IN-VIVO PHARMACOLOGICAL CHARACTERIZATION OF THE NONPEPTIDE ENDOTHELIN RECEPTOR ANTAGONIST SB-209670

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 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 mu g kg(-1) min(-1)) selectively inhibited the depressor and carotid vasodilator response to exogenous endothelin-1: 100 mu g 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 mu g kg(-1) min(-1) (+/-)-SB 209670. 4 Bolus i.v. administration of (+/-)-SB 209670 (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 presser 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.