RESUMO
Zinc is one of the most important essential trace elements. It is involved in more than 300 enzyme systems and is an indispensable participant in many biochemical processes. Zinc deficiency causes a number of disorders in the human body, the main ones being the delay of growth and puberty, immune disorders, and cognitive dysfunctions. There are over two billion people in the world suffering from zinc deficiency conditions. Acyzol, a zinc-containing medicine, developed as an antidote against carbon monoxide poisoning, demonstrates a wide range of pharmacological activities: Anti-inflammatory, reparative, detoxifying, immunomodulatory, bacteriostatic, hepatoprotective, adaptogenic, antioxidant, antihypoxic, and cardioprotective. The presence of zinc in the composition of Acyzol suggests the potential of the drug in the treatment and prevention of zinc deficiency conditions, such as Prasad's disease, immune system pathology, alopecia, allergodermatoses, prostate dysfunction, psoriasis, stomatitis, periodontitis, and delayed mental and physical development in children. Currently, the efficiency of Acyzol in the cases of zinc deficiency is shown in a large number of experimental studies. So, Acyzol can be used as a highly effective drug for pharmacologic therapy of a wide range of diseases and conditions and it opens up new perspectives in the treatment and prevention of zinc deficiency conditions.
Assuntos
Distúrbios Nutricionais/tratamento farmacológico , Distúrbios Nutricionais/etiologia , Oligoelementos/deficiência , Acetato de Zinco/uso terapêutico , Zinco/deficiência , Animais , Estudos Clínicos como Assunto , Avaliação Pré-Clínica de Medicamentos , Humanos , Imidazóis/química , Camundongos , Distúrbios Nutricionais/diagnóstico , Distúrbios Nutricionais/prevenção & controle , Resultado do Tratamento , Acetato de Zinco/química , Acetato de Zinco/farmacologiaRESUMO
The compound SS-68 has been selected among numerous new derivatives of indole and demonstrated antiarrhythmic effects in animal models. The present study concerns several aspects of SS-68 safety and efficacy as a potential antiarrhythmic drug. The first estimation of atrioventricular conduction in mammalian heart under SS-68 has been carried out; effects of SS-68 in Purkinje fibers and myocardium of pulmonary veins have been investigated. The drug weakly affects cardiac atrioventricular conduction: only high concentrations of SS-68 (≥10 µmol/L) significantly decrease this parameter. Also, the drug weakly affects Purkinje fibers automaticity, but effectively alters action potential waveform in Purkinje fibers in a concentration-dependent manner. SS-68 (0.1-100 µmol/L) failed to induce any early or delayed afterdepolarizations in Purkinje fibers both in basal conditions and under provocation of proarrhythmic activity by norepinephrine (NE). Moreover, 10 µmol/L SS-68 suppressed NE-induced extra-beats and rapid firing in Purkinje fibers. In pulmonary veins only high concentrations of SS-68 significantly increased action potential duration, while lower concentrations (0.1-1 µmol/L) were ineffective. Also, 0.1-100 µmol/L SS-68 was unable to elicit arrhythmogenic alternations of action potential waveform in pulmonary veins. In conclusion, SS-68 has no proarrhythmic effects, such as afterdepolarizations or abnormal automaticity in used experimental models.
Assuntos
Antiarrítmicos/farmacologia , Coração/efeitos dos fármacos , Indóis/farmacologia , Veias Pulmonares/efeitos dos fármacos , Ramos Subendocárdicos/efeitos dos fármacos , Potenciais de Ação/efeitos dos fármacos , Animais , Coração/fisiologia , Sistema de Condução Cardíaco/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Técnicas In Vitro , Masculino , Veias Pulmonares/fisiologia , Ramos Subendocárdicos/fisiologia , Coelhos , Ratos WistarRESUMO
SS-68 is a derivative of indole, which demonstrated strong antiarrhythmic effects not associated with significant QT prolongation in dog models of atrial fibrillation. Therefore, SS-68 was proposed as a new antiarrhythmic drug and the present study is the first describing its effects on action potentials (APs) configuration and elucidating the ionic mechanisms of these effects. Sharp microelectrodes were used to record APs in isolated preparations of mouse atrial and ventricular myocardium. In both types of myocardium 10(-6) M SS-68 produced reduction of AP duration, 3 × 10(-6) M failed to alter AP waveform and 10(-5) - 3 × 10(-5) M prolonged APs. Sensitivity of main ionic currents to SS-68 was determined using whole-cell patch clamp. Transient potassium current Ito was slightly inhibited by SS-68 with IC50 = 1.43 × 10(-4) M. IKur was more sensitive with IC50 = 1.84 × 10(-5) M. Background inward rectifier showed very low sensitivity to SS-68 - only 10(-4) M SS-68 caused significant reduction of IK1. ICaL was significantly inhibited by 10(-6)M - 3 × 10(-5) M SS-68. The IC50 value for the ICaL was 1.84 × 10(-6) M. Thus, main ionic currents of mouse cardiomyocytes are inhibited by SS-68 in the following order of potency: ICaL > IKur > Ito > IK1. While lower concentration of SS-68 shorten APs via suppression of ICaL, higher concentrations inhibit K(+)-currents leading to APs prolongation.
Assuntos
Potenciais de Ação/efeitos dos fármacos , Antiarrítmicos/farmacologia , Indóis/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/fisiologia , Animais , Células Cultivadas , Relação Dose-Resposta a Droga , Átrios do Coração , Ventrículos do Coração , Íons/química , Camundongos , Microeletrodos , Miócitos Cardíacos/metabolismo , Potássio/metabolismoRESUMO
Ageing is a complex process which affects all systems of the organism and therefore changes the environment where the heart is working. In this study we demonstrate the ageing-related changes in the mechanisms of parasympathetic regulation of mammalian heart. Electrophysiological effects produced by selective activation of M3-cholinoreceptors were compared in isolated cardiac preparations from young adult (4 months), adult (1 year) and ageing (2 years) rats using sharp glass microelectrode technique. M3-receptors were activated with muscarinic agonist pilocarpine (10-5M) in the presence of selective M2 antagonist AQ-RA741 (10-7M). In atrial and ventricular myocardium from young rats M3 stimulation induced shortening of action potentials(APs), while no significant effect was observed in both elder groups. The main mechanism of M3-induced AP shortening is inhibition of L-type Ca2+ current, estimated using whole-cell patch-clamp. It was negligible in atrial myocytes from ageing animals in comparison with young rats. The loss of sensitivity to stimulation of M3-receptors is due to decrease in M3 gene expression, shown by RT-PCR both in atrial and ventricular samples from ageing rats. Thus, in ageing rat heart M3-receptors are down-regulated and not involved in regulation of electrical activity.
RESUMO
Urotensin II (UT II) is an important factor of cellular homeostasis. This regulatory peptide is involved in the pathophysiology of many disorders. For example, it plays an important role in the pathogenesis of acute and chronic diseases, stressful and adaptive reactions of the body, in the development of cardiovascular pathologies, metabolic syndrome, inflammation, liver cirrhosis, renal failure, diabetic nephropathy, reproductive dysfunction, progression of psychosomatic, psychoendocrinal and psychiatric disorders. In this concern, the involvement of UT II in the pathophysiology of many processes determines the perspectives for the development of blockers of urotensin receptors for the treatment of the aforementioned diseases. It is important that even today this kind of perspective is feasible due to the synthesis of a series of GPR14 blockers. The objective of this review is to discuss current molecular mechanisms of biological activity, regulatory functions of UT II, its role in the pathogenesis of different nosologies, as well as analysis of the possible routes of exposure to GPR14 as potential therapeutic targets.
Assuntos
Urotensinas/metabolismo , Animais , Aterosclerose/tratamento farmacológico , Aterosclerose/metabolismo , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/metabolismo , Tratamento Farmacológico , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/metabolismo , Homeostase , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/metabolismo , Terapia de Alvo Molecular , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Insuficiência Renal/tratamento farmacológico , Insuficiência Renal/metabolismoRESUMO
Electrophysiological effects produced by selective activation of M3 cholinoreceptors were studied in isolated left atrium preparations from rat using the standard sharp glass microelectrode technique. The stimulation of M3 receptors was obtained by application of muscarinic agonist pilocarpine (10-5 M) in the presence of selective M2 antagonist methoctramine (10-7 M). Stimulation of M3 receptors induced marked reduction of action potential duration by 14.4 ± 2.4% and 16.1 ± 2.5% of control duration measured at 50 and 90% of repolarization, respectively. This effect was completely abolished by selective M3 blocker 4-DAMP (10-8 M). In isolated myocytes obtained from the rat left atrium, similar pharmacological stimulation of M3 receptors led to suppression of peak L-type calcium current by 13.9 ± 2.6% of control amplitude (measured at +10 mV), but failed to affect K+ currents I to, I Kur, and I Kir. In the absence of M2 blocker methoctramine, pilocarpine (10-5 M) produced stronger attenuation of I CaL and induced an increase in I Kir. This additive inward rectifier current could be abolished by highly selective blocker of Kir3.1/3.4 channels tertiapin-Q (10-6 M) and therefore was identified as I KACh. Thus, in the rat atrial myocardium activation of M3 receptors leads to shortening of action potentials via suppression of I CaL, but does not enhance the major potassium currents involved in repolarization. Joint stimulation of M2 and M3 receptors produces stronger action potential shortening due to M2-mediated activation of I KACh.
Assuntos
Canais de Cálcio Tipo L/metabolismo , Regulação para Baixo , Átrios do Coração/metabolismo , Canais de Potássio Corretores do Fluxo de Internalização/metabolismo , Receptor Muscarínico M3/metabolismo , Potenciais de Ação/efeitos dos fármacos , Animais , Animais não Endogâmicos , Canais de Cálcio Tipo L/química , Fármacos Cardiovasculares/farmacologia , Células Cultivadas , Regulação para Baixo/efeitos dos fármacos , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Escina/farmacologia , Átrios do Coração/citologia , Átrios do Coração/efeitos dos fármacos , Técnicas In Vitro , Camundongos , Microeletrodos , Agonistas Muscarínicos/farmacologia , Antagonistas Muscarínicos/farmacologia , Técnicas de Patch-Clamp , Bloqueadores dos Canais de Potássio/farmacologia , Canais de Potássio/agonistas , Canais de Potássio/metabolismo , Canais de Potássio Corretores do Fluxo de Internalização/agonistas , Canais de Potássio Corretores do Fluxo de Internalização/antagonistas & inibidores , Ratos , Receptor Muscarínico M3/agonistas , Receptor Muscarínico M3/antagonistas & inibidoresRESUMO
Electrophysiological effects produced by selective activation of M3 cholinoreceptors were studied in isolated left atrium preparations from rat using the standard sharp glass microelectrode technique. The stimulation of M3 receptors was obtained by application of muscarinic agonist pilocarpine (10-5 M) in the presence of selective M2 antagonist methoctramine (10-7 M). Stimulation of M3 receptors induced marked reduction of action potential duration by 14.4 ± 2.4% and 16.1 ± 2.5% of control duration measured at 50 and 90% of repolarization, respectively. This effect was completely abolished by selective M3 blocker 4-DAMP (10-8 M). In isolated myocytes obtained from the rat left atrium, similar pharmacological stimulation of M3 receptors led to suppression of peak L-type calcium current by 13.9 ± 2.6% of control amplitude (measured at +10 mV), but failed to affect K+ currents Ito, IKur, and IKir. In the absence of M2 blocker methoctramine, pilocarpine (10-5 M) produced stronger attenuation of ICaL and induced an increase in IKir. This additive inward rectifier current could be abolished by highly selective blocker of Kir3.1/3.4 channels tertiapin-Q (10-6 M) and therefore was identified as IKACh. Thus, in the rat atrial myocardium activation of M3 receptors leads to shortening of action potentials via suppression of ICaL, but does not enhance the major potassium currents involved in repolarization. Joint stimulation of M2 and M3 receptors produces stronger action potential shortening due to M2-mediated activation of IKACh (AU)
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