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The comparative effects of lisinopril, a third generation angiotensin converting enzyme (ACE) inhibitor, on components of the renin-angiotensin system were assessed in normal and in an animal model of diabetes-related hypertension, the streptozotocin-diabetic rat. Two weeks after injection of streptozotocin the mean systolic blood pressure of diabetic rats was elevated 11% above that of normal rats. This effect was prevented by daily injection of insulin. The mean serum ACE activity was elevated 71% above that of normal rats. Lisinopril reduced systolic blood pressure and inhibited serum ACE activity in both normal and diabetic rats in a dose-response fashion. In normal rats maximum inhibition of blood pressure occurred at a mean dose of 1.0 mg/kg and in the diabetic rat at a mean dose of 5.0 mg/kg. At a mean dose of 5 mg/kg, ACE was inhibited by 100 and 92% in normal and diabetic rats, respectively. Plasma renin activity (PRA) increased sharply in both groups of rats treated with the lower doses of lisinopril, only to decrease at the 5 mg/kg level. At 20 mg/kg, PRA continued to decline in normal animals, but not in diabetic rats. Formation of angiotensin II (Ang II) in both normal and diabetic rats was maximally inhibited at doses of 1.0 and 0.1 mg/kg of lisinopril, respectively without a significantly greater effect at the higher doses of the drug.In separate experiments the effects of chronic treatment with lisinopril at two dosage levels on various physiological parameters of streptozotocin-diabetic rats were compared with the effects of another hypotensive agent, hydralazine, an arteriolar vasodilator. Diabetes caused a systolic blood pressure increase ranging from 17 to 4% over a 26-week period. Lisinopril reduced the systolic blood pressure throughout the treatment period on average by 22% (range, 17-33%) at a mean dose of 4 mg/kg per day and 27% (range, 21-30%) at a mean dose of 20 mg/kg per day. Hydralazine (mean dose, 10 mg/kg per day) lowered systolic blood pressure somewhat less effectively. As expected, lisinopril (20 mg/kg) completely inhibited the serum ACE activity and reduced it by 91% at the lower dose. Surprisingly, chronic treatment with hydralazine significantly reduced serum ACE by 30%. Taken together these studies demonstrate:(1) a model of diabetes-related hypertension which is responsive to treatment with lisinopril,(2) the relative sensitivities to lisinopril of the renin-angiotensin system of normal and diabetic rats and(3) a difference in the response to lisinopril of PRA in normal compared to diabetic rats.