Difference among angiotensin-converting enzyme inhibitors in potentiating effects on bradykinin-induced microvascular leakage in guinea pig airways.
We investigated the effect of imidapril, a novel angiotensin-converting enzyme (ACE) inhibitor, on augmentation of airway microvascular leakage induced by bradykinin (BK) and substance P (SP) in guinea pigs and compared it with those of enalapril and captopril. The three ACE inhibitors significantly potentiated BK- and SP-induced airway microvascular leakage in a dose-dependent manner. In spite of the compatible or higher ACE inhibitory activity of imidapril, its potentiating activity in BK-induced leakage was lower than those of enalapril and captopril both by single administration (0.3-30 mg/kg, p.o.) and repeated administration for eight days (0.1-10 mg/kg/day, p.o.). The potentiating activities of the three ACE inhibitors were suppressed by pretreatment with a BK2-receptor antagonist, but not by neurokinin 1 and neurokinin 2 antagonists, suggesting that neurokinins may not be involved in BK-induced leakage under the conditions used. On the other hand, the potentiating effect of imidapril in SP-induced leakage was weaker than those of enalapril and captopril only after single high doses. The present study shows that the ACE inhibitors have different activity in potentiation of the airway microvascular leakage induced by BK, which may be ascribable to the difference in their inhibition of BK hydrolysis. This evidence may partly explain the smaller incidence of dry cough induced by imidapril compared with other ACE inhibitors when clinically used as antihypertensive drugs.
Murata
T
T
Pharmacological Research Laboratory, Tanabe Seiyaku Co., Ltd., Saitama, Japan.
Matsumoto
Y
Y
Kashida
T
T
Kaminuma
O
O
Naito
K
K
Ikezawa
K
K
Tsuzurahara
K
K
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D001920:Bradykinin / Q000494:pharmacology*; D002199:Capillary Permeability / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D008297:Male; D012137:Respiratory System / Q000187:drug effects*; D014132:Trachea / Q000187:drug effects
D000806:Angiotensin-Converting Enzyme Inhibitors; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001713:Biphenyl Compounds; D001920:Bradykinin; C066892:CP 96345