Potent inhibitory action of chlorethylclonidine on the positive inotropic effect and phosphoinositide hydrolysis mediated via myocardial alpha1-adrenoceptors in the rabbit ventricular myocardium

Abstract

The influence of the alpha 1b-adrenoceptor-selective antagonist chlorethylclonidine on the alpha 1-adrenergic positive inotropic effect and the phosphoinositide hydrolysis induced by phenylephrine was investigated in the rabbit ventricular myocardium. Pretreatment of membrane fractions derived from the rabbit ventricular muscle with 10(-5) mol/l chlorethylclonidine decreased the specific binding of [3H]prazosin (at a saturating concentration of 10(-9) mol/l) from the control value of 11.27 +/- 0.48 to 4.18 +/- 1.87 fmol/mg protein. The inhibition by adrenaline of the binding of [3H]prazosin (slope factor and affinity) was not affected by chlorethylclonidine. The positive inotropic effect of phenylephrine (in the presence of 3 x 10(-7) mol/l bupranolol) was inhibited by chlorethylclonidine in a concentration-dependent manner (10(-7)-10(-5) mol/l) and abolished by 10(-5) mol/l chlorethylclonidine. The concentration of chlorethylclonidine to inhibit the phenylephrine-induced maximum response to 50% was 2.4 x 10(-6) mol/l. The accumulation of [3H]inositol monophosphate and [3H]inositol trisphosphate induced by 10(-5) mol/l phenylephrine was inhibited by chlorethylclonidine in the same concentration range. These findings indicate that the myocardial alpha 1-adrenoceptors mediating a positive inotropic effect in the rabbit ventricular myocardium may belong to the chlorethylclonidine-sensitive alpha 1b-subtype, and that the subcellular mechanism of action involve phosphoinositide hydrolysis.

Sustained negative inotropism mediated by α‐adrenoceptors in adult mouse myocardial developmental conversion from positive response in the neonate

“…In the present study, both the positive and negative inotropic responses to phenylephrine were antagonized by prazosin but not by yohimbine indicating the involvement of ml-receptors. This was further confirmed with the observation that the concentration-response curves for phenylephrine were shifted to the right by 5-methylurapidil (Figures 2b, 3b (Rokosh & Sulakhe, 1991), while the O1B-subtype mediates responses of the rabbit myocardium (Takanashi et al, 1991). In the present study, both the positive and negative responses to phenylephrine in neonatal and adult mouse myocardia, respectively, were sensitive to WB4101 and 5-methylurapidil (Figures 2, 3), indicating that the receptors mediating both effects are of the alA-subtype.…”

Functional studies on α1‐adrenoceptor subtypes mediating inotropic effects in rat right ventricle

“…Since the cellular localization of the various adrenoceptor subtypes within the myocardium is unclear, a more detailed understanding of this interaction will probably require the use of a cell line co-expressing the subtypes. On the other hand such MIA/a1B-adrenoceptor cross-talk may not occur in all species since chloroethylclonidine treatment almost completely abolishes the MI-adrenoceptor-mediated inotropic effects in rabbit myocardium (Takanashi et al, 1991).…”

Signal Transduction and Ca2+ Signaling in Intact Myocardium

“…Concerning the α-adrenoceptor subtype involved in regulation of Ca 2+ signaling and contractile activity in the rabbit ventricular myocardium, the α 1B -subtype is predominant (approximately 80%), which is susceptible to chlorethylclonidine (56,59). Other subtypes, including the α 1A -subtype, which is inhibitable with WB 4101, 5-methylurapidil (57), (+)-niguldipine (58), and the α 1D -subtype, which is susceptible to BMY 7378 (62), contribute partially to the contractile regulation in the rabbit.…”