Urodilatin limits acute reperfusion injury in the isolated rat heart.
OBJECTIVE
Hypercontracture is an important mechanism of myocyte death during reperfusion. cGMP modulates the sensitivity of contractile myofilaments to Ca2+, and increasing cGMP concentration during the last minutes of anoxia prevents reoxygenation-induced hypercontracture in isolated cardiomyocytes. The purpose of this study was to determine whether stimulation of particulate guanylyl cyclase with the natriuretic peptide urodilatin, given at the time of reperfusion, reduces myocardial necrosis in the rat heart submitted to transient ischemia.


METHODS
Isolated rat hearts (n = 38) were submitted to either 40 or 60 min of no-flow ischemia and 2 h of reperfusion, and were allocated to receive or not receive 0.05 microM urodilatin during the first 15 min of reperfusion or non-reperfusion treatment.


RESULTS
A marked reduction in myocardial cGMP concentration was observed in control hearts during reperfusion after 40 or 60 min of ischemia. Urodilatin significantly attenuated cGMP depletion during initial reperfusion, markedly improved contractile recovery after 40 min of ischemia (P < 0.0309), and reduced reperfusion-induced increase in left ventricular end-diastolic pressure (P = 0.0139), LDH release (P = 0.0263), and contraction band necrosis (P = 0.0179) after 60 min of ischemia. The beneficial effect of urodilatin was reproduced by the membrane permeable cGMP analog 8-Bromo-cGMP.


CONCLUSIONS
These results indicate that reduced cGMP concentration may impair myocyte survival during reperfusion. Stimulation of particulate guanylyl cyclase may appear as a new strategy to prevent immediate lethal reperfusion injury.
Inserte
J
J
Servicio de Cardiología, Hospital General Universitari Vall d'Hebron, Barcelona, Spain.
Garcia-Dorado
D
D
Agulló
L
L
Paniagua
A
A
Soler-Soler
J
J
D000704:Analysis of Variance; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000627:therapeutic use*; D006152:Cyclic GMP / Q000378:metabolism; D020536:Enzyme Activators / Q000627:therapeutic use*; D006162:Guanylate Cyclase / Q000378:metabolism*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009336:Necrosis; D010446:Peptide Fragments / Q000627:therapeutic use*; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley
D020536:Enzyme Activators; D010446:Peptide Fragments; C056452:Ularitide; D009320:Atrial Natriuretic Factor; D007770:L-Lactate Dehydrogenase; D006162:Guanylate Cyclase; D006152:Cyclic GMP