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, Joshua M. Hare

Research output: Contribution to journalArticle

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)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume279
Issue number4 48-4
StatePublished - 2000

Fingerprint

Peroxynitrous Acid
Nitric Oxide Donors
Nitric Oxide
Guanylate Cyclase
Molsidomine
Iron Compounds
Nitroprusside
Ventricular Pressure
Superoxide Dismutase

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)

Cite this

cGMP-independent inotropic effects of nitric oxide and peroxynitrite donors : Potential role for nitrosylation. / Paolocci, Nazareno; Ekelund, Ulf E G; Isoda, Takayoshi; Ozaki, Michitaka; Vandegaer, Koenraad; Georgakopoulos, Dimitrios; Harrison, Robert W.; Kass, David A; Hare, Joshua M.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 279, No. 4 48-4, 2000.

Research output: Contribution to journalArticle

Paolocci, Nazareno ; Ekelund, Ulf E G ; Isoda, Takayoshi ; Ozaki, Michitaka ; Vandegaer, Koenraad ; Georgakopoulos, Dimitrios ; Harrison, Robert W. ; Kass, David A ; Hare, Joshua M. / cGMP-independent inotropic effects of nitric oxide and peroxynitrite donors : Potential role for nitrosylation. In: American Journal of Physiology - Heart and Circulatory Physiology. 2000 ; Vol. 279, No. 4 48-4.
@article{30dbaddea7ec419293bf9abc0e550e1f,
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 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.",
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",
author = "Nazareno Paolocci and Ekelund, {Ulf E G} and Takayoshi Isoda and Michitaka Ozaki and Koenraad Vandegaer and Dimitrios Georgakopoulos and Harrison, {Robert W.} and Kass, {David A} and Hare, {Joshua M.}",
year = "2000",
language = "English (US)",
volume = "279",
journal = "American Journal of Physiology",
issn = "0363-6135",
publisher = "American Physiological Society",
number = "4 48-4",

}

TY - JOUR

T1 - cGMP-independent inotropic effects of nitric oxide and peroxynitrite donors

T2 - Potential role for nitrosylation

AU - Paolocci, Nazareno

AU - Ekelund, Ulf E G

AU - Isoda, Takayoshi

AU - Ozaki, Michitaka

AU - Vandegaer, Koenraad

AU - Georgakopoulos, Dimitrios

AU - Harrison, Robert W.

AU - Kass, David A

AU - Hare, Joshua M.

PY - 2000

Y1 - 2000

N2 - 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.

AB - 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.

KW - 1H-(1,2,4) oxadiazolo-(4,3,-a)quinoxalin-1-one

KW - 3-morpholinosydnonimine

KW - Cyclic nucleotides

KW - Glutathione

KW - Guanosine 3',5'-cyclic monophosphate

KW - Myocardial contractility

KW - Superoxide dismutase

UR - http://www.scopus.com/inward/record.url?scp=0033713239&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0033713239&partnerID=8YFLogxK

M3 - Article

VL - 279

JO - American Journal of Physiology

JF - American Journal of Physiology

SN - 0363-6135

IS - 4 48-4

ER -