Kinetics of captopril- and enalapril-induced inhibition of pulmonary angiotensin converting enzyme in vivo.
The kinetics of angiotensin converting enzyme (ACE) inhibition by captopril (SQ 14225) and enalapril (MK 421) in anesthetized rabbits was investigated. Kinetic parameters, apparent Km, an index of enzyme-substrate affinity and apparent Vmax, a measure of maximal rate of substrate conversion, were determined from indicator dilution measurements of single pass pulmonary metabolism of a synthetic ACE substrate [3H]benzoyl-phenylalanyl-alanyl-proline. Two methods for determination of kinetics in vivo from metabolism data were used. One fit pulmonary venous outflow metabolism data to a nonlinear model of saturable lung metabolic processes. This method required injection of sufficient substrate (benzoyl-phenylalanyl-alanyl-proline) to produce a large range of intravascular substrate concentrations. An alternative method required use of only low intravascular substrate concentrations. Both methods rely primarily on similar Michaelis-Menten assumptions and generated very similar results. Both captopril (10 and 20 nmol/kg) and enalapril (4 and 7 nmol/kg) behaved as noncompetitive ACE inhibitors in vivo. ACE inhibition was characterized by depressed [3H]benzoyl-phenylalanyl-alanyl-proline hydrolysis and apparent Vmax whereas apparent Km was unaffected. Other studies have suggested that these inhibitors act as competitive or mixed competitive and noncompetitive ACE inhibitors in vitro. Significant differences, however, between in vivo and in vitro experimental conditions suggest that the kinetics of enzyme inhibition in vitro may not necessarily reflect the action of the inhibitor in vivo. Additionally, results obtained in vivo may more accurately reflect the therapeutic behavior of these compounds.
Moalli
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Howell
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Gillis
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D000806:Angiotensin-Converting Enzyme Inhibitors; D000818:Animals; D002216:Captopril / Q000494:pharmacology*; D004151:Dipeptides / Q000494:pharmacology*; D004656:Enalapril; D007700:Kinetics; D008168:Lung / Q000201:enzymology*; D008297:Male; D009842:Oligopeptides / Q000378:metabolism; D011392:Proline / Q000031:analogs & derivatives*; D011817:Rabbits
D000806:Angiotensin-Converting Enzyme Inhibitors; D004151:Dipeptides; D009842:Oligopeptides; C029689:benzoylphenylalanyl-alanyl-proline; D004656:Enalapril; D011392:Proline; D002216:Captopril