Antihypertensive Action of a Non-Sulfhydryl Angiotensin Converting Enzyme Inhibitor (CV-3317) in Various Hypertensive Models

Abstract

Abstract-The antihypertensive action of N-[N-[(S)-1-ethoxycarbonyl-3-phenyl propyl]-L-alanyl]-N-(indan-2-yl)glycinehydrochloride (CV-3317), a nonsulfhydryl compound characterized as an angiotensin converting enzyme inhibitor in our previous work, was examined in hypertensive animal models.In 2-kidney, 1 clip hypertensive rats and dogs, CV-331 7 (3 and/or 10 mg/kg, p.o.) produced a sustained antihypertensive action of about 15 to 25 mmHg. Daily oral administrations of CV-3317 (1 to 10 mg/kg/day) to spontaneously hypertensive rats (SHR) for 5 weeks produced a sustained antihypertensive action of 20 to 40 mmHg. When CV-3317 (3 mg/kg) was combined with hydrochlorothiazide (10 mg/kg), its anti hypertensive action was intensified in potency and duration.CV-3317 (30 mg/ kg) induced a slight hypotension (5 to 10 mmHg) in normotensive rats, but had no effect on the blood pressure of 1 -kidney, 1 clip hypertensive rats and on that of a low renin type of DOCA/salt hypertensive rat. The antihypertensive activity of CV-3317 was more potent than that of captopril.In pithed SHR, the pressor response induced by an electrical stimulation of the preganglionic sympathetic nerve, but not the pressor response to norepinephrine, was attenuated by both agents (0.3 mg/kg, i.v.). Both agents may exert their antihypertensive action not only primarily by inhibiting the renin-angiotensin system, but also by inhibiting norepinephrine release from the sympathetic nerve terminals indirectly by reducing the formation of vascular angiotensin II.

Inhibition of Angiotensin Converting Enzyme by CV-3317, a Non-Sulfhydryl Compound

“…It has been reported that in SHR, the level of plasma renin is normal and the levels of vascular renin and ACE are high (21,22); in 2-kidney, 1 clip hypertensive rats, the level of plasma renin, vascular renin and vascular ACE are high (23); and in 1 -kidney, 1 clip hypertensive rats, the level of vascular renin is high (24), but vascular ACE is normal (25). and captopril elicited an anti hypertensive action only in SHR and 2 kidney, 1 clip hypertensive rats with a high vascular ACE activity (12). These findings suggest that the antihypertensive effect of CV-3317 and captopril is closely related to the inhibition of vascular ACE.…”

Inhibition of Angiotensin Converting Enzyme by (R)-3-[(S)-1-Carboxy-5-(4-Piperidyl)pentyl]amino-4-Oxo-2,3,4,5-Tetrahydro-1,5-Benzothiazepine-5-Acetic Acid (CV-5975), a Non-Sulfhydryl Compound

“…In conclusion, CV-5975 is a highly potent and long acting inhibitor of ACE activity and possesses a long-lasting anti hypertensive action in animal models of hypertension (10).…”

“…1), seemed to be the most promising ACE inhibitor (9). This agent has a potent and long lasting antihypertensive activity, as noted in various models of hyper tension in laboratory animals (10). We report here the ACE inhibitory activity of CV-5975, in vitro and in vivo, as compared with the findings on enalapril and enalaprilat.…”

Long-Term Effects of Delapril Hydrochloride on Procollagen Type III Amino-Terminal Peptide, Left Ventricular Mass and Left Ventricular Function in Hypertensive Patients

“…It is reported that angiotensin converting enzyme (ACE) inhibitors are more effective than -blockers, calcium antagonists, and diuretics in reducing left ventricular mass (LVM). 5 We therefore assessed the clinical effect of delapril hydrochloride (an ACE inhibitor) 6 from the viewpoint of echocardiographically determined cardiac function and LVH, as well as the serum concentrations of procollagen type III aminoterminal peptide (PIIIP) as reflected in the production of collagen type III.…”