Norota I, Endoh M
Department of Pharmacology, Yamagata University School of Medicine, Japan.
Mol Cell Biochem. 1996 Jul-Aug;160-161:67-74. doi: 10.1007/BF00240033.
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 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 binding of [125I]ET-1 and of [125I]ET-3 with a high- and a low-affinity site for competition. ETB selective ligands, RES-701-1 and sarafotoxin S6c, displaced [125Iuc]ET-3 with high affinity but they scarcely affected the [125I]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 ETA1 receptors that are susceptible to PD 145065 as well as BQ-123 and FR139317, and partially mediated by 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.
内皮素 -3（ET -3）对兔乳头肌产生浓度依赖性的正性肌力作用，最大反应约为异丙肾上腺素最大反应的65%。ET -1在浓度低于10⁻⁹ M范围内诱导正性肌力作用，在此浓度下ET -3未产生正性肌力作用，但ET -1的最大反应等同于或略低于ET -3。非选择性ET受体拮抗剂PD 145065以浓度依赖性方式有效拮抗ET -3的正性肌力作用，并在10⁻⁵ M时将其消除。PD 145065在较低浓度（<10⁻⁹ M）时降低ET -1诱导的正性肌力作用，但不影响正性肌力作用浓度 - 反应曲线的主要部分，即高浓度（>10⁻⁹ M）ET -1诱导的作用。PD 145065也拮抗了sarafotoxin S6c的正性肌力作用。PD 145065抑制[¹²⁵I]ET -1和[¹²⁵I]ET -3与高亲和力和低亲和力竞争位点的特异性结合。ETB选择性配体RES -701 -1和sarafotoxin S6c以高亲和力置换[¹²⁵Iuc]ET -3，但它们几乎不影响[¹²⁵I]ET -1的结合。这些发现表明，ET受体的不同亚型负责ET -3和ET -1正性肌力作用的诱导。参与兔心室心肌正性肌力作用产生的ET受体具有与最初基于非心脏组织药理学发现分类的传统ET受体不同的药理学特征。ET -3在兔心室肌中的正性肌力作用可能主要由对PD 145065以及BQ -123和FR139317敏感的ETA1受体介导，部分由可被RES -701 -1抑制的ETB受体介导。对ETA选择性及非选择性拮抗剂均耐药的ETA2受体可能主要负责ET -1在兔心室肌中的正性肌力作用。
