Interaction of nitric oxide and endothelin-1 in ischemia/reperfusion injury of rat heart.
Although several studies have demonstrated that nitric oxide appears to be cardioprotective and endothelin-1 (ET-1) deleterious in myocardial ischemia/reperfusion injury, their interactions in the intact heart are unknown. Therefore, coronary effluent and interstitial fluid ("transudate") levels of ET-1 and cyclic GMP, an indirect measure of nitric oxide production, were determined simultaneously in normoxic and reperfused hearts and compared with myocardial and coronary function. Rat hearts were buffer-perfused at 9 ml/min/g heart wet weight for 45 min (baseline), followed either by another 45 min of perfusion (normoxia), or 15 min of total global ischemia and 30 min reperfusion. Hearts received, from 42-90 min, either vehicle, the inhibitor of nitric oxide formation NG-nitro-L-arginine (L-NNA; 200 micromol/l), the nitric oxide donor S-nitroso-N-acetyl-DL-penicillamine (SNAP; 200 micromol/l), or the ET receptor antagonist PD 142893 (200 nmol/l). Both mediators were released preferentially into the vascular lumen which resulted in similar luminal and interstitial concentrations of cyclic GMP, but three-fold higher levels of ET-1 in tissue because of the higher effluent than transudate flow rate. L-NNA increased the release of ET-1 and worsened coronary function, whereas SNAP had opposite effects. On reperfusion, considerable functional impairment was observed, although levels of cyclic GMP both in the vascular and tissue compartment were not reduced, but even increased. Reperfusion functional impairment was aggravated after inhibiting the synthesis of nitric oxide, whereas SNAP restored cardiac and coronary function close to pre-ischemic level. Deterioration of function corresponded with an increased level, and improvement with a decreased level of intersitial ET-1 at the onset of reperfusion. PD 142893 was similarly cardioprotective as SNAP both in normoxia and reperfusion. These results suggest that in reperfusion, cardiac function is depressed, despite increased rather than decreased endogenous nitric oxide production, largely due to the prevalence of the deleterious effects of ET-1 which are overcome by antagonism of ET receptors or exogenous nitric oxide supplied by SNAP.
Brunner
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Institut für Pharmakologie und Toxikologie, Karl-Franzens-Universität Graz, Universitätsplatz 2, A-8010 Graz, Austria.
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D000242:Cyclic AMP / Q000032:analysis / Q000378:metabolism; D019332:Endothelin-1 / Q000187:drug effects / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005122:Exudates and Transudates; D006339:Heart Rate; D066298:In Vitro Techniques; D017202:Myocardial Ischemia / Q000378:metabolism*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism; D009569:Nitric Oxide / Q000032:analysis / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D019335:Nitroarginine / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley; D026423:S-Nitroso-N-Acetylpenicillamine
D019332:Endothelin-1; D004791:Enzyme Inhibitors; D009842:Oligopeptides; C076213:PD 142893; D019335:Nitroarginine; D009569:Nitric Oxide; D026423:S-Nitroso-N-Acetylpenicillamine; D000242:Cyclic AMP; D019001:Nitric Oxide Synthase; D010396:Penicillamine; D000109:Acetylcholine