RAMIPRIL PREVENTS IMPAIRED ENDOTHELIUM-DEPENDENT RELAXATION IN ARTERIES FROM RABBITS FED AN ATHEROGENIC DIET

Endothelium-dependent relaxation in arteries is attenuated in clinical and experimental atherosclerosis. This study investigates the endothelial preservation properties of the angiotensin converting enzyme inhibitor, ramipril, by assessing its ability to restore endothelium-dependent responsiveness in blood vessels from rabbits fed an atherogenic diet (0.25% cholesterol; 3% coconut oil; 12 weeks). Seven rabbits fed the atherogenic diet received ramipril (3 mg/kg mixed into their food daily) and 6 rabbits were maintained on the atherogenic diet alone. Control rabbits (n = 6) were fed a standard diet and did not receive ramipril. At the end of the dietary intervention, the rabbits were killed and blood was collected for measurement of the lipid profile. The thoracic aorta was isolated and half was frozen for pathologic review while the other half was cut into rings and placed in a muscle bath for measurement of isometric force development. Dose response curves to phenylephrine (10(-9) to 10(-5) M) and angiotensin II (10(-10) to 3 x 10(-7) M) were completed. There was a minimal decrease in responsiveness to phenylephrine in vessels from rabbits eating the atherogenic diet compared with controls and no significant differences in the response to angiotensin II for any of the vessels. Following contraction by phenylephrine, acetylcholine (10(-9) to 10(-5) M) and nitroglycerin (10(-10) to 10(-5) M) dose response curves were completed. Relaxation to acetylcholine in aortic rings from control rabbits was observed, . although in arteries from atherogenic rabbits relaxation was attenuated. This effect was prevented in the atherogenic rabbits fed ramipril. Responsiveness to the endothelium-independent vasodilator, nitroglycerin, was similar in arteries from the three rabbit groups. Total cholesterol levels were elevated in the rabbits fed the atherogenic diet and in the rabbits fed the atherogenic diet containing ramipril. High density lipoprotein (HDL) cholesterol levels were not affected by the atherogenic diet alone, but when ramipril was added, there was a significant increase in HDL cholesterol levels. The percentage of aortic surface covered with lipid streaks was not significantly different in the three rabbit groups. We conclude that ramipril prevents endothelial dysfunction in arteries from rabbits fed an atherogenic diet. Mechanistically, this effect of ramipril on the endothelium must occur prior to the release of nitric oxide as no alteration in the dose response curve to nitroglycerin could be identified. Additionally, this improvement in endothelial function in rabbits supplemented with ramipril appears to be independent of morphologic changes in the aorta in response to the atherogenic diet.