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

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cGMP-independent inotropic effects of nitric oxide and peroxynitrite donors: potential role for nitrosylation. / Paolocci, N; Ekelund, Ulf; Isoda, T; Ozaki, M; Vandegaer, K; Georgakopoulos, D; Harrison, R W; Kass, D A; Hare, J M.

I: American Journal of Physiology: Heart and Circulatory Physiology, Vol. 279, Nr. 4, 2000, s. 1982-1988.

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

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Paolocci, N, Ekelund, U, Isoda, T, Ozaki, M, Vandegaer, K, Georgakopoulos, D, Harrison, RW, Kass, DA & Hare, JM 2000, 'cGMP-independent inotropic effects of nitric oxide and peroxynitrite donors: potential role for nitrosylation', American Journal of Physiology: Heart and Circulatory Physiology, vol. 279, nr. 4, s. 1982-1988.

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Paolocci, N ; Ekelund, Ulf ; Isoda, T ; Ozaki, M ; Vandegaer, K ; Georgakopoulos, D ; Harrison, R W ; Kass, D A ; Hare, J M. / cGMP-independent inotropic effects of nitric oxide and peroxynitrite donors: potential role for nitrosylation. I: American Journal of Physiology: Heart and Circulatory Physiology. 2000 ; Vol. 279, Nr. 4. s. 1982-1988.

RIS

TY - JOUR

T1 - cGMP-independent inotropic effects of nitric oxide and peroxynitrite donors: potential role for nitrosylation

AU - Paolocci, N

AU - Ekelund, Ulf

AU - Isoda, T

AU - Ozaki, M

AU - Vandegaer, K

AU - Georgakopoulos, D

AU - Harrison, R W

AU - Kass, D A

AU - Hare, J 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 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.

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 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.

KW - 3-morpholinosydnonimine

KW - myocardial contractility

KW - cyclic nucleotides

KW - superoxide dismutase

KW - glutathione

KW - 1H-(1

KW - 4) oxadiazolo-(4

KW - 2

KW - 3

KW - -a)quinoxalin-1-one

KW - guanosine 3'

KW - 5'-cyclic monophosphate

M3 - Article

VL - 279

SP - 1982

EP - 1988

JO - American Journal of Physiology - Heart and Circulatory Physiology

T2 - American Journal of Physiology - Heart and Circulatory Physiology

JF - American Journal of Physiology - Heart and Circulatory Physiology

SN - 1522-1539

IS - 4

ER -