title: Heterogeneous receptors mediate endothelin-1-induced changes in blood pressure, hematocrit, and platelet aggregation.
abstract: 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.
authors.affiliation: William Harvey Research Institute, St. Bartholomew's Hospital Medical College, London, England.
authors.forename: L
authors.initials: L
authors.lastname: McMurdo
authors.forename: P S
authors.initials: PS
authors.lastname: Lidbury
authors.forename: R
authors.initials: R
authors.lastname: Corder
authors.forename: C
authors.initials: C
authors.lastname: Thiemermann
authors.forename: J R
authors.initials: JR
authors.lastname: Vane
mesh_terms: D000818:Animals; D001381:Azepines / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects*; D016232:Endothelins / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D006400:Hematocrit; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D008297:Male; D009842:Oligopeptides / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects*; D011817:Rabbits; D017466:Receptors, Endothelin / Q000187:drug effects*
chemical_list: D001381:Azepines; D016232:Endothelins; D007211:Indoles; D009842:Oligopeptides; D017466:Receptors, Endothelin; C079574:FR 139317; C082887:PD 145065