© 2000 American Heart Association, Inc.
Integrative Physiology |
Endogenous Nitric Oxide and Myocardial Adaptation to Ischemia
From the Abteilungen für Pathophysiologie (G.H., H.P., R.S.) and für Nieren- und Hochdruckkrankheiten (M.C.M.), Zentrum für Innere Medizin des Universitätsklinikums Essen, and the Abteilung für Kardiologie, Heinrich Heine-Universität Düsseldorf (M.K.), Germany.
Correspondence to Prof Dr Gerd Heusch, FESC, FACC, Abteilung für Pathophysiologie, Zentrum für Innere Medizin, Universitätsklinikum Essen, Hufelandstraße 55, 45122 Essen, Federal Republic of Germany. E-mail gerd.heusch{at}uni-essen.de
Abstract—Ischemic myocardium does not inevitably undergo necrosis but rather can survive through downregulation of contractile function, ie, "hibernate." To study the role of endogenous NO in this adaptation, 41 enflurane-anesthetized swine were subjected to 90 minutes of moderate left anterior descending coronary artery hypoperfusion and assigned to placebo (P), to 30 mg/kg NG-nitro-L-arginine (L-NNA) IV to inhibit NO synthase, or to aortic constriction (AO) to match the increased left ventricular pressure observed with L-NNA. During normoperfusion, a regional myocardial external work index (WI, mm Hg · mm, sonomicrometry and micromanometry) was reduced with L-NNA (from 326±27 [SEM] to 250±19, P<0.05) but increased with AO (from 321±16 to 363±19, P<0.05 versus L-NNA). At 10 minutes of ischemia, WI was lower with L-NNA (109±10, P<0.05) than P (180±22) and AO (170±11) and did not change further at 85 minutes of ischemia. Relationships between WI and transmural myocardial blood flow and oxygen consumption were shifted rightward by L-NNA versus P and AO at both 10 and 85 minutes of ischemia. The maximal increment in calcium-activated external work was not different during normoperfusion among groups but was decreased during ischemia with L-NNA. L-NNA transiently increased myocardial contractile calcium sensitivity along with systemic pressure but reduced it during ongoing ischemia. The free-energy change of ATP hydrolysis after an early ischemic decrease recovered toward baseline values in all groups, and necrosis was absent after 2 (triphenyltetrazolium chloride staining) or 8 (histology) hours of reperfusion. Thus, endogenous NO contributes to hibernation by reducing oxygen consumption and preserving calcium sensitivity and contractile function without an energy cost during ischemia. (Circ Res. 2000;87:146-152.)
Key Words: contractile function • oxygen consumption • ischemia
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