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Peroxynitrite is a positive inotropic agent in atrial and ventricular fibres of the frog heart

Abstract : We report opposite inotropic effects of NO donors in frog cardiac fibres. The negative effect, elicited by either 3morpholinosydnonimine (SIN_1) or SnitrosoNacetylpenicillamine (SNAP), involved cyclic GMP (cGMP) production. However, SIN_1, unlike SNAP, could elicit a positive effect, in a superoxide dismutase (SOD)sensitive manner. SIN_1, unlike SNAP, can release both NO and superoxide anion, the precursors of peroxynitrite (OONO¦). The role of these messengers was examined. Catalase did not reduce the positive inotropic effect of SIN_1. Thus, a conversion of superoxide anion into hydrogen peroxide was not involved in this effect. In addition, catalase did not modify the negative effects of SIN_1 plus SOD, or SNAP plus SOD. LY 83583, a superoxide anion generator, elicited a positive inotropic effect, like SIN_1. The effect of LY 83583 was additive to the negative effects of SIN_1 or SNAP, and to the positive effect of SIN_1. Thus, superoxide anion generation, per se, did not account for the positive effect of SIN_1. Authentic peroxynitrite (OONO¦), but not mockOONO (negative control plus decomposed OONO¦), exerted a dramatic positive inotropic effect in cardiac fibres. The effect of OONO¦ was larger in atrial fibres, as compared with ventricular fibres. The positive effect of OONO¦ was not additive with that of SIN_1, suggesting a common mechanism of action. In contrast, the effects of either OONO¦ or SIN_1 were additive with the negative inotropic effect of SNAP. Furthermore, the effect of OONO¦, like that of SIN_1, was not antagonized by 1H[1,2,4]xidiazolo[4,3a] quinoxaline1one (ODQ; 10 ìÒ), the guanylyl cyclase inhibitor. The positive inotropic effects of SIN_1 nd OONO¦ were not modified by hydroxyl radical scavengers, such as dimethylthiourea (DMTU; 10 mÒ). The positive inotropic effect of SIN_1 (100 ìÒ) was abolished in sodium free solutions, a treatment that eliminates the activity of the sodium—calcium exchanger. In contrast, the effect of SIN_1 was unchanged by a potassium channel inhibitor (tetraethylammonium, 20 mÒ), or a sodium—potassium pump inhibitor (ouabain 10 ìÒ). We conclude that OONO¦ is a positive inotropic agent in frog cardiac fibres. The generation of OONO¦ accounts for the positive inotropic effect of SIN_1. OONO¦ itself was responsible for the positive inotropic effect, and appeared to modulate the activity of the sodium—calcium exchanger.
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https://hal-universite-paris-saclay.archives-ouvertes.fr/hal-03612168
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Submitted on : Thursday, March 17, 2022 - 3:26:51 PM
Last modification on : Wednesday, March 23, 2022 - 3:34:25 AM
Long-term archiving on: : Saturday, June 18, 2022 - 7:28:50 PM

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Jean-Michel Chesnais, Rodolphe Fischmeister, Jean‐michel Chesnais, Pierre‐françois Méry. Peroxynitrite is a positive inotropic agent in atrial and ventricular fibres of the frog heart. The Journal of Physiology, Wiley, 1999, 521 (2), pp.375-388. ⟨10.1111/j.1469-7793.1999.00375.x⟩. ⟨hal-03612168⟩

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