Cardiovascular responses to intravenous injection of a novel isoindolin-1-one derivate in conscious rats

An isoindolin-1-one derivate, JM-1232(−), was recently developed as a sedative and hypnotic agent with a strong affinity for the central benzodiazepine binding site of gamma-aminobutyric acidA (GABAA) receptors. The purpose of this study was to examine the effects of JM-1232(−) on the cardiovascular and sympathetic functions of conscious rats. We investigated the effect of JM-1232(−) on the mean arterial pressure (MAP), heart rate (HR), baroreflex activity, and plasma catecholamine levels in conscious rats. The intravenous (i.v.) administration of JM-1232(−) (0.1, 0.3, and 1.0 mg/kg/min) for 20 min decreased MAP and increased HR in intact rats. In sinoaortic denervated (SAD) rats, JM-1232(−) decreased MAP and HR. A decrease in MAP induced by JM-1232(−) was prevented by pre-treatment with hexamethonium and enhanced by SAD. An increase in HR induced by JM-1232(−) was prevented by pre-treatment with atropine, propranolol, or hexamethonium. A decrease in MAP and an increase in HR induced by JM-1232(−) were antagonized by co-administration of flumazenil. A high dose of JM-1232(−) decreased the plasma norepinephrine concentration, and a subdepressor dose of JM-1232(−) did not affect the baroreceptor reflex. These results show that the i.v. administration of JM-1232(−) decreased MAP mediated by benzodiazepine–GABAA receptors.