In vivo pharmacological characterization of the non‐peptide endothelin receptor antagonist SB 209670

Abstract

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. 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. 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. 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. (±)‐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. 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.

Blockade of Endothelin Receptors Reduces Diet-Induced Hypercholesterolemia and Atherosclerosis in Apolipoprotein E-Deficient Mice

“…Mice were given SB209670 (10 mg/kg/day; SmithKline Beecham Pharmaceuticals, Philadelphia, Pa., USA) or placebo (0.9% saline) by subcutaneously implanted osmotic minipumps (Alzat; model 2001, Palo Alto, Calif., USA). This dose and regimen were selected based on studies performed in rats [21,22]. The systolic blood pressure, body weight, and plasma lipid levels were measured at baseline (10 weeks of age), then periodically (14, 18, and 22 weeks of age) during the study.…”

“…In this study, we examined the effect of the nonselective ET receptor antagonist SB209670 [21,22] on atherosclerotic lesions in ApoEdeficient mice, a suitable animal model of atherosclerosis [23,24]. We found that chronic administration of SB209670 reduces diet-induced hypercholesterolemia and atherosclerosis in ApoE-deficient mice.…”

Enhancement of the haemodynamic effects of NG‐monomethyl‐l‐arginine by transforming growth factor‐β1 in conscious, normal, but not endotoxaemic, rats

“…Effects of SB 209670 on responses to TGF-f, and on subsequent responses to L-NMMA in saline-infused animals Animals (n= 8) were given a continuous infusion of saline for 5 h before the onset of a continuous infusion of SB 209670 (10 jig kg-' min-) (Douglas et al, 1995); the latter was given for 1 h before and for 3 h after a bolus injection of TGF-fij (as above). Seventeen hours later the infusion of SB 209670 was resumed, 1 h before an infusion of L-NMMA (as above) was started; SB 209670 and L-NMMA were co-infused for 3 h. In pilot experiments (n = 3) we found this dose of SB 209670 completely reversed the effects of an infusion of ET-1 (120 pmol h-') which increased mean arterial pressure by 30-40 mmHg.…”

“…In the same animals we then determined if fluenced responses to L-NMMA. Since TGF-f, had clear-cut haemodynamic effects and enhanced the cardiovascular responses to L-NMMA in control animals (see Results) we carBrkkh Jow=l of Phomecology (1995) 116, 3042 -3048 TGF-fp1 and L-NMMA ried out a separate experiment to determine if the non-selective ET antagonist, SB 209670 (OhIstein et al, 1994;Douglas et al, 1995) affected haemodynamic responses to TGF-fI, or its ability to enhance responses to L-NMMA.…”

Action of the endothelin receptor (ETA) antagonist BQ-123 on forearm blood flow in young normotensive subjects

“…SB 209670, a mixed ET A \ET B receptor antagonist, had no effect on basal haemodynamic parameters in conscious and anaesthetized Sprague-Dawley rats in one study [25], although prolonged infusion for over 20 h has been reported to reduce mean arterial pressure in the same strain [26]. In contrast, Bunting and Widdop [27] recorded a significant increase in mesenteric and hindquarters blood flow in both spontaneously hypertensive rats and Wistar Kyoto rats in response to infusion of SB 209670.…”