Increased endothelin-1 and endothelin receptor expression in myocytes of ischemic and reperfused rat hearts and ventricular myocytes exposed to ischemic conditions and its inhibition by nitric oxide generation.
Endothelin-1 (ET-1) and nitric oxide (NO) exert opposite effects in the cardiovascular system, and there is evidence that the NO counters the potential deleterious effects of ET-1. We investigated whether NO affects the increased mRNA expression of ET-1 and endothelin receptors induced by (i) 30 min of ischemia with or without 30 min reperfusion in myocytes from isolated rat hearts or (ii) ischemic conditions (acidosis or hypoxia) in cultured rat neonatal ventricular myocytes. Ischemia with or without reperfusion produced more than a twofold increase in mRNA expression of ET-1 as well as the ET(A) and ET(B) receptor (P < 0.05), although these effects were completely blocked by the NO donor 3-morpholinosydnonimine (SIN-1; 1 microM). To assess the possible factors regulating ET expression, myocytes were exposed to acidosis (pH 6.8-6.2) or to hypoxic conditions in an anaerobic chamber for 24 h in the presence or absence of SIN-1. At all acidic pHs, ET-1 and ET(A) receptor mRNA expression was significantly (P < 0.05) elevated approximately threefold, although the magnitude of elevation was independent of the degree of acidosis. These effects were completely prevented by SIN-1. ET(B) receptor expression was unaffected by acidosis. Hypoxia increased ET-1 as well as ET(A) and ET(B) receptor expression threefold (P < 0.05), although this was unaffected by SIN-1. Our results demonstrate that myocardial ischemia and reperfusion upregulate the ET system, which is inhibited by NO. Although increased expression of the ET system can be mimicked by both acidosis and hypoxia, only the effects of the former are NO sensitive. NO may serve an endogenous inhibitory factor which regulates the expression of the ET system under pathological conditions.
Gan
Xiaohong Tracey
XT
Department of Physiology & Pharmacology, University of Western Ontario, London, ON N6A 5C1, Canada.
Chakrabarti
Subrata
S
Karmazyn
Morris
M
D000138:Acidosis / Q000503:physiopathology; D000818:Animals; D000831:Animals, Newborn; D015139:Blotting, Southern; D002478:Cells, Cultured; D004586:Electrophoresis; D019332:Endothelin-1 / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000235:genetics*; D015870:Gene Expression; D008297:Male; D008981:Molsidomine / Q000031:analogs & derivatives* / Q000494:pharmacology; D009154:Mutation; D015428:Myocardial Reperfusion Injury / Q000235:genetics* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000502:physiology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D012313:RNA / Q000302:isolation & purification; D051381:Rats; D017207:Rats, Sprague-Dawley; D014158:Transcription, Genetic
D019332:Endothelin-1; D020030:Nitric Oxide Donors; C002385:linsidomine; D012313:RNA; D008981:Molsidomine