Vasodilator effects of the endothelin ET_A receptor selective antagonist BMS‐193884 in healthy men

Abstract

AimsA number of endothelin receptor antagonists (ERAs) are currently in clinical development as potential therapies in states characterized by vasoconstriction, such as systemic hypertension. We investigated the haemodynamic effects of locally and systemically active doses of BMS-193884, an endothelin A (ET A ) receptor selective ERA, and its influence on vasoconstriction to endothelin-1 (ET-1) in healthy men. MethodsIn three separate randomized, placebo-controlled studies, the forearm blood flow (FBF) response to intra-arterial (i.a.) infusion of ET-1 (5 pmol min − 1 ) was assessed during i.a. co-infusion of BMS-193884 (5 and 50 nmol min − 1 ), and at 12 and at 24 h after oral administration of BMS-193884 (50, 100 and 200 mg at 12 h; and 200 mg at 24 h). Data were examined by repeated-measures analysis of variance ( ANOVA ) with treatment and subject as factors. ResultsET-1 caused significant forearm vasoconstriction, attenuated after oral dosing with BMS-193884 (200 mg) at 12 ( P < 0.01) and 24 h ( P < 0.0001). BMS-193884 (50 nmol min − 1 , i.a.) caused local vasodilatation (25 ± 11%) when infused alone ( P = 0.02) and abolished forearm vasoconstriction to ET-1 ( P < 0.0001 vs. ET-1 alone). Orally, BMS-193884 (200 mg) caused a reduction in total systemic vascular resistance at 12 ( − 14 ± 9%, P = 0.03) and 24 h ( − 12 ± 7%, P < 0.0001). There was no rise in plasma ET-1 levels. ConclusionBMS-193884 causes local and systemic vasodilatation and attenuation of local vasoconstriction to ET-1. The absence of a rise in plasma endothelin levels suggests BMS-193884 is selective for the ET A receptor. This form of pharmacodynamic modelling may be useful in the development of ERAs in cardiovascular disease.

Prolonged pharmacodynamic effects of S‐0139, an intravenously administered endothelin A (ETA) antagonist, in the human forearm blood flow model

“…These data agree well with preclinical efficacy data from the middle cerebral artery occlusion models; in particular, in the cat model positive effects were seen at S-0139 levels of 700-1000 ng ml -1 [7]. S-0139 did not appear to have an overt effect on systemic haemodynamics, which is consistent with results from another selective ETA antagonist, BMS-193884 [13]. TAK-044, a non-selective ET antagonist, reduced total peripheral resistance by approximately 25% [9].…”

“…S‐0139 did not appear to have an overt effect on systemic haemodynamics, which is consistent with results from another selective ET A antagonist, BMS‐193884 [13]. TAK‐044, a non‐selective ET antagonist, reduced total peripheral resistance by approximately 25% [9].…”

Restoring the Dysfunctional Endothelium

“…In different experimental models of hypertension, ET-1 antagonism lowers blood pressure, preventing or reducing cardiac and vascular hypertrophy [190,191]. In healthy humans different ET-1 receptors blockers induce local and sistemic vasodilatation, blunting vasoconstriction secondary to ET-1 infusion [192]. In hypertensive patients, both selective ET A and ET A /ET B non selective antagonists effectively reduced blood pressure [193,194].…”

Intra‐Target Microdosing (ITM): A Novel Drug Development Approach Aimed at Enabling Safer and Earlier Translation of Biological Insights Into Human Testing

“…In 2005, Dhaun et al . evaluated local responses to the novel endothelin ET A receptor selective antagonist BMS‐193884 in the human forearm vasculature by infusing low doses of the test article . However, the lowest dose administered (300 nmol = 5 nmol min −1 x 60 min) of the new biologic is 10 times the upper limit of the microdose definition for biologics, which would make it consistent with the starting dose for regular phase I studies.…”