[Phe22]-big endothelin-1[19-37]: a new and potent inhibitor of the endothelin-converting enzyme.

To develop a new family of endothelin-converting enzyme (ECE) inhibitors, we assessed the inhibitory properties of an N- and C-terminal-truncated analogue of big endothelin (ET)-1[1-38], [Phe22]-big-ET-1 [19-37], on the renal vasoconstrictor properties of big ET-1 and ET-1. We had previously shown that a 60-min infusion of phosphoramidon (100 microM) potently inhibits big-ET-1 but not ET-1-induced vasoconstriction in the rabbit perfused kidney. A 1-min preinfusion of the analogue (100 microM) was sufficient to markedly blunt the vasoconstrictor actions of big ET-1 (250 pmol) (control 19.3 +/- 1.0 mm Hg; in presence of [Phe22]-big ET-1[19-37] 4.8 +/- 1.6 mm Hg; n = 6, p < 0.001). A 10- and 60-min preinfusion of the substrate analogue at concentrations of 50 and 5 microM, respectively, reduced the response of big ET-1 to 9.3 +/- 2.3 mm Hg and 3.6 +/- 1.8 mm Hg (n = 3, p < 0.01 compared to control). [Phe22]-big ET-1[19-37] was inactive against ET-1-induced vasoconstriction (10 pmol) and was devoided of intrinsic vasoactivity. All experiments were performed on kidneys pretreated with SQ-28603 (1 microM), a neutral endopeptidase inhibitor. Our results suggest that [Phe22]-big ET-1[19-37] may be a useful lead molecule for the development of more selective and enzyme-resistant inhibitors of the membrane-bound ECE.