Lisinopril and ramiprilat protection of the vascular endothelium against free radical-induced functional injury.
We reported earlier that the vasodilator response to acetylcholine (ACh) in lungs exposed to indomethacin and preconstricted with an analog of thromboxane (U46619) is converted to vasoconstriction by brief electrolysis of inflowing perfusion medium and suggested that this effect reflected endothelial injury. The purpose of our present study was 2-fold. First, because captopril, a sulfhydryl-containing inhibitor of angiotensin-converting enzyme inhibitor, prevented this effect (we assumed by scavenging electrolysis generated free radicals of oxygen), we determined whether two angiotensin-converting enzyme inhibitors lacking this moiety, namely lisinopril and ramiprilat, provided similar protection. Second, we studied whether electrolysis, like other forms of experimental lung injury, impaired uptake of serotonin (5-HT) by the endothelium. Our study confirmed that within 5 min of electrolytic injury, the ACh response is converted to vasoconstriction. This effect was completely prevented by lisinopril (18 microM) or ramiprilat (30 microM), neither of which affected ACh vasodilatation in control lungs. Lower concentrations of either drug exerted lesser degrees of protection. Five or 20 min after electrolysis, single-pass uptake of [14C]5-HT was significantly (P less than .01; N = 11) lower than control (82.4 +/- 3.4% vs. 71 +/- 3.2 and 46.5 +/- 6%, respectively). In contrast, 5-HT uptake was unaltered by electrolysis in the presence of 18 microM lisinopril. We conclude that loss of ACh vasodilation is an early reflection of lung endothelial injury that is accompanied by reduced [14C]5-HT uptake. Also, the protective property of nonsulfhydryl-containing angiotensin-converting enzyme inhibitors may be related to unexpected antioxidant actions.
Gillis
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CN
Department of Anesthesiology, Yale University School of Medicine, New Haven, Connecticut.
Chen
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Merker
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D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D004656:Enalapril / Q000031:analogs & derivatives* / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects*; D005609:Free Radicals / Q000037:antagonists & inhibitors; D017706:Lisinopril; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology*; D011817:Rabbits; D017257:Ramipril / Q000031:analogs & derivatives*; D012701:Serotonin / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D000806:Angiotensin-Converting Enzyme Inhibitors; D005609:Free Radicals; D011450:Prostaglandin Endoperoxides, Synthetic; D011758:Pyrroles; D014662:Vasoconstrictor Agents; D012701:Serotonin; D004656:Enalapril; C052549:ramiprilat; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D017706:Lisinopril; D017257:Ramipril