COMPARISON OF THE ANTIATHEROGENIC EFFECTS OF ISRADIPINE AND RAMIPRIL IN CHOLESTEROL-FED RABBITS .1. EFFECT ON PROGRESSION OF ATHEROSCLEROSIS AND ENDOTHELIAL DYSFUNCTION

This study was designed to compare the effects of a calcium antagonist (isradipine) and a converting enzyme inhibitor (ramipril) on progress ion and regression of atherosclerosis in hypercholesterolemic rabbits. Sixty rabbits in three groups were fed a 0.3% cholesterol diet for 4 weeks. After this induction period, group II received the 0.3% cholest erol diet, group III received cholesterol diet with isradipine (0.33 m g/kg/day), and group IV received cholesterol with ramipril (0.33 mg/kg /day) for 12 more weeks. A group of 20 rabbits received a standard die t throughout the study (group I). After 16 weeks, 10 rabbits were rand omly chosen from each group and used in the progression study. The oth er rabbits were placed on a standard diet and remained on their respec tive drug regimen for 12 more weeks. In the progression phase of the s tudy, ramipril significantly attenuated the percentage of aortic lesio ns in group IV (35 +/- 6%) as compared with group II (56 +/- 6%, p < 0 .05), whereas isradipine had no effect. Acetylcholine (ACh)-induced ma ximum endothelium-dependent relaxations (EDR) of aortic rings were sig nificantly reduced by the atherogenic diet to 37 +/- 4 versus 77 +/- 2 % in group I (p < 0.05). Treatment with ramipril significantly improve d maximum EDR to 53 +/- 3% (p < 0.05 vs. group II), Isradipine had no significant effect on impaired EDR. Aortic rings with endothelium from group II developed supersensitivity to sodium nitroprusside (SNP) and had significantly reduced basal cyclic GMP levels as compared with th ose of group I. Both drugs prevented development of supersensitivity t o SNP and blunted the cholesterol-induced reduction in basal cyclic GM P levels. These data demonstrate that ramipril, but not isradipine, ef fectively suppresses further development of atherosclerotic lesions in face of continued hypercholesterolemia. Both drugs appear to prevent reduction of basal endothelium-derived relaxing factor/nitric oxide (E DRF/NO) release in hypercholesterolemic rabbits, however, thus preserv ing part of the antithrombotic function of the endothelium.