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

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title = "cGMP-independent inotropic effects of nitric oxide and peroxynitrite donors: potential role for nitrosylation",
abstract = "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 x 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.",
keywords = "3-morpholinosydnonimine, myocardial contractility, cyclic nucleotides, superoxide dismutase, glutathione, 1H-(1, 4) oxadiazolo-(4, 2, 3, -a)quinoxalin-1-one, guanosine 3', 5'-cyclic monophosphate",
author = "N Paolocci and Ulf Ekelund and T Isoda and M Ozaki and K Vandegaer and D Georgakopoulos and Harrison, {R W} and Kass, {D A} and Hare, {J M}",
year = "2000",
language = "English",
volume = "279",
pages = "1982--1988",
journal = "American Journal of Physiology - Heart and Circulatory Physiology",
issn = "1522-1539",
publisher = "American Physiological Society",
number = "4",