Inhibition of calcium ionophore-stimulated leukotriene generation from intact human neutrophils by captopril.

Effects of captopril on the formation of leukotrienes (LTs) from stimulated intact human neutrophils were investigated. Neutrophils were stimulated with 1 microM calcium ionophore A23187 for the generation of LTs. A reverse phase high performance liquid chromatography technique and UV spectroscopy were used to detect and quantitate the released LTs namely, LTB4. LTC4. delta6-trans-LTB4 and delta6-trans-12-epi-LTB4. Preincubation of neutrophils with captopril significantly reduced LTB4 formation in a concentration-dependent manner, as compared to diluent-treated control cells. Since LTA4 is the substrate for both LTB4 and LTC4, thus in presence of captopril, shunting of LTA4 from synthesis of LTB4 was not directed to LTC4 formation. This finding was evidenced by the significant decrease of LTC4 production under the influence of high concentration of the drug. Formation of LTB4 stereoisomers, delta6-trans-LTB4 and delta6-trans-12-epi-LTB4 was not markedly altered by captopril. In subsequent experiments, when neutrophils were stimulated with A23187 after preincubation with exogenous arachidonic acid (75 microM), and treatment with captopril, similar findings were obtained for LTB4 and LTC4. Meanwhile, formation of the nonenzymatic hydrolysis products of LTA4 tended to rise reaching significant level in case of delta6-trans-LTB4, at the high concentration of captopril. These results demonstrate that captopril is an inhibitor of enzymatically generated LTs produced by intact human neutrophils, being more potent against LTB4. These effects of captopril on LTs are not mediated via an inhibition of arachidonic acid formation from membrane phospholipids. It could be suggested that captopril, at doses used clinically. could inhibit the generation of LTB4 without affecting LTC4. Consequently, these findings might account for possible antiinflammatory activity for captopril, and further suggest that some of the observed side effects of captopril might not be related to an overproduction of LTC4.