Sakamoto Koh-ichi, Sugimoto Koh-ichi, Sudoh Toshiaki, Fujimura Akio
Department of Clinical Pharmacology, Jichi Medical School, Minamikawachi-machi, Kawachi-gun, Tochigi 329-0498, Japan.
Hypertens Res. 2005 Mar;28(3):243-7. doi: 10.1291/hypres.28.243.
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.
据报道，在高血压患者中，血管紧张素转换酶（ACE）抑制剂咪达普利引起的干咳发生率明显低于依那普利。气管中的缓激肽（BK）被认为在这种不良反应中起一定作用。本研究旨在评估咪达普利和依那普利对小鼠气管中BK代谢酶之一的氨肽酶P（APP）活性的影响。将咪达普利（0.5mg/kg）或依那普利（0.5mg/kg）每日一次口服给予小鼠，持续7天。在实验结束时测定气管中的药物浓度和APP活性。重复给药7天后，在气管中检测到活性代谢物（咪达普利拉和依那普利拉），但未检测到母体药物（咪达普利和依那普利）。咪达普利拉和依那普利拉的组织浓度无显著差异。第7次给予咪达普利后，气管中的APP活性无显著变化。然而，最后一次给予依那普利后，酶活性受到显著抑制。因此，本研究表明，在重复给药期间，依那普利而非咪达普利抑制气道APP活性。这一发现与先前关于咪达普利干咳发生率低于依那普利的报道以及ACE抑制剂引起的干咳可能与气管中BK积累有关的假设相符。
