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In vivo pharmacological characterization of the non‐peptide endothelin receptor antagonist SB 209670
Author(s) -
Douglas Stephen A.,
Edwards Richard M.,
Elliott John D.,
Ohlstein Eliot H.
Publication year - 1995
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1995.tb13241.x
Subject(s) - endocrinology , endothelins , endothelin receptor , antagonist , medicine , receptor antagonist , hemodynamics , endothelin 3 , in vivo , vasodilation , endothelin 1 , biology , receptor , microbiology and biotechnology
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 n m K i s at human cloned ET A and ET B 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 μg kg −1 min −1 ) selectively inhibited the depressor and carotid vasodilator response to exogenous endothelin‐1: 100 μg 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 μg 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‐1 in the control of cardiovascular function under both physiological and pathophysiological conditions.