angiotensin-i and delapril

An oral controlled-release drug delivery system based on microspheres of polyglycerol esters of fatty acids (PGEFs), was applied to an anti-hypertensive, delapril hydrochloride. The in-vitro release profile was controlled by selecting a PGEF with an appropriate hydrophilic-lipophilic balance value for the matrix. The microspheres from which 80% of the drug was released in 6 h were orally administered to rats. The plasma concentration of the active metabolite was sustained after administration of the microspheres in comparison with administration of a solution. The in-vivo release profile was in good agreement with the in-vitro release profile. When the microspheres were administered, the pharmacological effect of delapril hydrochloride on the angiotensin I-induced pressor response was also sustained showing consistency with the plasma concentration-time curve.

Topics: Administration, Oral; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Delayed-Action Preparations; Glycerides; Hydrogen-Ion Concentration; Indans; Male; Microspheres; Polymers; Rats; Rats, Sprague-Dawley; Solubility; Stearates

The pathophysiological role of angiotensin II in the development of renal sclerosis was investigated in 5/6-nephrectomized, 12-week-old male spontaneously hypertensive rats. After 1 week of a control period, nephrectomized rats received one of the following treatments for 4 weeks: the selective nonpeptide angiotensin II type 1 receptor antagonist TCV-116 (1 mg/kg per day), the angiotensin converting enzyme inhibitor delapril (30 mg/kg per day), hydralazine (15 mg/kg per day), or vehicle. Urinary protein and albumin excretions and systolic blood pressure were determined every week. Rats with reduced renal mass treated with vehicle had a poor survival rate (30%). Although TCV-116, delapril, and hydralazine treatment significantly improved the survival rate for 4 weeks, hydralazine failed to improve proteinuria and albuminuria as well as the decline in renal function compared with delapril or TCV-116. Histological examination revealed that both TCV-116 and delapril protected glomeruli from sclerosis, whereas hydralazine did not improve histological findings (5%, 7%, and 30% of glomeruli were affected, respectively). These results indicate that angiotensin II plays a dominant role through its type 1 receptor in the pathogenesis of renal deterioration by hypertension.

Topics: Albuminuria; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Chromatography, High Pressure Liquid; Hydralazine; Hypertension; Indans; Kidney; Male; Proteinuria; Rats; Rats, Inbred SHR; Survival Analysis; Tetrazoles

The synthesis and biological activity of novel L-lysyl-N-substituted glycine derivatives which exhibit in vitro and in vivo angiotensin converting enzyme (ACE) inhibition, are described. Particularly, N-[N alpha-(1-carboxy-3-phenylpropyl)-L-lysyl]-N-(4-phenylcyclohexyl)glycine (11e), N-[N alpha-(1-carboxy-3-cyclopentylpropyl)-N epsilon-carbobenzoxy-L- lysyl]-N-cyclopentyl glycine (9h) and N-[N alpha-[1(S)-carboxy-3-cyclohexylpropyl]-L-lysyl]-N-cyclopentyl glycine (19a) showed a strong inhibitory activity at IC50 as low as 0.65, 0.64 and 0.11 nmol/l, respectively. The most potent activity in vivo was observed with the compound 19a after i.v. administration in the rat.

Topics: Angiotensin I; Angiotensin-Converting Enzyme Inhibitors; Animals; Chemical Phenomena; Chemistry; Glycine; In Vitro Techniques; Indans; Indenes; Lung; Lysine; Peptidyl-Dipeptidase A; Rabbits; Rats; Rats, Inbred Strains; Stereoisomerism

N-[N-[(S)-1-Ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-N-(indan-2- yl)glycine hydrochloride (CV-3317) and its de-esterified products, CV-3317-COOH and CV-3317-(5-OH)-COOH, inhibited rabbit lung angiotensin converting enzyme (ACE) with the IC50s of 1.2 X 10(-7), 4.0 X 10(-8) and 4.9 X 10(-8) M, respectively, angiotensin I (A-I)-induced vasoconstriction of the rat aorta (IC50: 2.6 X 10(-7), 2.6 X 10(-8) and 5.4 X 10(-8) M, respectively), and A-I-induced pressor response of the rat kidney (IC50: 3.9 X 10(-7), 3.5 X 10(-8) and 2.8 X 10(-8) M, respectively). In these 3 experiments, both de-esterified products were 4 to 14 times more potent than captopril. In rats, CV-3317 (0.0138 to 138 mumol/kg, p.o.) inhibited plasma and lung ACEs, and the effects at a dose of 0.46 mumol/kg lasted more than 8 hr. CV-3317 inhibited the A-I-induced pressor action in rats (0.138 to 13.8 mumol/kg, p.o. or 0.046 to 0.138 mumol/kg i.v.) and dogs (0.46 to 4.6 mumol/kg, p.o.) in a dose-related manner. CV-3317 was more potent and longer acting than captopril in these in vivo ACE inhibitions. CV-3317 augmented bradykinin-induced hypotension (dogs) and contraction of the ileum (guinea pigs) less potently than captopril. In spontaneously hypertensive rats (SHR), CV-3317 (3 mg/kg, p.o.) markedly inhibited plasma and tissue (aorta, kidney, lung and brain) ACEs; and when administered daily for 2 weeks, it inhibited the plasma, aorta, kidney and lung ACEs; in particular, it markedly inhibited the aortic ACE. Captopril (30 mg/kg, p.o.) markedly inhibited tissue ACEs and slightly plasma ACE, but its inhibitory effects on tissue ACEs, except for the aorta, were unclear by repeated dosings and its effect on plasma ACE was rather enhanced. Thus, the inhibition of vascular ACE may be particularly important for the antihypertensive effect of the ACE inhibitors, including CV-3317, in SHR.

Topics: Angiotensin I; Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta, Thoracic; Blood Pressure; Bradykinin; In Vitro Techniques; Indans; Indenes; Kidney; Lung; Male; Muscle Contraction; Muscle, Smooth; Peptidyl-Dipeptidase A; Rabbits; Rats; Rats, Inbred Strains; Vasoconstriction