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

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

Research output: Contribution to journalArticle

92 Scopus citations

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 DEAfNO +dP/dt increase persisted despite guanylyl cyclase inhibition with 1H-(1,2,4)oxadia 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.

Original languageEnglish (US)
Pages (from-to)H1982-H1988
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume279
Issue number4 48-4
DOIs
StatePublished - 2000
Externally publishedYes

Keywords

  • 1H-(1,2,4) oxadiazolo-(4,3,-a)quinoxalin-1-one
  • 3-morpholinosydnonimine
  • Cyclic nucleotides
  • Glutathione
  • Guanosine 3',5'-cyclic monophosphate
  • Myocardial contractility
  • Superoxide dismutase

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

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