cGMP-independent inotropic effects of nitric oxide and peroxynitrite donors: potential role for nitrosylation

Nitric oxide (NO) has concentration-dependent biphasic myocardial contracti le effects. We tested the hypothesis, in isolated rat hearts, that NO cardi ostimulation is primarily non-cGMP dependent. Infusion of 3-morpholinosydno nimine (SIN-1, 10(-5) M), which may participate in S-nitrosylation (S-NO) v ia peroxynitrite formation, increased the rate of left ventricular pressure rise (+dP/dt; 19 +/- 4%, P< 0.001, n = 11) without increasing effluent cGM P or cAMP. Superoxide dismutase (SOD; 150 U/ml) blocked SIN-1 cardiostimula tion and led to cGMP elaboration. Sodium nitroprusside (10(-10)-10(-7) M), an iron nitrosyl compound, did not augment +dP/dt but increased cGMP approx imately eightfold (P< 0.001), whereas diethylamine/ NO (DEA/NO; 10(-7) M), a spontaneous NO . donor, increased +dP/dt (5 +/- 2%, P< 0.05, n = 6) witho ut augmenting cGMP. SIN-1 and DEA/NO +dP/dt increase persisted despite guan ylyl cyclase inhibition with 1H-(1,2,4) oxadiazolo-( 4,3,-a) quinoxalin-1-o ne (10(-5) M, P< 0.05 for both donors), suggesting a cGMP-independent mecha nism. Glutathione (5 x 10(-4) M, n = 15) prevented SIN-1 cardiostimulation, suggesting S-NO formation. SIN-1 also produced SOD-inhibitable cardiostimu lation in vivo in mice. Thus peroxynitrite and NO donors can stimulate myoc ardial contractility independently of guanylyl cyclase activation, suggesti ng a role for S-NO reactions in NO/peroxynitrite-positive inotropic effects in intact hearts.