Effects of the new angiotensin-I-converting enzyme inhibitor imidapril on the responses of isolated vascular preparations to various agonists.
Effects of imidapril hydrochloride ((-)-(4S)-3-[(2S)-2-[[(1S)-1- ethoxycarbonyl-3-phenylpropyl]amino]propionyl]-1-methyl-2- oxoimidazolidine-4-carboxylic acid hydrochloride, imidapril, TA-6366, CAS 89396-94-1), a new prodrug type angiotensin converting enzyme (ACE) inhibitor, and 6366 A (CAS 89371-44-8), an active metabolite of imidapril, on isolated vascular preparations were studied. 6366 A inhibited angiotensin I (AT-I)-induced contraction of the rabbit thoracic aorta at 3 x 10(-10) mol/l or more and augmented bradykinin (BK)-induced relaxation of the dog renal artery precontracted with prostaglandin F2 alpha PGF2 alpha at 10(-9) mol/l or more, whereas imidapril at 10(-7) mol/l did not affect these responses. However, 6366 A, like imidapril, had no effect on angiotensin II (AT-II), norepinephrine, serotonin-, KCl- and PGF2 alpha-induced contractions. The inhibitory effect of 6366 A on AT-I-induced contraction was attenuated by denudation of the endothelium, but it was still maintained even after washing out the aorta that had been previously exposed to the medium containing 6366 A. This suggests that 6366 A persistently inhibits the angiotensin I converting enzyme located preferentially in the endothelium. Therefore, the antihypertensive action of imidapril is mainly attributable to the vasodilation through the inhibitory effects of 6366 A on AT-II synthesis and BK degradation in the vasculature.
Kubo
M
M
Pharmacological Research Laboratory, Tanabe Seiyaku Co., Ltd., Osaka, Japan.
Fujitsuka
T
T
Ishida
R
R
D000803:Angiotensin I / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D001920:Bradykinin / Q000494:pharmacology; D015237:Dinoprost / Q000494:pharmacology; D004285:Dogs; D004730:Endothelium, Vascular / Q000502:physiology; D005260:Female; D007093:Imidazoles / Q000494:pharmacology*; D048289:Imidazolidines; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009638:Norepinephrine / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D011817:Rabbits; D012701:Serotonin / Q000494:pharmacology
D000806:Angiotensin-Converting Enzyme Inhibitors; D007093:Imidazoles; D048289:Imidazolidines; D000804:Angiotensin II; D012701:Serotonin; D011189:Potassium Chloride; D000803:Angiotensin I; D015237:Dinoprost; C065166:imidapril; D001920:Bradykinin; D009638:Norepinephrine