Mechanism of the negative inotropic effects of α1-adrenoceptor agonists on mouse myocardium

Abstract

This study was done to identify the mechanism of the α1-adrenoceptor (AR) mediated negative inotropic effects of phenylephrine (PE) on adult mouse myocardium. As reported by others, we also found that the nonselective α1AR agonist PE produced a negative inotropic effect on ventricular strips from adult mice that was inhibited by the α1AAR antagonist 5-methylurapidil (5MU) but not by the α1BAR antagonist chloroethylclonidine (CEC) or the α1DAR antagonist BMY 7378. The selective α1AAR agonist A61603 also produced a negative inotropic effect, which was antagonized by 5MU. Phorbol 12,13-dibutyrate (activator of all PKC isoforms) mimicked the negative inotropic responses to PE and A61603. The negative inotropic effects of PE were inhibited by bisindolylmaleimide (inhibitor of all PKC isoforms) but not by Gö 6976 (inhibitor of Ca2+-dependant PKC). Rottlerin, an inhibitor of Ca2+-independent PKCδ, antagonized the negative inotropic effects of PE and A61603. PE and A61603 increased the translocation of PKCδ, which was prevented by rottlerin. These data suggest that the α1AR-mediated negative inotropy on adult mouse myocardium is signaled by Ca2+-independent PKCδ.Key words: phorbol 12,13-dibutyrate, 5-methylurapidil, BMY 7378, chloroethylclolidine, Ca2+-dependant PKC isoforms, α1A-adrenoceptor.