RESUMO
Ventricular fibrillation (VF) remains a major cause of death in the industrialized world. Alternans (a period-doubling bifurcation of cardiac electrical activity) have recently been causally linked to the progression from ventricular tachycardia (VT) to VF, a more spatiotemporally disorganized electrical activity. In this paper, we show how alternans and thus VT degenerate to chaos via multiple, specific dynamical routes, largely associated with spatial components of VF dynamics, explaining failures of many recently proposed antiarrhythmic drugs. Identification of dynamical mechanisms for the onset of VF should lead to the design of future experiments and consequently to more effective antiarrhythmic drugs.
Assuntos
Fibrilação Ventricular/fisiopatologia , Potenciais de Ação , Antiarrítmicos , Arritmias Cardíacas/tratamento farmacológico , Progressão da Doença , Eletrofisiologia , Humanos , Taquicardia Ventricular/tratamento farmacológico , Taquicardia Ventricular/fisiopatologia , Fibrilação Ventricular/tratamento farmacológicoRESUMO
Previously we have shown that both insufficient (combined with vitamin E deficiency) and excess intake of selenium (Se) impairs isoproterenol (ISO)-induced contractions of rat papillary muscle. In the present study, we used patch-clamp and biochemical techniques to investigate mechanisms of this effect in rats fed a Se- and vitamin E-deficient, a Se-excess or a normal diet. Whole-cell configuration of patch-clamp technique was used to investigate L-type Ca(2+) currents (I(Ca,L)) and their regulation by beta-adrenergic receptor stimulation in enzymatically isolated single rat ventricular myocytes. Alteration of Se and vitamin E intake did not affect peak I(Ca,L), but the threshold potential of activation was significantly different among groups. Maximal I(Ca,L) responses to ISO were depressed in both experimental groups, but the EC(50) values were not affected. In the Se-deficient group, basal, ISO- or forskolin-induced adenylate cyclase (AC) activity, measured in cardiac membrane preparations, was reduced when compared to the control, whereas 5' guanylyimidodphosphate (GppNHp) stimulated activity was unaffected. Decreased beta-adrenoceptor density and reduced GppNHp-induced affinity shift in ISO binding were also observed in the deficient group. No such differences were present in the excess group. These results suggest that combined Se and vitamin E deficiency interferes with beta-adrenoceptor-AC coupling, whereas excess intake of Se does not affect it. Thus, in the deficient group, the impairment of I(Ca) responses to ISO may be a result of a defect in beta-adrenoceptor-AC pathway. Impairment of I(Ca) response in the excess group, however, appears to have a different underlying mechanism.
Assuntos
Adenilil Ciclases/metabolismo , Canais de Cálcio Tipo L/metabolismo , Miocárdio/metabolismo , Receptores Adrenérgicos beta/metabolismo , Selênio/administração & dosagem , Vitamina E/administração & dosagem , Agonistas Adrenérgicos beta/farmacologia , Animais , Canais de Cálcio Tipo L/fisiologia , Membrana Celular/metabolismo , Dieta , Condutividade Elétrica , Feminino , Subunidades alfa Gs de Proteínas de Ligação ao GTP/metabolismo , Isoproterenol/farmacologia , Cinética , Masculino , Miocárdio/citologia , Ratos , Ratos Wistar , Selênio/farmacologia , Vitamina E/farmacologia , Deficiência de Vitamina E/metabolismoRESUMO
The present study was designed to investigate and compare the effects of dietary antioxidants on the mechanical characteristics of the rat heart. Both sex weanling rats were fed for 12 to 14 weeks a standardized selenium (Se)- and vitamin E-deficient diet, a Se-excess diet, or a control diet. Deficiency or toxicity of Se was verified by direct (tissue Se analysis and histopathological investigations) methods. The hearts of both experimental groups revealed some alterations in contractile performance with increased heart rate and coronary perfusion pressure. The average peak contractile force of the electrically stimulated papillary muscle measured in both experimental groups was not significantly different from the control values. When expressed as a percentage, the maximal increase in the peak contractile force of papillary muscle (PCF) that was obtained with 100 nM isoproterenol, respectively, was less in both experimental groups (26% in PCF of deficient group; 34% in PCF of rich group) than in the control group (80% in PCF). A decreased stimulation of contractile force of papillary muscle strips by a beta-adrenergic agonist seems to be in agreement with possible alterations in the response to inotropic agents due to a modification of the receptor function.
Assuntos
Antioxidantes/farmacologia , Dieta , Coração/efeitos dos fármacos , Selênio/farmacologia , Vitamina E/farmacologia , Animais , Interações Medicamentosas , Estimulação Elétrica , Feminino , Testes de Função Cardíaca , Isoproterenol/farmacologia , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Contração Muscular/efeitos dos fármacos , Miocárdio/patologia , Músculos Papilares/efeitos dos fármacos , Músculos Papilares/metabolismo , Músculos Papilares/patologia , Ratos , Ratos Wistar , Selênio/deficiência , Selênio/toxicidade , Deficiência de Vitamina E/fisiopatologiaRESUMO
In this study, we demonstrated that sodium selenite with high doses (> or = 10(-3) M) were potent in inducing a contracture type effect on heart and smooth muscles. Selenite (Se), at a concentration of 10(-3) M, caused a contracture effect in heart preparations. Also, low Se concentrations did not have any significant effect. Although low concentrations of Se (> or = 10(-5) M) had a biphasic effects on acetylcholine (ACh) induced and spontaneous ileum contractions, 10(-3) M selenite enhanced once more a contracture effect similar to that of the heart preparations. Replacing Ca2+ concentration of the bathing solution by twofold Ca2+ or Ca2+-free did not change the effects of selenite (10(-5) M) on contractility of ileum preparations. In vascular smooth muscle, low concentration of selenite (< 10(-4)) had no significant effects on KCl, and phenylephrine-induced contractions and acetylcholine-induced endothelium-dependent relaxations of isolated rabbit aorta. However, the contractions induced by phenylephrine and the relaxations induced by acetylcholine in rabbit aorta were depressed significantly by high concentration of selenite (10(-3) M). The results obtained by selenite exposure from these three different types of tissue preparations first suggest that the high concentration of selenite exposure induces some alterations in the functions of muscles and endothelium in a tissue- and dose-dependent manner. Second, this observed irreversible type of dysfunction of tissues induced by 10(-3) M selenite is not directly dependent on the Ca2+ entrance into the cytosol, but might be induced by the increase of intracellular Ca2+ with the disturbance of Ca2+ regulation.
Assuntos
Contração Muscular/efeitos dos fármacos , Músculo Liso Vascular/fisiologia , Músculo Liso/fisiologia , Contração Miocárdica/efeitos dos fármacos , Selenito de Sódio/farmacologia , Acetilcolina/farmacologia , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/fisiologia , Endotélio Vascular/fisiologia , Feminino , Átrios do Coração , Íleo , Técnicas In Vitro , Masculino , Músculo Liso/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Fenilefrina/farmacologia , Cloreto de Potássio/farmacologia , Coelhos , RatosRESUMO
OBJECTIVE: The study aimed at characterizing the effects of selenite, known for its reactivity with thiols, on cardiac contractility and excitation-contraction coupling. METHODS: The inotropic effects of selenite were studied on rat papillary muscles. Freshly isolated rat ventricular myocytes were used to determine the selenite-induced alterations in thiol contents, free Ca2+ levels (in fura-2 loaded cells), Ca2+ currents and contractile properties of skinned cells. RESULTS: Selenite, at concentrations > or = 0.1 mM, affected muscle contractions by inducing a transient positive inotropic effect (up to 120 +/- 3% of control in 1 mM selenite) followed by a gradual decline of developed tension together with an increase in resting tension (respectively to 37 +/- 3 and 166 +/- 5% of their control values after 20 min exposure). These changes, irreversible on washout, could be reversed by the disulfonic reducing agent dithiothreitol (DTT, 1 mM). Lowering temperature from 35 degrees to 22 degrees C or preincubating the muscles with the disulfonic stilbene SITS (0.2 mM) completely prevented the selenite-induced transient positive inotropy and rise in resting tension. In isolated myocytes, 10 min exposure to 1 mM selenite induced a 40 +/- 9% decrease of total sulfhydryl content. At this concentration, selenite rapidly caused a rise of basal [Ca2+]i together with a diminution of the Ca2+ spike amplitude (respectively to 165 +/- 15 and 45 +/- 9% of their control values after 5 min exposure). In addition, selenite significantly enhanced at each Ca2+ concentration the force generated by skinned myocytes. Ca2+ currents, measured at 22 degrees C, decreased by 28 +/- 8% in the presence of 1 mM selenite. These effects were reversed by DTT. CONCLUSIONS: The results demonstrate that selenite, through alterations of cellular thiol redox status, induced a dual action on muscle contraction that can be imputed to a combined action on Ca2+ channels, Ca2+ transporters and contractile proteins. Extracellular negative effects of selenite are due to a partial reduction of Ca2+ current magnitude. Intracellular effects are mediated both by a diminution of Ca2+ handing by intracellular organelles and by a sensitization of the contractile to Ca2+ ions. The results further indicate that selenite uptake into the cardiac cells occurs mainly through the temperature-sensitive anion exchanger.