TY - JOUR
T1 - cGMP-independent inotropic effects of nitric oxide and peroxynitrite donors
T2 - Potential role for nitrosylation
AU - Paolocc, 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
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U2 - 10.1152/ajpheart.2000.279.4.h1982
DO - 10.1152/ajpheart.2000.279.4.h1982
M3 - Article
C2 - 11009488
AN - SCOPUS:0033713239
SN - 0363-6135
VL - 279
SP - H1982-H1988
JO - American Journal of Physiology - Heart and Circulatory Physiology
JF - American Journal of Physiology - Heart and Circulatory Physiology
IS - 4 48-4
ER -