General pharmacology of the novel angiotensin converting enzyme inhibitor benazepril hydrochloride. Effects on cardiovascular, visceral and renal functions and on hemodynamics.

The effects of benazepril hydrochloride (CGS 14824 A, CAS 86541-74-4), a novel angiotensin I converting enzyme inhibitor, on cardiovascular, visceral and renal functions and on hemodynamics, were studied in various experimental animals. Even at a high dose of 100 mg/kg p.o. benazepirl hydrochloride had no influence on the respiration, heart rate and ECG of normotensive anesthetized cats and, except at higher doses, had little effect on the contractile tension of mammalian isolated atrium, ileum, trachea, stomach fundus strips, vas deferens or uterus. Benazepril hydrochloride even at a high dose of 100 mg/kg p.o. had little effect on spontaneous uterine motility, charcoal transportation and gastrointestinal tract motility. In addition, it did not cause gastric irritation, alter the secretion of gastric and biliary juices, and did not affect the tension of the nictitating membrane or the twitch tension of the gastrocnemius muscle in various experimental animals. Benazepril hydrochloride had no effect on the blood glucose and cholesterol levels in alloxan-induced diabetic rats but decreased the triglyceride and total cholesterol levels in normotensive rats at a dose of 30 mg/kg p.o. Benazepril hydrochloride at 3 mg/kg.day s.c. for 10 weeks caused a significant decrease in aortic atherosclerosis without reducing hypercholesterolemia in cholesterol-fed rabbits. Benazepril hydrochloride at a high dose of 100 mg/kg p.o. showed no effect on the urine volume and urinary excretion of electrolytes but decreased PSP excretion in normotensive rats. At a dose of 3 or 10 mg/kg.day p.o. for 4 weeks benazepril hydrochloride inhibited the increase in the excretion of urinary protein in DOCA/salt spontaneously hypertensive rats. It caused hemolysis at concentrations as high as 0.1-1% in rabbits, however, even at a high dose of 100 mg/kg p.o. it did not affect red blood cell fragility in rats, and, except at a high dose of 10(-4) g/ml, showed little effect on the platelet aggregation response induced by collagen or arachidonic acid in rabbits. From these results, benazepril hydrochloride is considered to be a safe and well-tolerated addition to the therapeutic armamentarium of cardiovascular drugs.

[Effects of cadralazine on the respiration, circulation, kidney, autonomic nervous system, digestive system, blood and so on].

The general pharmacological effects of cadralazine and its major metabolite ISF 2405 were studied by comparing them with those of hydralazine. Cadralazine at 3.0 mg/kg, i.v., increased respiratory movement and heart rate and decreased blood pressure in cats. Cadralazine at 3.0 mg/kg, i.v., inhibited the hypertensive response induced by adrenaline, but showed little effect on the hypotensive response induced by acetylcholine in cats. Cadralazine and ISF 2405 at 10(-4) g/ml had negative chronotropic effects on isolated guinea-pig atria. The drug at 2.5 mg/kg, p.o., inhibited the passage of BaSO4 in the gastrointestinal tract in mice. The drug at 5.0 mg/kg, i.d. or more inhibited gastric secretion in rats. Cadralazine, except at higher doses, had little effect on spontaneous gastric motility and uterine spontaneous movement in rats. Cadralazine at 2.5 mg/kg, p.o., or more reduced or tended to reduce urine volume and urinary excretion of electrolytes. The drug showed little effect on coagulation and osmotic fragility in blood cell in rats nor on hemolysis and platelet aggregation in rabbits. ISF 2405, however, showed slight or moderate influence on hemolysis at concentrations as high as 0.01-1.0%. Cadralazine at 5.0 mg/kg, p.o. or more antagonized carrageenin-induced hind paw edema in rats. In conclusion, these effects of cadralazine were found to be qualitatively identical with those of hydralazine.