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Am J Physiol Heart Circ Physiol 279: H1982-H1988, 2000;
0363-6135/00 $5.00
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Vol. 279, Issue 4, H1982-H1988, October 2000

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

Nazareno Paolocci, Ulf E. G. Ekelund, Takayoshi Isoda, Michitaka Ozaki, Koenraad Vandegaer, Dimitrios Georgakopoulos, Robert W. Harrison, David A. Kass, and Joshua M. Hare

Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, Maryland 21287-6568

Nitric oxide (NO) has concentration-dependent biphasic myocardial contractile effects. We tested the hypothesis, in isolated rat hearts, that NO cardiostimulation is primarily non-cGMP dependent. Infusion of 3-morpholinosydnonimine (SIN-1, 10-5 M), which may participate in S-nitrosylation (S-NO) via peroxynitrite formation, increased the rate of left ventricular pressure rise (+dP/dt; 19 ± 4%, P < 0.001, n = 11) without increasing effluent cGMP or cAMP. Superoxide dismutase (SOD; 150 U/ml) blocked SIN-1 cardiostimulation and led to cGMP elaboration. Sodium nitroprusside (10-10-10-7 M), an iron nitrosyl compound, did not augment +dP/dt but increased cGMP approximately 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) without augmenting cGMP. SIN-1 and DEA/NO +dP/dt increase persisted despite guanylyl cyclase inhibition with 1H-(1,2,4)oxadiazolo-(4,3,-a)quinoxalin-1-one (10-5 M, P < 0.05 for both donors), suggesting a cGMP-independent mechanism. Glutathione (5 × 10-4 M, n = 15) prevented SIN-1 cardiostimulation, suggesting S-NO formation. SIN-1 also produced SOD-inhibitable cardiostimulation in vivo in mice. Thus peroxynitrite and NO donors can stimulate myocardial contractility independently of guanylyl cyclase activation, suggesting a role for S-NO reactions in NO/peroxynitrite-positive inotropic effects in intact hearts.

myocardial contractility; 3-morpholinosydnonimine; cyclic nucleotides; superoxide dismutase; glutathione; 1H-(1,2,4) oxadiazolo-(4,3,-a)quinoxalin-1-one; guanosine 3',5'-cyclic monophosphate


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