RESUMO
The effect of SR 33805, a novel calcium entry blocker, on calcium overload was studied in six vascular beds in rat. Fantofarone, a parent compound, and verapamil were used as reference calcium entry blockers. Calcium overload induced with a single dose (300,000 IU, i.m. of vitamin D3) was measured by means of atomic absorption and histological techniques. From the time-course of calcium overload, a treatment period of 3 days was selected to determine the effects of drug treatment. The compounds were given orally twice a day in the following dose ranges: SR 33805 2-100 mg/kg, fantofarone 10-300 mg/kg, verapamil 100 mg/kg. SR 33805 significantly decreased the calcium content beginning at the dose of 2 mg/kg in the thoracic aorta, 5 mg/kg in the mesenteric artery and 30 mg/kg in the heart. Fantofarone and verapamil had the same effect at the dose of 100 mg/kg. Histological assessment of the heart revealed that lesions appearing in the tissue adjacent to the arteries were significantly diminished by treatment with SR 33805 at a dose which produced a significant decrease in the arterial calcium content. Thus, SR 33805 can inhibit both calcium overload and its deleterious consequences and its actions are evident at doses as low as 2 mg/kg.
Assuntos
Calcinose/tratamento farmacológico , Bloqueadores dos Canais de Cálcio/farmacologia , Cálcio/metabolismo , Doenças Cardiovasculares/tratamento farmacológico , Colecalciferol/administração & dosagem , Indóis/farmacologia , Sulfonas/farmacologia , Animais , Aorta Torácica/química , Aorta Torácica/metabolismo , Calcinose/metabolismo , Cálcio/análise , Doenças Cardiovasculares/metabolismo , Colecalciferol/metabolismo , Relação Dose-Resposta a Droga , Indolizinas/farmacologia , Masculino , Artérias Mesentéricas/química , Artérias Mesentéricas/metabolismo , Miocárdio/química , Miocárdio/metabolismo , Fenetilaminas/farmacologia , Ratos , Ratos Sprague-Dawley , Coloração e Rotulagem , Verapamil/farmacologiaRESUMO
The effect of SR 33557, a novel calcium entry blocker, on calcium overload, and regulation of calcium channels and beta-adrenergic receptors was investigated in the rat heart. Calcium overload and infarct-like lesions were produced by a large dose of isoproterenol (40 mg/kg, subcutaneously) to rats. Calcium overload was maximal 8 hours after administration of isoproterenol (control: 5.7 mmol Ca2+/kg dry weight, isoproterenol: 34.9 mmol Ca2+/kg dry weight). At that time, a decrease in the total number of beta-adrenergic receptors (-27%) and calcium channels (-20% and -23%) was observed. Intravenous injection of SR 33557 (0.5-10 mg/kg), 30 minutes before administration of isoproterenol, attenuated the increase in calcium content in a dose-related manner, such that 5 mg/kg SR 33557 reduced calcium overload by 50%. At this dose, SR 33557 had no effect on the number of beta-adrenergic receptors but prevented the decrease in the number of calcium channels. The total number of binding sites and the dissociation constants of each radioligand were estimated from saturation isotherms. The dissociation constants were unchanged when animals given isoproterenol or SR 33557 and isoproterenol were compared to the control group. The results indicate that SR 33557 is able to protect against the calcium overload induced by sympathetic over-stimulation. This over-stimulation of the sympathetic system causes a down-regulation of the number of active beta-adrenergic receptors and calcium channels. The down-regulation of calcium channels is selectively reduced by earlier administration of SR 33557.