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.
authors.affiliation: Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, Maryland 21287-6568, USA.
authors.forename: N
authors.initials: N
authors.lastname: Paolocci
authors.forename: U E
authors.initials: UE
authors.lastname: Ekelund
authors.forename: T
authors.initials: T
authors.lastname: Isoda
authors.forename: M
authors.initials: M
authors.lastname: Ozaki
authors.forename: K
authors.initials: K
authors.lastname: Vandegaer
authors.forename: D
authors.initials: D
authors.lastname: Georgakopoulos
authors.forename: R W
authors.initials: RW
authors.lastname: Harrison
authors.forename: D A
authors.initials: DA
authors.lastname: Kass
authors.forename: J M
authors.initials: JM
authors.lastname: Hare
mesh_terms: D000818:Animals; D006152:Cyclic GMP / Q000378:metabolism / Q000502:physiology*; D004048:Diethylamines / Q000494:pharmacology; D004338:Drug Combinations; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005978:Glutathione / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008981:Molsidomine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology; D009200:Myocardial Contraction / Q000187:drug effects*; D009566:Nitrates / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism* / Q000494:pharmacology; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D009599:Nitroprusside / Q000494:pharmacology; D009712:Nucleotides, Cyclic / Q000378:metabolism; D010069:Oxadiazoles / Q000494:pharmacology; D010084:Oxidation-Reduction; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013482:Superoxide Dismutase / Q000494:pharmacology
chemical_list: C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D004048:Diethylamines; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D009566:Nitrates; D020030:Nitric Oxide Donors; D009712:Nucleotides, Cyclic; D010069:Oxadiazoles; D011810:Quinoxalines; D009599:Nitroprusside; C039642:peroxynitric acid; D009569:Nitric Oxide; C002385:linsidomine; C034281:diethylamine; D008981:Molsidomine; D013482:Superoxide Dismutase; D005978:Glutathione; D006152:Cyclic GMP