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

Abstract

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 Cterminal fragment of big endothelin-1, by selective solid-phase extraction and specific radio- block > 95% of ETA but <5% ETB 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 ETA and >75% ETB receptors), the immunoreactive plasma endothelin concentrations were increased 3.3 fold over basal levels (P<0.01). The concentrations of big endothelin-l 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.

Contrasting Actions of Endothelin ETAand ETBReceptors in Cardiovascular Disease

“…Following intravenous injection, ET-1 is rapidly removed from circulation, being retained in tissues (primarily the lungs, kidney and liver), and this effect is inhibited by ET B but not ET A receptor blockade (44). In further support of ET B receptor-mediated clearance of endothelin, plasma ET-1 concentrations are increased during ET B receptor blockade (45) and in rats genetically deficient in ET B receptors (42). The ability of the ET B receptor, but not the ET A receptor, to "clear" endothelins is not fully understood because studies have shown that ET A receptor selective antagonism can also elevate plasma ET-1 levels (46) and ET A binding kinetics are not too dissimilar to those of ET B receptors.…”

Tanshinone IIA inhibits endothelin-1 production in TNF-?-induced brain microvascular endothelial cells through suppression of endothelin-converting enzyme-1 synthesis

“…However, although preliminary clinical data has indicated the safety, there are still limited effects of the ET A or ET B receptor antagonists in treating cerebral vasospasm after SAH in humans. It may provoke a drastic elevation of intracerebral ET-1 concentrations as the result of antagonists competing for ET binding sites [27,28] . Therefore, reducing the synthesis and release of ET-1 from endothelial or parenchymal cells may prove a worthwhile alternative or adjunctive therapeutic option.…”

The endothelin system in pulmonary and renal vasculopathy: les liaisons dangereuses

“…Upon activation by ET-1, ETB receptors mediate the beneficial release of endothelium-derived relaxing factors, such as NO, in a feedback mechanism that limits ETA vasoconstriction. High densities of ETB receptors are present in the lung, kidney and liver, where this subtype functions as a clearing receptor to internalise the ligand-receptor complex and remove ET-1 from circulation [16][17][18][19]. As a result, the plasma half-life of ET-1 is comparatively short [20].…”

“…In practice, it is difficult to achieve a steady-state concentration with precision, even in experimental clinical studies; selectivities .1,000-fold may be necessary and are currently only achieved with sitaxentan. Blocking the ETB subtype increases the level of circulating plasma ET-1 [17], which can serve as a biomarker of ETB receptor antagonism. In contrast with the experience in pulmonary hypertension, all clinical trials of heart failure have used mixed antagonists or doses of modestly selective ETA antagonists high enough to block the ETB receptor (evidenced by a rise in plasma ET-1), with disappointing results [45].…”