Captopril inhibits neutrophil synthesis of leukotriene B4 in vitro and in vivo.
The aim of this investigation was to determine the effects of metalloproteinase inhibitors on leukotriene (LT) A4 hydrolase in human neutrophil cytosol and to examine the effects of captopril on intact neutrophils in vitro and in vivo. Cytosolic fractions were assayed for LTA4 hydrolase and 5-lipoxygenase activity in the presence or absence of inhibitors. Only bestatin, 1,10-O-phenanthroline, captopril and fosinoprilat demonstrated significant effects. The IC50 of captopril and fosinoprilat for LTA4 hydrolase activity were 500 microM and 1 mM, respectively. No inhibition of 5-lipoxygenase activity in cytosolic fractions was detected. The effect of captopril was only minimally reversed by ZnSO4. The IC50 of captopril for inhibition of LTB4 synthesis in intact neutrophils was 63 microM. Furthermore, 5-HETE production in intact cells was diminished 25.3 +/- 8.5% in the presence of 1 mM captopril. Oral captopril inhibited stimulated LTB4 release by subsequently isolated neutrophils by 48.1 +/- 5.6% and 5-HETE release by 43.2 +/- 5.5%. Thus, captopril is an inhibitor of LTB4 synthesis in neutrophils in vitro and in vivo. However, there are differences between the potency of this drug as assessed in cytosol and intact cell studies. This study significantly extends previous reports in that it demonstrates that captopril is a more potent inhibitor of LTB4 synthesis in intact neutrophils than in cytosol and in that it demonstrates an inhibitory effect of captopril on synthesis of LTB4 by neutrophils exposed to captopril in vivo.
Shindo
K
K
Veteran Affairs Medical Center, San Diego, CA 92161.
Baker
J R
JR
Munafo
D A
DA
Bigby
T D
TD
D001094:Arachidonate 5-Lipoxygenase / Q000097:blood; D002216:Captopril / Q000494:pharmacology*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors / Q000097:blood; D006801:Humans; D066298:In Vitro Techniques; D007975:Leukotriene B4 / Q000096:biosynthesis*; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D013431:Sulfates / Q000494:pharmacology; D017967:Zinc Compounds / Q000494:pharmacology; D019287:Zinc Sulfate
D013431:Sulfates; D017967:Zinc Compounds; D007975:Leukotriene B4; D019287:Zinc Sulfate; D002216:Captopril; D001094:Arachidonate 5-Lipoxygenase; D004851:Epoxide Hydrolases; C043134:leukotriene A4 hydrolase