Urodilatin limits acute reperfusion injury in the isolated rat heart

Objectives: Hypercontracture is an important mechanism of myocyte death dur ing reperfusion. cGMP modulates the sensitivity of contractile myofilaments to Ca2+, and increasing cGMP concentration during the last minutes of anox ia prevents reoxygenation-induced hypercontracture in isolated cardiomyocyt es. The purpose of this study was to determine whether stimulation of parti culate guanylyl cyclase with the natriuretic peptide urodilatin, given at t he time of reperfusion, reduces myocardial necrosis in the rat heart submit ted to transient ischemia. Methods: Isolated rat hearts (n=38) were submitt ed to either 40 or 60 min of no-flow ischemia and 2 h of reperfusion, and w ere allocated to receive or not receive 0.05 mu M urodilatin during the fir st 15 min of reperfusion or non-reperfusion treatment. Results: A marked re duction in myocardial cGMP concentration was observed in control hearts dur ing reperfusion after 40 or 60 min of ischemia. Urodilatin significantly at tenuated cGMP depletion during initial reperfusion, markedly improved contr actile recovery after 40 min of ischemia (P<0.0309), and reduced reperfusio n-induced increase in left ventricular end-diastolic pressure (P=0.0139), L DH release (P=0.0263), and contraction band necrosis (P=0.0179) after 60 mi n of ischemia. The beneficial effect of urodilatin was reproduced by the me mbrane permeable cGMP analog 8-Bromo-cGMP. Conclusions: These results indic ate that reduced cGMP concentration may impair myocyte survival during repe rfusion. Stimulation of particulate guanylyl cyclase may appear as a new st rategy to prevent immediate lethal reperfusion injury. (C) 2000 Elsevier Sc ience B.V. All rights reserved.