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

1 We examined the effects of systemic infusion, in healthy human volun teers, of the endothelin antagonist TAK-044 on the plasma concentratio ns of mature endothelin, big endothelin-l and the C-terminal fragment of big endothelin-l, by selective solid-phase extraction and specific radioimmunoassays. 2 Unlabelled TAK-044 competed with specific [I-125] -endothelin-1 binding to human left ventricle tissue in a biphasic man ner giving K-D values of 0.11 nM and 26.8 nM at the ET(A) and ET(B) re ceptor subtypes, respectively, indicating a 244 fold selectivity for t he 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 immu noreactive plasma concentrations of the three peptides. 4 At the highe r dose of 750 mg TAK-044 (giving a serum concentration of 80 nM, calcu lated to block >99% of ET(A) and >75% ET(B) receptors), the immunoreac tive plasma endothelin concentrations were increased 3.3 fold over bas al levels (P<0.01). The concentrations of big endothelin-l or C-termin al fragment of big endothelin-l were unchanged. 5 At both doses of TAK -044, there were significant decreases in diastolic blood pressure, an d peripheral vascular resistance, with corresponding increases in card iac index and stroke index. There were no changes in systolic or mean arterial blood pressures or heart rate. 6 Since only the concentration s of the mature peptide were increased, we conclude that the most like ly sources of endothelin contributing to the observed rise were displa cement of receptor-bound peptide and reduction in plasma clearance rat her than peptide synthesis.