NITRIC-OXIDE INDUCED CONTRACTILE DYSFUNCTION IS RELATED TO A REDUCTION IN MYOCARDIAL ENERGY GENERATION

Objective: It has been suggested that nitric oxide (NO) is involved in the regulation of myocardial function in a variety of diseases such a s dilated cardiomyopathy, myocarditis, heart transplant rejection, and septic shock. However, the underlying mechanism of NO mediated reduct ion of cardiac contractility has not been clearly established so far. Therefore, we studied the effects of authentic NO on left ventricular function and myocardial energy status in the isolated heart. Methods: In 43 isolated perfused guinea pig hearts quantitative and kinetic cha nges in coronary flow (CF), left ventricular developed pressure (LVDP) , the cardiac release of adenosine, lactate, cyclic GMP, and norepinep hrine were measured during infusion of authentic NO. In parallel, myoc ardial phosphocreatine (PCr), ATP and the free energy change of ATP-hy drolysis (Delta G(ATP)) were measured using P-31 nuclear magnetic reso nance spectroscopy. Results: At low concentrations (0.01 to 1.0 mu mol /L) NO increased CF only; at higher concentrations (1 to 100 mu mol/L) CF remained elevated and LVDP was significantly reduced. Onset and of fset of changes in LVDP occurred always within 2 to 5 a after start an d cessation of NO infusion. Contractile dysfunction was significantly correlated to a pronounced increase in adenosine formation (>70-fold), a significant decrease in myocardial PCr (-78%), ATP (-25%) and a dec rease in Delta G(ATP) from -61.76 kJ/mol to -50.75 kJ/mol. This was pa ralleled by a significant decrease in myocardial oxygen consumption (- 65%) and a tenfold increase in lactate production. Coronary vasodilati on (NO: 0.001 to 1.0 mu mol/L) significantly correlated with the incre ase in cGMP release, whereas at negative inotropic concentrations (NO: 10 to 100 mu mol/L) a clear quantitative and kinetic dissociation bet ween NO-induced changes in cGMP and LVDP was observed, Contractile dys function was not related to cardiac release of norepinephrine. Conclus ions: In the isolated heart NO can potently depress myocardial energy generation thus being an effective modulator of cardiac contractility, This effect of NO may be of pathophysiological significance in cardia c muscle disorders in vivo. (C) 1997 Elsevier Science B.V.