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The increase in human plasma immunoreactive endothelin but not big endothelin‐1 or its C‐terminal fragment induced by systemic administration of the endothelin antagonist TAK‐044
Author(s) -
Plumpton Christopher,
Ferro Charles J.,
Haynes William G.,
Webb David J.,
Davenport Anthony P.
Publication year - 1996
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1996.tb15987.x
Subject(s) - endothelin receptor , endocrinology , medicine , radioimmunoassay , endothelins , receptor , antagonist , endothelin 1 , endothelin receptor antagonist , receptor antagonist , peptide hormone , chemistry
1 We examined the effects of systemic infusion, in healthy human volunteers, of the endothelin antagonist TAK‐044 on the plasma concentrations of mature endothelin, big endothelin‐1 and the C‐terminal fragment of big endothelin‐1, by selective solid‐phase extraction and specific radioimmunoassays. 2 Unlabelled TAK‐044 competed with specific [ 125 I]‐endothelin‐1 binding to human left ventricle tissue in a biphasic manner giving K D values of 0.11 nM and 26.8 nM at the ET A and ET B receptor subtypes, respectively, indicating a 244 fold selectivity for the ET A receptor subtype. 3 A 15 min intravenous infusion of placebo or 30 mg TAK‐044 (giving a serum concentration of 2 nM, calculated to block > 95% of ET A but <5% ET B receptors) had no effect on the immunoreactive plasma concentrations of the three peptides. 4 At the higher dose of 750 mg TAK‐044 (giving a serum concentration of 80 nM, calculated to block > 99% of ET A and > 75% ET B receptors), the immunoreactive plasma endothelin concentrations were increased 3.3 fold over basal levels ( P < 0.01). The concentrations of big endothelin‐1 or C‐terminal fragment of big endothelin‐1 were unchanged. 5 At both doses of TAK‐044, there were significant decreases in diastolic blood pressure, and peripheral vascular resistance, with corresponding increases in cardiac index and stroke index. There were no changes in systolic or mean arterial blood pressures or heart rate. 6 Since only the concentrations of the mature peptide were increased, we conclude that the most likely sources of endothelin contributing to the observed rise were displacement of receptor‐bound peptide and reduction in plasma clearance rather than peptide synthesis.