RAT BIG ENDOTHELIN-1-INDUCED BRONCHOCONSTRICTION AND VASOCONSTRICTIONIN THE ISOLATED-PERFUSED RAT LUNG - ROLE OF ENDOTHELIN-CONVERTING ENZYME AND NEUTRAL ENDOPEPTIDASE-24.11

Treatment of animals with big endothelin-1 (bET) causes pulmonary hype rtension and bronchoconstriction, both in vivo and in perfused lungs. The biological activity of bET requires proteolytic cleavage to ET-1 b y endothelin converting enzymes (ECE) and possibly other proteases suc h as neutral endopeptidase 24.11 (NEP 24.11). Since the role of NEP 24 .11 in the physiological activation of bET is unclear, we investigated the effects of the selective NEP 24.11 inhibitor thiorphan on bET-ind uced vaso- and bronchoconstriction in the isolated perfused rat lung. We also studied the effects of phosphoramidon and -yl-1-(1H-tetraol-5- yl)-ehtylaminomethylphosphonic acid (CGS-26303), i.e. agents which blo ck not only NEP 24.11 but also ECE. The bET-induced vasoconstriction w as much less prominent than the bronchoconstriction, i.e. after exposu re for 110 min vascular and airway conductance were decreased by 33% a nd 80% respectively. The small bET-induced vasoconstriction was attenu ated to a similar degree by pretreatment with any of the three proteas e inhibitors. However, thiorphan up to a concentration of 10 mu M had only little effect on the bET-induced bronchoconstriction, while 10 mu M phosphoramidon or CGS-26303 provided half-maximal and 100 mu M phos phoramidon complete protection in this model. This profile of inhibito r action suggests that in rat lung ECE is the major enzyme responsible for activation of bET.