title: Peroxynitrite is a positive inotropic agent in atrial and ventricular fibres of the frog heart.
abstract: 1. 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. 2. 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. 3. 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. 4. 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. 5. 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 microM), the guanylyl cyclase inhibitor. 6. The positive inotropic effects of SIN-1 and OONO- were not modified by hydroxyl radical scavengers, such as dimethyl-thio-urea (DMTU; 10 mM). 7. The positive inotropic effect of SIN-1 (100 microM) 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 mM), or a sodium-potassium pump inhibitor (ouabain 10 microM). 8. 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.
authors.affiliation: INSERM U-446, Laboratoire de Cardiologie Cellulaire et Moleculaire, Universite Paris-Sud, Faculte de Pharmacie, Châtenay-Malabry, France. michel.chesnais@cep.u-psud.fr
authors.forename: J M
authors.initials: JM
authors.lastname: Chesnais
authors.forename: R
authors.initials: R
authors.lastname: Fischmeister
authors.forename: P F
authors.initials: PF
authors.lastname: Mery
mesh_terms: D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D016275:Atrial Function; D002374:Catalase / Q000494:pharmacology; D006152:Cyclic GMP / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D006325:Heart Atria / Q000187:drug effects; D006352:Heart Ventricles / Q000187:drug effects; D017665:Hydroxyl Radical / Q000378:metabolism; D008981:Molsidomine / Q000031:analogs & derivatives / Q000494:pharmacology; D018485:Muscle Fibers, Skeletal / Q000187:drug effects* / Q000201:enzymology; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000166:cytology*; D009566:Nitrates / Q000494:pharmacology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D010069:Oxadiazoles / Q000494:pharmacology; D016877:Oxidants / Q000494:pharmacology*; D011810:Quinoxalines / Q000494:pharmacology; D011893:Rana esculenta; D012964:Sodium / Q000494:pharmacology; D019831:Sodium-Calcium Exchanger / Q000378:metabolism; D016276:Ventricular Function
chemical_list: C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D000634:Aminoquinolines; D004791:Enzyme Inhibitors; D009566:Nitrates; D020030:Nitric Oxide Donors; D010069:Oxadiazoles; D016877:Oxidants; D011810:Quinoxalines; D019831:Sodium-Calcium Exchanger; C039642:peroxynitric acid; D017665:Hydroxyl Radical; C002385:linsidomine; C041715:6-anilino-5,8-quinolinedione; D012964:Sodium; D008981:Molsidomine; D002374:Catalase; D006162:Guanylate Cyclase; D006152:Cyclic GMP