title: In vivo pharmacological characterization of the non-peptide endothelin receptor antagonist SB 209670.
abstract: 1. The aim of the present study was to assess the ability of SB 209670, a high affinity non-peptide endothelin receptor antagonist (0.4 and 18 nM Kis at human cloned ETA and ETB receptors, respectively), to inhibit the haemodynamic actions of endothelin-1 in vivo. 2. Systemic administration of (+/-)-SB 209670, given either as a bolus i.v. injection or as a continuous i.v. infusion, did not alter basal haemodynamic parameters in the anaesthetized rat. 3. Infusion of (+/-)-SB 209670 (10 micrograms kg-1 min-1) selectively inhibited the depressor and carotid vasodilator response to exogenous endothelin-1: 100 micrograms kg-1 min-1 was required to inhibit significantly the biphasic haemodynamic actions of endothelin-1. The haemodynamic actions of angiotensin II and calcitonin gene-related peptide were unaltered by 100 micrograms kg-1 min-1 (+/-)-SB 209670. 4. Bolus i.v. administration of (+/-)-SB 209670 (1 mg kg-1) selectively inhibited the depressor and carotid vasodilator actions of endothelin-1: 10 mg kg-1 (+/-)-SB 209670 was required to inhibit the secondary vasoconstrictor actions of endothelin-1. 5. (+/-)-SB 209670 (10 mg kg-1) was also effective at antagonizing the pressor actions of endothelin-1 in the conscious rat for up to 3 h after intraduodenal administration thereby demonstrating that the antagonist was bioavailable upon enteric administration. This dose of (+/-)-SB 209670 did not alter basal haemodynamic parameters in the conscious rat. 6. Thus, ( +/- )-SB 209670 is an effective endothelin receptor antagonist in vivo. Using the doses defined in this study, SB 209670 may, therefore, serve as a useful tool for understanding the role of endogenous endothelin-I in the control of cardiovascular function under both physiological and pathophysiological conditions.
authors.affiliation: Department of Cardiovascular, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406-0939.
authors.forename: S A
authors.initials: SA
authors.lastname: Douglas
authors.forename: R M
authors.initials: RM
authors.lastname: Edwards
authors.forename: J D
authors.initials: JD
authors.lastname: Elliott
authors.forename: E H
authors.initials: EH
authors.lastname: Ohlstein
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001682:Biological Availability; D001794:Blood Pressure / Q000187:drug effects; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology; D002339:Carotid Arteries / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D007189:Indans / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D007262:Infusions, Intravenous; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D014664:Vasodilation / Q000187:drug effects
chemical_list: D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D007189:Indans; C087551:1H-Indene-2-carboxylic acid, 1-(1,3-benzodioxol-5-yl)-3-(2- (carboxymethoxy)-4-methoxyphenyl)-2,3-dihydro-5-propoxy-, (1S,2R,3S)-; D000804:Angiotensin II; D015740:Calcitonin Gene-Related Peptide