Heterogeneous receptors mediate endothelin-1-induced changes in blood pressure, hematocrit, and platelet aggregation

Using selective endothelin (ET) receptor antagonists, we investigated which ET receptor subtypes mediate the changes in blood pressure and hematocrit produced by intraarterial injection of ET-1 in the anesthetized rabbit. In addition, the receptor through which ET-1 stimulates the release of prostacyclin (PGI2) and, hence, inhibits ex vivo platelet aggregation, was identified. FR 139317 (ETA antagonist, 0.6 mg kg-1 min-1 preceded by a loading dose of 3 mg kg-1 i.v.) and PD 145065 (nonselective ETA/ETB antagonist, 0.6 mg kg-1 min-1 preceded by a loading dose of 3 mg kg-1 i.v.) attenuated the ET-1 (1 nmol kg-1 i.a.)-induced rise in mean arterial pressure (MAP) by 89% and 75%, respectively. In contrast to FR 139317, PD 145065 also abolished the initial, transient depressor response brought about by ET-1. ET-1 caused a significant increase in hematocrit 15 min after its injection. PD 145065 caused a significantly greater inhibition of this hemoconcentration than FR 139317. ET-1 inhibited ex vivo platelet aggregation by 96%, measured 5 min after injection of the peptide. PD 145065, but not FR 139317, abolished the antiaggregatory effects of ET-1. Thus, the ET-1-induced vasoconstriction in the anesthetized rabbit is predominantly mediated via the ETA receptor, whereas the depressor and antiaggregatory actions of ET-1 are caused by activation of the ETB receptor. Moreover, activation of both receptor subtypes by ET-1 accounts for the increase in hematocrit produced by ET-1 in vivo.