The peptide endothelin receptor antagonist, TAK‐044, produces sustained inhibition of endothelin‐1 mediated arteriolar vasoconstriction

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Abstract
Endothelin-1 (ET-1) has been implicated in the pathophysiology of a number of cardiovascular diseases for which endothelin receptor antagonists are currently under clinical development. We have previously reported that systemic administration of the combined endothelin A/B receptor antagonist, TAK-044, abolishes the forearm vasoconstriction caused by intrabrachial ET-1 infusion for at least 3 h. In this study we investigated whether TAK-044 can inhibit ET-1 mediated forearm vasoconstriction for longer periods. Eighteen subjects were recruited to a randomized, placebo-controlled, single-blind, three-way, crossover study. Subjects were divided into three groups of six. Groups received 25 mg, 50 mg or 100 mg TAK-044 on two separate occasions, 6 and 10 h before the start of a 2 h intrabrachial infusion of ET-1 (5 pmol min(-1)). On a third occasion subjects received only placebo before intra-arterial ET-1 infusion. Forearm vasoconstriction to ET-1 was measured by venous occlusion plethysmography. In the placebo phase, ET-1 caused significant, slowly-progressive local forearm vasoconstriction of approximately 30% (P<0.01) in all three groups. All three doses of TAK-044, administered at both timepoints, tended to blunt the vasoconstriction caused by ET-1. When the responses from all three groups were combined, TAK-044 significantly reduced ET-1 mediated vasoconstriction compared with placebo -9% (95% CI -15 to -3; P=0.01) at 8 h and by -9% (95% CI -17 to -2; P=0.01) 12 h after dosing. TAK-044 attenuated, but did not abolish, local ET-1 mediated vasoconstriction, for up to 12 h after administration. Vasoconstriction to local intra-arterial administration of ET-1 appears to represent a safe and reproducible pharmacodynamic index of systemic endothelin receptor antagonism in humans.

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