S-17162 IS A NOVEL SELECTIVE INHIBITOR OF BIG ET-1 RESPONSES IN THE RAT

Endothelin-1 (ET-1) is a powerful renal vaseconstrictor peptide that m ay be implicated in acute renal failure. The aim of the present study was to test the effects of the novel endothelin-converting enzyme inhi bitor S 17162 (N-(2,3 dihydroxy propyl phosphonyl)-(S)-Leu(S)-Trp-OH, disodium salt) on presser responses to ET-1 and its precursor, big ET- 1, in isolated perfused rat kidneys and in pithed rats. In both models , phosphoramidon selectively inhibited the presser responses to big ET -1 without influencing those to ET-1, angiotensins (AT-1 and AT-II) or norepinephrine. S 17162 was active against big ET-1 in both test syst ems. It selectively inhibited the presser responses to big ET-1 with I D50 values of 160 mu g/kg/min (phosphoramidon: 120 mu g/kg/min) in the spinal rat and 6 mu M (phosphoramidon: 5 mu M) in the perfused rat ki dney. In the nonanesthetized rat, S 17162 at 20 mg/kg p.o. inhibited t he presser responses to big ET-1, demonstrating its oral bioavailabili ty. Therefore, S 17162 is a potential candidate for development as an orally active anti-endothelin drug.