CONVERSION OF BIG ET-1 IN THE RAT LUNG - ROLE OF PHOSPHORAMIDON-SENSITIVE ENDOTHELIN-1-CONVERTING ENZYME

We examined conversion of Big endothelin-1 (ET-1) to mature ET-1 and p resser action during perfusion of the isolated perfused rat lung with Big ET-1. Big ET-1 caused a concentration-related increase in perfusio n pressure and the presser molar potency of the peptide was fivefold l ess than that of ET-1. Presser responses to Big ET-1 were accompanied by an increase in immunoreactive-ET (IR-ET) levels in the perfusate an d in the lung tissues. Pretreatment with phosphoramidon (10(-4) M), a metalloproteinase inhibitor, markedly suppressed the presser action an d increment in IR-ET in the tissues. Unexpectedly, the amount of IR-ET in the perfusate during perfusion of Big ET-1 was not influenced by p hosphoramidon treatment. On the other hand, chymostatin, an inhibitor of chymotrypsin-like enzymes, effectively suppressed IR-ET levels in t he perfusate; however, this enzyme inhibitor was without effect on the presser action of Big ET-1 or on the increase in IR-ET levels in lung tissues. We tentatively conclude that the phosphoramidon-sensitive co nversion of Big ET-1 to ET-1 is linked to the presser action of Big ET -1 in the isolated perfused rat lung. In addition, it seems likely tha t chymostatin-sensitive conversion of Big ET-1 to ET-1 does not play a major role in the conversion of the precursor to the mature form. We propose that IR-ET present in the tissues rather than that in the perf usate is a better indicator of the functional conversion of Big ET-1 i n the rat lung.