Pharmacological characteristics of endothelin receptors in the rabbit ventricular myocardium: The nonselective endothelin receptor antagonist PD 145065 antagonizes the positive inotropic effect of endothelin-3 but not of endothelin-1

Endothelin-3 (ET-3) elicited a concentration-dependent positive inotropic effect on rabbit papillary muscle, the maximal response being approximately 65% of the maximal response to isoproterenol. ET-1 induced a positive inotropic effect over the concentration range below 10^–9 M, at which ET-3 did not produce a positive inotropic effect, but the maximal response to ET-1 was equivalent to or slightly lower than that of ET-3. The nonselective ET receptor antagonist PD 145065 effectively antagonized the positive inotropic effect of ET-3 in a concentration-dependent manner and abolished it at 10^–5 M. PD 145065 decreased the positive inotropic effect induced by ET 1 at lower concentrations (< 10^–9 M) but it did not affect the main portion of the concentration-response curve for the positive inotropic effect, i.e., the effect induced by high concentrations (> 10^–9 M) of ET-1. PD 145065 antagonized also the positive inotropic effect of sarafotoxin S6c. PD 145065 inhibited the specific binding of ¹²⁵I]ET-1 and of ¹²⁵I]ET-3 with a high- and a low-affinity site for competition. ET_B selective ligands, RES-701-1 and sarafotoxin S6c, displaced ¹²⁵I^uc]ET-3 with high affinity but they scarcely affected the 1251]ET-1 binding. These findings indicate that different subtypes of the ET receptor are responsible for the induction of the positive inotropic effect of ET-3 and ET-1. ET receptors involved in the production of the positive inotropic effect in the rabbit ventricular myocardium have pharmacological characteristics that are different from those of conventional ET receptors originally classified based on the pharmacological findings in noncardiac tissues. The positive inotropic effect of ET-3 in the rabbit ventricular muscle may be mediated predominantly by ET_A1 receptors that are susceptible to PD 145065 as well as BQ-123 and FR139317, and partially mediated by ET_B receptors that are inhibitable with RES-701-1. ET_A2 receptors that are resistant to ET_A selective as well as nonselective antagonists may mainly be responsible for the positive inotropic effect of ET-1 in the rabbit ventricular muscle.