Rapid reversal of angiotensin converting enzyme inhibition by lisinopril in the perfused rabbit lung.
Lisinopril is a potent competitive inhibitor of purified rabbit lung ACE (dissociation t1/2 = 105 min). To examine reversibility of binding and ACE functional activity in situ, the single-pass extraction (E) of an 125I-lisinopril analogue (351A) and the hydrolysis of an ACE substrate, benz-phe-ala-pro (BPAP) were studied. Lungs were perfused at 50 ml/min with a Krebs-albumin (3%) solution. A bolus containing [14C]dextran, [3H]BPAP, and 351A was injected and (E)351A measured by multiple indicator dilution technique. BPAP metabolism (M) was reflected by the appearance of its hydrolysis product [3H]benz-phe in lung effluent. Control (E)351A was 66 +/- 5% (mean +/- SD, n = 6) and (M)BPAP was 69 +/- 9% (n = 6). Unlabeled lisinopril (30 nmol) in the bolus significantly reduced E(351A) and M(BPAP) to 16 +/- 16% and 3 +/- 3%, respectively. Ten minutes later E(351A) and M(BPAP) had returned to control values. Reduction of E(351A) was partially reversible and M(BPAP) completely reversible after 1 min. After recirculation with 0.25 mM lisinopril for 30 min, however, significant depression of E(351A) was evident for 60 min after exposure to lisinopril was discontinued. Thus, rapid as well as slowly reversible components of inhibition of ACE inhibitor binding can be demonstrated in the perfused rabbit lung.
Rimar
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Department of Anesthesiology, Yale University School of Medicine, New Haven, Connecticut 06510.
Gillis
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CN
D000418:Albumins / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D004151:Dipeptides / Q000378:metabolism / Q000494:pharmacology; D004656:Enalapril / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D017706:Lisinopril; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D011817:Rabbits
D000418:Albumins; D000806:Angiotensin-Converting Enzyme Inhibitors; D004151:Dipeptides; C042037:L-proline, N2-((1S)-1-carboxy-3-phenylpropyl)-N6-((4-hydroxyphenyl)iminomethyl)-L-lysyl-; D004656:Enalapril; D017706:Lisinopril