Different effects of imidapril and enalapril on aminopeptidase P activity in the mouse trachea.
It has been reported that the incidence of angiotensin-converting enzyme (ACE) inhibitor-related dry cough is significantly less with the ACE inhibitor imidapril than with the ACE inhibitor enalapril in hypertensive patients. Bradykinin (BK) in the trachea is believed to play some role in this adverse effect. The present study was undertaken to evaluate the effects of imidapril and enalapril on the activity of aminopeptidase P (APP), one of the BK-metabolizing enzymes, in the mouse trachea. Imidapril (0.5 mg/kg) or enalapril (0.5 mg/ kg) was given orally to mice once daily for 7 days. Drug concentrations and APP activity in the trachea were determined at the end of the experiment. Active metabolites (imidaprilat and enalaprilat), but not parent drugs (imidapril and enalapril) were detected in the trachea after a repeated dose for 7 days. Tissue concentrations of imidaprilat and enalaprilat did not significantly differ. The APP activity in the trachea did not significantly change after the 7th dose of imidapril. However, the enzyme activity was significantly inhibited after the final dose of enalapril. Thus, the present study showed that enalapril, but not imidapril inhibited the airway APP activity during repeated dosing. This finding is compatible with previous reports that the incidence of dry cough is lower with imidapril than with enalapril, and with the hypothesis that the dry cough induced by ACE inhibitors may be related to accumulation of BK in the trachea.
Sakamoto
Koh-ichi
K
Department of Clinical Pharmacology, Jichi Medical School, Minamikawachi-machi, Kawachi-gun, Tochigi 329-0498, Japan.
Sugimoto
Koh-ichi
K
Sudoh
Toshiaki
T
Fujimura
Akio
A
D000626:Aminopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001920:Bradykinin / Q000378:metabolism; D003371:Cough / Q000139:chemically induced; D004656:Enalapril / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D048289:Imidazolidines / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D014132:Trachea / Q000187:drug effects* / Q000201:enzymology
D000806:Angiotensin-Converting Enzyme Inhibitors; D048289:Imidazolidines; D004656:Enalapril; C065166:imidapril; D000626:Aminopeptidases; C022750:X-Pro aminopeptidase; D001920:Bradykinin