CHRONIC ANGIOTENSIN-CONVERTING ENZYME-INHIBITION AND ENDOTHELIAL FUNCTION OF RAT AORTA

To determine whether chronic angiotensin-converting enzyme (ACE) inhibition produces functional changes in the aorta of normotensive rats, four groups of rats were studied in parallel for 6 weeks. Group 1 orally received ramipril 10 mg/kg per day for 6 weeks; group 2, ramipril 10 mg/kg per day for 4 weeks and then a cotreatment with ramipril and beta(2)-kinin antagonist HOE140 500 mu g/kg per day SC by injection for the remaining 2 weeks; group 3, hydralazine 100 mg/kg per day PO for 6 weeks; group 4, (control), subcutaneous injections of saline solution during the last 2 of 6 weeks. In aorta isolated from group 1 the relaxations induced by bradykinin, acetylcholine, and histamine were significantly potentiated compared with those of group 4. In group 3, despite a decrease in systolic blood pressure similar to that induced by ramipril treatment, the responses to these three endothelium-dependent vasodilators were not different from those of group 4. In group 2, bradykinin-induced relaxations were completely abolished whereas acetylcholine-induced and histamine-induced relaxations were similar to those of group 4. The inhibitory effect of the endothelium on serotonin-induced contractions was significantly increased in preparations of group 1 compared with those of groups 2 through 4. Indirect measurements of nitric oxide formation such as contractions evoked by N-G-monomethyl-L-arginine (L-NMMA) and aortic cGMP content were also significantly enhanced in preparations from group 1 compared with those of groups 2 and 4. Moreover, because the relaxations to nitroglycerin and nitroprusside were similar in groups 1, 2, and 4 an alteration of the guanylate cyclase activity by ramipril treatment is quite unlikely. Thus long-term treatment with ramipril potentiates the endothelium-dependent responses in the rat aorta by enhancing nitric oxide availability. This effect seems to involve an inhibition of bradykinin breakdown facilitating nitric oxide release via endothelial beta(2)-receptors.