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The peptide endothelin receptor antagonist, TAK‐044, produces sustained inhibition of endothelin‐1 mediated arteriolar vasoconstriction
Author(s) -
Ferro C. J.,
Haynes W. G.,
Johnston N. R.,
Lomax C. C.,
Newby D. E.,
Webb D. J.
Publication year - 1997
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1046/j.1365-2125.1997.00595.x
Subject(s) - vasoconstriction , endothelin receptor , medicine , placebo , endothelins , antagonist , forearm , endocrinology , anesthesia , pharmacology , receptor , surgery , pathology , alternative medicine
Aims 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. Methods 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. Results In the placebo phase, ET‐1 caused significant, slowly‐progressive local forearm vasoconstriction of ∼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. Conclusions 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.