Comparison of the effect of imidaprilat and ramiprilat on broncho-constriction and hypotension induced by bradykinin in guinea pigs.
OBJECTIVE
To demonstrate tissue selective brady-kinin (BK) potentiating action of angiotensin converting enzyme inhibitors, we studied effects of imidaprilat and ramiprilat, active metabolites of imidapril and ramipril, respectively, on bronchoconstriction and hypotension both induced by BK in vasopressin-infused anesthetized guinea pigs.


METHODS
We measured pulmonary inflation pressure and blood pressure in vasopressin-infused anesthetized guinea pigs at the same time. BK-induced changes in pulmonary inflation pressure and blood pressure before and after the administration of ACE inhibitor were compared.


RESULTS
Imidaprilat and ramiprilat enhanced BK-induced hypotension comparably, and this effect was inhibited by Nomega-nitro-L-arginin-methylester (L-NAME, a nitric oxide synthetase inhibitor). Although imidaprilat did not affect BK-induced bronchoconstriction, ramiprilat enhanced the broncho-constriction significantly. SR48968, a selective NK2 receptor antagonist, significantly inhibited the enhancing effect of ramiprilat on BK-induced bronchoconstriction.


CONCLUSIONS
These results suggest that enhancement of BK-induced hypotension by imidaprilat and ramiprilat is mediated by nitric oxide (NO), but the mediator of the enhancing action of ramiprilat on BK-induced bronchoconstriction is mainly neurokinin A.
Doi
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Discovery Research Laboratory, Tanabe Seiyaku Co., Ltd., Toda, Saitama, Japan. h-doi@tanabe.co.jp
Narita
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D000803:Angiotensin I / Q000037:antagonists & inhibitors; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects*; D001920:Bradykinin / Q000494:pharmacology*; D016084:Bronchoconstriction / Q000187:drug effects*; D006168:Guinea Pigs; D007093:Imidazoles / Q000494:pharmacology*; D048289:Imidazolidines; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D017257:Ramipril / Q000031:analogs & derivatives* / Q000494:pharmacology
D000806:Angiotensin-Converting Enzyme Inhibitors; D001549:Benzamides; D001713:Biphenyl Compounds; D007093:Imidazoles; D048289:Imidazolidines; D010880:Piperidines; C052549:ramiprilat; C073839:SR 48968; D000803:Angiotensin I; D017257:Ramipril; D001920:Bradykinin; D019331:NG-Nitroarginine Methyl Ester; C066892:CP 96345; C078006:imidaprilat