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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