Advanced

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

Paolocci, N; Ekelund, Ulf LU ; Isoda, T; Ozaki, M; Vandegaer, K; Georgakopoulos, D; Harrison, R W; Kass, D A and Hare, J M (2000) In American Journal of Physiology: Heart and Circulatory Physiology 279(4). p.1982-1988
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;... (More)
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. (Less)
Please use this url to cite or link to this publication:
author
publishing date
type
Contribution to journal
publication status
published
subject
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
in
American Journal of Physiology: Heart and Circulatory Physiology
volume
279
issue
4
pages
1982 - 1988
publisher
American Physiological Society
external identifiers
  • pmid:11009488
  • scopus:0033713239
ISSN
1522-1539
language
English
LU publication?
no
id
1531a8b0-c61f-4270-9c5d-0422355bb1d1 (old id 1117160)
alternative location
http://ajpheart.physiology.org/cgi/content/full/279/4/H1982
date added to LUP
2008-07-03 08:44:57
date last changed
2017-02-26 03:23:59
@article{1531a8b0-c61f-4270-9c5d-0422355bb1d1,
  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 &lt; 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 &lt; 0.001), whereas diethylamine/NO (DEA/NO; 10(-7) M), a spontaneous NO. donor, increased +dP/dt (5 +/- 2%, P &lt; 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 &lt; 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.},
  author       = {Paolocci, N and Ekelund, Ulf and Isoda, T and Ozaki, M and Vandegaer, K and Georgakopoulos, D and Harrison, R W and Kass, D A and Hare, J M},
  issn         = {1522-1539},
  keyword      = {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},
  language     = {eng},
  number       = {4},
  pages        = {1982--1988},
  publisher    = {American Physiological Society},
  series       = {American Journal of Physiology: Heart and Circulatory Physiology},
  title        = {cGMP-independent inotropic effects of nitric oxide and peroxynitrite donors: potential role for nitrosylation},
  volume       = {279},
  year         = {2000},
}