INHIBITION OF GRANULOCYTE-DERIVED PROTEASES REDUCES THE INCREASE IN PLASMA ENDOTHELIN ASSOCIATED WITH MYOCARDIAL-ISCHEMIA IN THE PIG

Plasma endothelin (ET) is increased in association with myocardial inf arction. The aim of the present study was to get insight into the mech anisms behind this ischemia-induced increase in plasma ET Since granul ocytes increase ET production in vitro, we examined to what extent inh ibition of granulocyte-derived proteases could reduce the increase in plasma ET observed in association with myocardial ischemia. We infused Eglin C, a selective inhibitor of the granulocyte-derived proteases e lastase, cathepsin G, and chymotrypsin, in pigs subjected to 90 min le ft anterior descending coronary artery occlusion followed by 210 min r eperfusion (n = 7). Arterial plasma ET increased in an untreated contr ol group (n = 7) from 5.0 +/- 0.6 (mean +/- SEM) fmol . ml(-1) before myocardial ischemia to 6.1 +/- 0.6 fmol . ml(-1) at 90 min ischemia an d reached a maximum of 6.8 +/- 0.9 fmol . ml(-1) at 90 min reperfusion . The increase in plasma ET associated with myocardial ischemia was al most completely abolished in the Eglin C treated group (p = 0.005). Pl asma ET in the Eglin C treated animals was 4.7 +/- 0.4, 4.7 +/- 0.4, a nd 4.6 +/- 0.4 fmol ml(-1) before myocardial ischemia, at 90 min ische mia, and at 90 min reperfusion, respectively. Our study suggests a rol e for granulocyte-derived proteases in the increase in plasma ET assoc iated with myocardial ischemia. We have shown that the increase in pla sma ET associated with myocardial ischemia was reduced by inhibition o f granulocyte-derived proteases using the selective protease inhibitor Eglin C.