Comparison of the antiatherogenic effects of isradipine and ramipril in cholesterol-fed rabbits: II. Effect on regression of atherosclerosis and restoration of endothelial function.
We report the effects of isradipine and ramipril on regression of diet-induced atherosclerosis in rabbits. Regression of diet-induced atherosclerosis was not significantly affected by ramipril, but isradipine significantly retarded regression. Thirty rabbits in three groups were fed a 0.3% cholesterol diet for 4 weeks. After this induction period, group IIr received the 0.3% cholesterol diet, group IIIr received the 0.3% cholesterol diet with isradipine (0.33 mg/kg/day), and group IVr received the 0.3% cholesterol diet with ramipril (0.33 mg/kg/day) for 12 more weeks. The rabbits then received a standard diet and remained on their respective drug regimen for 12 more weeks. Group Ir (10 rabbits) received a standard diet for 28 weeks. Acetylcholine (ACh)-induced maximal endothelium-dependent relaxations (EDR) of aortic rings were significantly less in group IIr (22.8 +/- 3.2%) than in group Ir (66.4 +/- 4.0%; p < 0.05). Ramipril and isradipine did not improve EDR as compared with group IIr. Regression of atherosclerosis was accompanied by an improved endothelium-dependent releasing factor (EDRF) release from the endothelium, but ramipril and isradipine did not promote this process. In addition, regression was associated with increasing sensitivity of vascular smooth muscle to EDRF that was significantly retarded by isradipine but not ramipril. Basal cyclic GMP levels were significantly reduced in aortic rings from group IIr as compared with group Ir. Ramipril, but not isradipine, restored basal cyclic GMP levels to control values. Both isradipine and ramipril protect against endothelial degeneration in hypercholesterolemic rabbits. However, isradipine but not ramipril inhibits regression of diet-induced atherosclerosis in rabbits.
Riezebos
J
J
Department of Pharmacotherapy, University of Utrecht, The Netherlands.
Vleeming
W
W
Beems
R B
RB
van Amsterdam
J G
JG
Meijer
G W
GW
de Wildt
D J
DJ
Porsius
A J
AJ
Wemer
J
J
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D001161:Arteriosclerosis / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D015415:Biomarkers; D002784:Cholesterol / Q000097:blood; D002791:Cholesterol, Dietary / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D004036:Diet, Atherogenic; D004730:Endothelium, Vascular / Q000473:pathology / Q000503:physiopathology*; D066298:In Vitro Techniques; D017275:Isradipine / Q000627:therapeutic use*; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009569:Nitric Oxide / Q000378:metabolism / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D010743:Phospholipids / Q000097:blood; D011817:Rabbits; D017257:Ramipril / Q000627:therapeutic use*; D014280:Triglycerides / Q000097:blood
D015415:Biomarkers; D002791:Cholesterol, Dietary; D010743:Phospholipids; D014280:Triglycerides; D009599:Nitroprusside; D009569:Nitric Oxide; D002784:Cholesterol; D000242:Cyclic AMP; D006152:Cyclic GMP; D017257:Ramipril; D000109:Acetylcholine; D017275:Isradipine