Captopril-Induced Increase in Coronary Flow: An SH-Dependent Effect on Arachidonic Acid Metabolism?

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The effect of captopril (80 μg/ml) on coronary flow in the isolated rat heart was compared with the effects of a nonsuflhydryl-converting enzyme inhibitor, ramipril (15 μg/ml), and of a sulfhydryl-containing compound with no converting enzyme-inhibiting properties. glutathione (112 μg/ml). Drug concentrations were equipotent in their effect on angiotensin I pressor response and equimolar with respect to the sulfydryl group. Cyclo-oxygenase products or their stable metabolites (TXB:2 6-keto-PGF and PGF.2) were measured in the coronary effluent. Furthermore, the effect of mepacrin (1 μM), in-domethacin (1 μM), and FPL 55712 (10 μM) on the changes in coronary flow induced by captopril was studied. Both captopril- and glutathionc-treated hearts showed a significant increase in coronary flow already after 5 min treatment. After 60 min treatment, coronary flow was further increased to 185 ± 9% for captopril-treated hearts and to 210 ± 11% for glutathione-treatcd hearts when compared to saline treatment. Ramipril treatment resulted in a slower increase in coronary flow, which was significant after 20 min treatment. After 60 min treatment, this increase was 122 ± 3% when compared to saline-treated hearts. This effect of ramipril was associated with a significant increase in 6-keto-PGF overflow when compared to saline-treated hearts. Captopril and glutathione had no significant effect on overflow of the measured cyclooxygenase products. The effect of captopril and glutathione on coronary flow appeared to be dose dependent in an equimolar range. Simultaneous mepacrin treatment diminished the effect of captopril on coronary flow; indomcthacin had no effect, and FPL 55712 potentiated the effect of captopril. It is suggested that ramipril increases coronary flow by reducing bradykinin breakdown and subsequently increasing PGF synthesis. Apart from this effect, captopril interferes by a more potent mechanism with arachidonic acid metabolism. This effect probably depends on the presence of the sulfhydryl group, and an effect on the lipoxygenase pathway is discussed.

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