title: Endothelin-1 enhances vascular permeability in conscious rats: role of thromboxane A2.
abstract: The purpose of the present experiments was to study the effects of endothelin-1 (ET-1) on vascular permeability and the involvement of the cyclooxygenase metabolites in the vascular responses to ET-1. Bolus intravenous injection of ET-1 (0.1-1.0 nmol/kg) into conscious rats induced immediate hypotension lasting for 30 s followed by sustained dose-dependent hypertension. A low dose of ET-1 (0.1 nmol/kg) did not modify the hematocrit value but the 1.0-nmol/kg dose increased the hematocrit value from 39.7 to 44.4%. Pretreatment of the animals with BM-13505 (1 mg/kg), a thromboxane A2 (TxA2) receptor antagonist, prolonged the duration of the hypotensive response to ET-1 (1.0 nmol/kg) but had no effect on the pressor response. Pretreatment with OKY-046 (10 mg/kg), a TxA2 synthesis inhibitor, or indomethacin (10 mg/kg), a cyclooxygenase inhibitor, had no significant effect on ET-1-induced changes in blood pressure. Evans blue dye extravasation, a marker of vascular permeability, increased up to 235% over control levels in specific vascular beds including the upper and lower bronchi, stomach, duodenum and kidney of ET-1 (1.0 nmol/kg)-treated animals. Pretreatment of the animals with BM-13505, OKY-046 or indomethacin reduced by 60-100% the Evans blue extravasation in these tissues. These results suggest that the effect of ET-1 on vascular permeability is partly mediated and/or modulated by the secondary release of TxA2, whereas its action on arterial blood pressure appears to be independent from prostanoid release in conscious rats.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, University of Sherbrooke, Canada.
authors.forename: M G
authors.initials: MG
authors.lastname: Sirois
authors.forename: J G
authors.initials: JG
authors.lastname: Filep
authors.forename: A
authors.initials: A
authors.lastname: Rousseau
authors.forename: A
authors.initials: A
authors.lastname: Fournier
authors.forename: G E
authors.initials: GE
authors.lastname: Plante
authors.forename: P
authors.initials: P
authors.lastname: Sirois
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002199:Capillary Permeability / Q000187:drug effects* / Q000502:physiology; D016232:Endothelins / Q000008:administration & dosage / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D008689:Methacrylates / Q000494:pharmacology; D009928:Organ Specificity; D010648:Phenylacetates / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D012709:Serum Albumin / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D013928:Thromboxane A2 / Q000502:physiology*; D013931:Thromboxanes / Q000037:antagonists & inhibitors
chemical_list: D016232:Endothelins; D008689:Methacrylates; D010648:Phenylacetates; D012709:Serum Albumin; D013449:Sulfonamides; D013931:Thromboxanes; D013928:Thromboxane A2; C034364:ozagrel; C051762:daltroban; D007213:Indomethacin