Antihypertensive action of a new angiotensin converting enzyme inhibitor, (R)-3-[(S)-1-carboxy-5-(4-piperidyl)pentyl]amino-4-oxo-2,3,4,5-tetr ahy dro-1,5-benzothiazepine-5-acetic acid (CV-5975), in various hypertensive models.
The antihypertensive activity of a new angiotensin converting enzyme (ACE) inhibitor, CV-5975, (R)-3-[(S)-1-carboxy-5-(4-piperidyl)pentyl] amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid, was examined in normotensive rats and various hypertensive animal models. In spontaneously hypertensive rats, CV-5975 (1 to 10 mg/kg, p.o.) had a dose-related, sustained antihypertensive action, which was more potent and longer than that of enalapril. The potency and duration of action of CV-5975 was intensified when it was administered repeatedly or combined with hydrochlorothiazide. CV-5975 (1 mg/kg, p.o.) inhibited the ACE activity of plasma and tissues; inhibition on the ACE activity of the aorta, kidney, and brain was marked when CV-5975 was administered repeatedly. In 2-kidney, 1 clip hypertensive rats (1 to 10 mg/kg, p.o.) and dogs (0.3 and 1 mg/kg, p.o.), CV-5975 had a marked, sustained antihypertensive action, which was more marked than that of enalapril. In normotensive rats (10 mg/kg), 1-kidney, 1 clip hypertensive rats (3 and 10 mg/kg), and hyporeninemic DOCA/salt hypertensive rats (1 to 10 mg/kg/day), CV-5975 administered orally once or repeatedly reduced blood pressure, whereas enalapril did not. These results indicate that CV-5975 is a potent and long-lasting antihypertensive agent, the action of which is mediated primarily by inhibiting ACE activity and partly by some unknown mechanisms.
Inada
Y
Y
Biology Laboratories, Takeda Chemical Industries, Ltd., Osaka, Japan.
Tanabe
M
M
Kawazoe
K
K
Nishikawa
K
K
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000959:Antihypertensive Agents; D001794:Blood Pressure / Q000187:drug effects; D004285:Dogs; D004656:Enalapril / Q000494:pharmacology; D006852:Hydrochlorothiazide / Q000627:therapeutic use; D006973:Hypertension / Q000188:drug therapy* / Q000503:physiopathology; D006977:Hypertension, Renal / Q000188:drug therapy; D008297:Male; D007703:Peptidyl-Dipeptidase A / Q000097:blood; D051381:Rats; D011918:Rats, Inbred SHR; D011919:Rats, Inbred Strains; D012083:Renin / Q000097:blood; D013045:Species Specificity; D013841:Thiazepines / Q000494:pharmacology* / Q000627:therapeutic use
D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D013841:Thiazepines; D006852:Hydrochlorothiazide; C054055:CV 5975; D004656:Enalapril; D007703:Peptidyl-Dipeptidase A; D012083:Renin