[Analysis of membrane current system involved in the inotropic effects mediated by alpha-adrenoceptors in the heart]

Abstract

In order to clarify the underlying mechanism of the inotropic effects mediated by alpha-adrenoceptor, changes of electrophysiological properties induced by alpha-adrenoceptor stimulation were investigated in rat and guinea-pig ventricular muscles. In the presence of atenolol (10 microM), phenylephrine increased dose-dependently the developed tension in rat papillary muscles. The time course of the positive inotropic effect produced by phenylephrine (10 microM) consisted of an initial transient positive inotropic phase, followed by a negative inotropic phase and then, a second positive inotropic phase. Phenylephrine also prolonged action potential duration (APD) and increased resting membrane potential (hyperpolarization). The APD prolongation was coincident with the positive inotropic phase, and the hyperpolarization of resting membrane potential developed with the negative inotropic phase and maintained irrelevantly to the following positive inotropic phase. The inotropic and electro-physiological responses by phenylephrine was blocked by prazosin (0.1 microM), but not by yohimbine (0.1 microM), indicating that the changes were mediated by alpha 1-adrenoceptors. Nifedipine (3 microM) abolished the positive inotropic effect and attenuated the APD prolongation. However, nifedipine failed to affect the negative inotropic effect and the hyperpolarization. The hyperpolarization was also observed in the quiscent muscles, and abolished by pretreatment with barium ion (0.5 mM), suggesting the increased potassium premeability by alpha-adrenoceptor stimulation. In the single cell voltage-clamp experiments, alpha-adrenoceptor stimulation was found to increase calcium current (ICa) and to decrease transient outward current (Ito). The changes of both currents explain the APD prolongation and the positive inotropic effect mediated by alpha-adrenoceptors. Protein Kinase C (C-Kinase) is suggested to be one of candidates for intracellular signal transduction systems during alpha-adrenoceptor stimulation. However, TPA, a stimulator of C-Kinase, failed to increase Ica, although it increased the delayed outward current (IK) in guinea-pig single cell, indicating that C-Kinase activation by alpha-adrenoceptors stimulation was not related to the positive inotropic effect. These results suggest that the ponitive inotropic effect mediated by alpha-adrenoceptors is evoked by an increase in Ica and a decrease in Ito, and the negative inotropic effect is related to the resting membrane potassium permeability. Both electro-physiological changes constitute the triphasic inotropic effect mediated by alpha-adrenoceptors in rat cardiac muscles.