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

• Published in: The Journal of physiology 1999-12, Vol.521 (2), p.375-388
• Main Authors: Chesnais, J M, Fischmeister, R, Mery, P F
• Format: Article
• Language: English
• Subjects: Aminoquinolines - pharmacology; Animals; Anura; Atrial Function; Cardiology and cardiovascular system; Catalase - pharmacology; Cyclic GMP - metabolism; Enzyme Inhibitors - pharmacology; Freshwater; Guanylate Cyclase - antagonists & inhibitors; Heart Atria - drug effects; Heart Ventricles - drug effects; Human health and pathology; Hydroxyl Radical - metabolism; Life Sciences; Molsidomine - analogs & derivatives; Molsidomine - pharmacology; Muscle Fibers, Skeletal - drug effects; Muscle Fibers, Skeletal - enzymology; Myocardial Contraction - drug effects; Myocardium - cytology; Nitrates - pharmacology; Nitric Oxide Donors - pharmacology; Original; Oxadiazoles - pharmacology; Oxidants - pharmacology; Pharmaceutical sciences; Pharmacology; Quinoxalines - pharmacology; Rana esculenta; Sodium - pharmacology; Sodium-Calcium Exchanger - metabolism; Ventricular Function
• ISSN: 0022-3751; 1469-7793
• DOI: 10.1111/j.1469-7793.1999.00375.x

We report opposite inotropic effects of NO donors in frog cardiac fibres. The negative effect, elicited by either 3-morpholino-sydnonimine (SIN-1) or S- nitroso- N- acetyl-penicillamine (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 mock-OONO − (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[4,3-a]quinoxaline-1-one (ODQ; 10 μ m ), the guanylyl cyclase inhibitor. The positive inotropic effects of SIN-1 and OONO − were not modified by hydroxyl radical scavengers, such as dimethyl-thio-urea (DMTU; 10 m m ). The positive inotropic effect of SIN-1 (100 μ m ) 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 (tetraethyl-ammonium, 20 m m ), or a sodium-potassium pump inhibitor (ouabain 10 μ m ). 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.