Endothelin-1 elicited a positive inotropic effect (PIE) on isolated rabbit, guinea pig, and rat but not on dog ventricular myocardium. Specific high-affinity binding of 125I-labeled endothelin-1 was detected in the ventricular membrane fraction of these species. Maximal binding capacity was the highest in the rabbit, lowest in the dog, and in between in the guinea pig and rat; this rank order corresponds roughly to the effectiveness of endothelin-1 in producing a PIE. There was no difference in the potency or efficacy for the PIE of the endothelin isoforms endothelin-1, -2, and -3 in the rabbit papillary muscle. A tumor-promoting phorbol ester, phorbol 12,13-dibutyrate, inhibited selectively the PIE and the accumulation of [3H]inositol monophosphate induced by endothelin-1 as well as those of myocardial alpha 1-adrenoceptor stimulation in a concentration that did not (10(-8) M) or only slightly (10(-7) M) reduced the PIE of BAY K 8644. Phorbol 12,13-dibutyrate did not affect the specific binding of 125I-labeled endothelin-1 in the ventricular membrane fraction of the rabbit. The present findings indicate that the characteristics of the endothelin-induced PIE in mammalian ventricular myocardium are similar to those of myocardial alpha 1-adrenoceptor activation that may involve phosphoinositide hydrolysis. The receptor density and the PIE of endothelin on mammalian cardiac muscle show a wide range of variation among species.

Species-dependent variations of myocardial ca1-adrenoceptor-mediated positive inotropic effects of epinephrine were assessed in relation to characteristics of ael-receptor bindings and acceleration of phosphatidylinositol metabolism in the isolated rat, rabbit, and dog ventricular myocardium. Epinephrine in the presence of the /3-adrenoceptor antagonist bupranolol (10-6 M) elicited a positive inotropic effect through activation of ael-adrenoceptors in rat and rabbit, whereas in dog ventricular myocardium, bupranolol abolished the positive inotropic effect of epinephrine.

Methylprednisolone improved the cardiac index, intriguingly, in patients with long term catecholamine treatment in circulatory shock. Myocardial beta-adrenergic receptor also increased in number after the administration of methylprednisolone. However, the hemodynamic improvement caused by methylprednisolone was not observed in patients without beta-adrenergic down-regulation.

The positive inotropic effect (PIE) of endothelin (ET) isoforms, ET-1 and ET-3, was similar in that 1) the PIE was associated with prolongation of isometric contractions, 2) the maximal response was approximately 60% of that to isoproterenol (Isomax), 3) the PIE was associated with acceleration of PI hydrolysis, and 4) it was selectively antagonized by phorbol 12,13-dibutyrate. Because the concentration-response curve for ET-1 was biphasic (whereas that for ET-3 was monophasic), ET-1 had a PIE greater than ET-3 up to 10(-8) M. ET-1 induced a PIE at 3 x 10(-14) M and higher, which reached a plateau of 10-20% of Isomax at 10(-12) M (first phase); the curve became steeper at 10(-9) M and higher (second phase), achieving the maximal response at 10(-7) M to 3 x 10(-7) M. An ETA-selective antagonist, BQ-123, did not affect the PIE of ET-1 up to 10(-7) M; it abolished the first phase at 10(-6) M but did not affect the second phase. BQ-123 at 10(-8) to 10(-6) M antagonized the PIE of ET-3, [Thr2]sarafotoxin S6b, and [Glu9]sarafotoxin S6b in a concentration-dependent manner. The PIE of ET-3 was abolished by 10(-6) M BQ-123. An ETB-selective partial agonist IRL-1620 neither elicited a PIE nor affected the PIE of ET-3. These findings indicate that the PIE of ET receptor agonists on rabbit ventricular myocardium cannot be totally explained by occupancy of the ETA or ETB receptor.

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.