PKC is involved in the negative inotropic effect of alpha₁-adrenoceptor stimulation in mouse myocardium

Abstract

It is generally known that α₁-adrenoceptor stimulation shows a positive inotropic effect on mammalian myocardium. In mouse myocardium, however, we reported that an α₁-adrenoceptor stimulation showed a negative inotropic effect. In the present study, we explored the mechanism of the negative inotropic effect in mouse myocardium. We used isolated ventricular papillary muscles of mouse and simultaneously measured isometric tension and the intracellular Ca²⁺ concentration ([Ca²⁺]_i) using the aequorin method. In twitch contraction, phenylephrine (Phe) dose- dependently (1~100 μM) decreased the Ca²⁺ transient and tension. To estimate the Ca²⁺ sensitivity, tetanic contraction was produced and the relation between [Ca²⁺]_i and tension at the steady-state was measured. Phe (10 μM) decreased the Ca²⁺ sensitivity and this effect was completely blocked by prazosin (3 μM). Phorbol 12- myristate 13-acetate (PKC activator, 1 μM) decreased the Ca²⁺ transient and the Ca²⁺ sensitivity, which was almost the same as that of Phe. After PKC activation, the negative inotropic effect of Phe was not observed. The negative inotropic effect of Phe was completely blocked by calphostin C (PKC inhibitor, 1 μM). These results suggest that the negative inotropic effect of Phe in mouse myocardium is due to the decrease in the Ca²⁺ transient and the Ca²⁺ sensitivity. The activation of PKC pathway is involved in the negative inotropic effect of α₁-adrenoceptor stimulation in mouse myocardium. [Jpn J Physiol 54 Suppl:S97 (2004)]