CAPTOPRIL INHIBITS NEUTROPHIL SYNTHESIS OF LEUKOTRIENE B-4 IN-VITRO AND IN-VIVO

The aim of this investigation was to determine the effects of metallop roteinase inhibitors on leukotriene (LT) A(4) hydrolase in human neutr ophil cytosol and to examine the effects of captopril on intact neutro phils in vitro and in vivo. Cytosolic fractions were assayed for LTA(4 ) hydrolase and 5-lipoxygenase activity in the presence or absence of inhibitors. Only bestatin, 1,10-O-phenanthroline, captopril and fosino prilat demonstrated significant effects. The IC50 of captopril and fos inoprilat for LTA(4) hydrolase activity were 500 mu M and 1 mM, respec tively. No inhibition of 5-lipoxygenase activity in cytosolic fraction s was detected. The effect of captopril was only minimally reversed by ZnSO4. The IC50 of captopril for inhibition of LTB(4) synthesis in in tact neutrophils was 63 mu M. Furthermore, 5-HETE production in intact cells was diminished 25.3 +/- 8.5% in the presence of 1 mM captopril. Oral captopril inhibited stimulated LTB(4) release by subsequently is olated neutrophils by 48.1 +/- 5.6% and 5-HETE release by 43.2 +/- 5.5 %. Thus, captopril is an inhibitor of LTB(4) synthesis in neutrophils in vitro and in vivo. However, there are differences between the poten cy of this drug as assessed in cytosol and intact cell studies. This s tudy significantly extends previous reports in that it demonstrates th at captopril is a more potent inhibitor of LTB(4) synthesis in intact neutrophils than in cytosol and in that it demonstrates an inhibitory effect of captopril on synthesis of LTB(4) by neutrophils exposed to c aptopril in vivo.