Open AccessPharmacological Studies on (4S)-1-Methyl-3-{(2S)-2-[N-((1S)-1-Ethoxycarbonyl-3-Phenylpropyl)amino] Propionyl}-2-Oxolmidazolidine-4-Carboxylic Acid Hydrochloride (TA-6366), a New ACE Inhibitor: I. ACE Inhibitory and Anti-Hypertensive Activities
Author(s) -
Masami Kubo,
Jien Kato,
Takashi Ochiai,
Ryuichi Ishida
Publication year - 1990
Publication title -
japanese journal of pharmacology/japanese journal of pharmacology
Language(s) - English
Resource type - Journals
eISSN - 1347-3506
pISSN - 0021-5198
DOI - 10.1254/jjp.53.201
Subject(s) - captopril , enalapril , bradykinin , chemistry , blood pressure , pharmacology , enzyme inhibitor , renin–angiotensin system , angiotensin converting enzyme , active metabolite , endocrinology , potency , hydrochloride , oral administration , plasma renin activity , kidney , angiotensin ii , medicine , metabolite , enzyme , in vitro , biochemistry , receptor
TA-6366 and its active metabolite 6366A inhibited swine renal angiotensin converting enzyme (ACE) activity with IC50s of 9900 and 2.6 nM, respectively. TA-6366 (0.05-0.5 mg/kg, p.o.) inhibited the angiotensin I (AT-I)-induced pressor response in rats. 6366A augmented bradykinin (BK)-induced contraction of guinea pig ileum more potently than captopril. However, when the augmentation on BK-induced hypotension in rats was used as an indicator, TA-6366 was less active than captopril. TA-6366 increased plasma renin activity and plasma AT-I concentration. Oral administration of TA-6366 lowered the blood pressure in two-kidney one-clip renal hypertensive rats at 0.5 to 2 mg/kg and in spontaneously hypertensive rats (SHRs) at 2 to 10 mg/kg. The antihypertensive effect of TA-6366 was approximately 5 times more potent than that of captopril and almost as potent as that of enalapril. In SHRs, the antihypertensive action of TA-6366 was intensified in potency when administered repeatedly. The duration of action was longer than those of captopril and enalapril. However, TA-6366 had no substantial effect on the blood pressure in DOCA/saline hypertensive rats. These results indicate that TA-6366 is a potent and long lasting antihypertensive agent and that its antihypertensive action is attributable to the inhibition of ACE.