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

摘要

Endothelin-3 (ET-3) elicited a concentration-dependent positive inotropic effect on rabbit papillary muscle, the maximal re-sponse 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 an-tagonized the positive inotropic effect of ET-3 in a concentration-dependent manner and abolished it at 10~5 M. PD 145065 d ecreased the positive inotropic effect induced by ET1 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 bind-ing of [I25I]ET-1 and of [l25I]ET-3 with a high- and a low-affinity site for competition. ETB selective ligands, RES-701-1 and sarafotoxin S6c, displaced [l25P'c]ET-3 with high affinity but they scarcely affected the [I25I]ET-1 binding. These findings in-dicate 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 phar-macological characteristics that are different from those of conventional ET receptors originally classified based on the phar-macological findings in noncardiac tissues. The positive inotropic effect of ET-3 in the rabbit ventricular muscle may be mediated predominantly by ETA1 receptors that are susceptible to PD 145065 as well as BQ-123 and FR139317, and partially mediated fc>y ETB receptors that are inhibitable with RES-701 -1. ETA2 receptors that are resistant to ETA selective as well as nonselective antagonists may mainly be responsible for the positive inotropic effect of ET-1 in the rabbit ventricular muscle.