069:Oxadiazoles / Q000494:pharmacology; D015221:Potassium Channels / Q000145:classification / Q000172:deficiency* / Q000378:metabolism; D011810:Quinoxalines / Q000037:antagonists & inhibitors / Q000494:pharmacology; D013552:Swine; D014655:Vascular Resistance / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D010069:Oxadiazoles; D015221:Potassium Channels; D011810:Quinoxalines; D018999:Charybdotoxin; D009599:Nitroprusside; D019335:Nitroarginine; D009569:Nitric Oxide; D000068438:Brimonidine Tartrate; D000255:Adenosine Triphosphate; D019001:Nitric Oxide Synthase; D006162:Guanylate Cyclase; D001920:Bradykinin; D005905:Glyburide; D007213:Indomethacin