Effect of nisoldipine on atherosclerosis in the cholesterol fed rabbit: endothelium dependent relaxation and aortic cholesterol content.
OBJECTIVE
The aim was to determine the effect of the calcium channel blocker nisoldipine on the loss of endothelium dependent relaxation and the accumulation of cholesterol in the aorta produced by feeding a diet enriched with cholesterol.


METHODS
12 week old New Zealand white rabbits were assigned randomly to four groups with the following dietary and drug regimens: group A--standard diet + 2.5% cholesterol (n = 45); group B--standard diet + nisoldipine (n = 9); group C--standard diet + nisoldipine + 2.5% cholesterol (n = 9); group D--standard diet (n = 9). After 3 weeks the cholesterol supplements were stopped and all animals were given the standard rabbit diet. The animals in groups B and C were given nisoldipine (1 mg.kg-1.d-1) by mouth for the entire 7 week period.


METHODS
Aortic tissue was removed for measurement of cholesterol content, endothelium dependent relaxation to acetylcholine, contractile responses to noradrenaline, relaxant responses to sodium nitrite, and sudan staining. Serum was obtained for measurement of cholesterol and triglyceride concentration.


RESULTS
At 7 weeks, endothelium dependent relaxation to acetylcholine was impaired in group A compared to group D, while that in group C was not. Aortic tissue cholesterol content in group A was significantly greater than in groups B, C, and D. At 15 weeks, ie, 12 weeks after reversal of the diet, endothelium dependent relaxation had recovered in the animals in group A. There was a significant reduction in the aortic cholesterol content at this stage. In two subgroups of A (groups A2 and A4) which were given nisoldipine immediately after and 4 weeks after cessation of cholesterol feeding respectively, the drug was found to have no influence upon restoration of endothelium dependent relaxation. However, the drug appeared to promote the retention of cholesterol within the aorta after cessation of cholesterol feeding.


CONCLUSIONS
Nisoldipine protects against the accumulation of cholesterol and loss of endothelium dependent relaxation in the aorta of rabbits fed a diet supplemented with 2.5% cholesterol for three weeks. Administration of the drug after the lesions are established in the aorta also appears to retard the removal of cholesterol from the aorta.
Kappagoda
C T
CT
Department of Medicine, University of Alberta, Edmonton, Canada.
Thomson
A B
AB
Senaratne
M P
MP
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D001161:Arteriosclerosis / Q000473:pathology / Q000517:prevention & control*; D002784:Cholesterol / Q000097:blood / Q000378:metabolism; D002791:Cholesterol, Dietary / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects; D008855:Microscopy, Electron, Scanning; D015737:Nisoldipine / Q000494:pharmacology*; D009638:Norepinephrine / Q000494:pharmacology; D011817:Rabbits; D012977:Sodium Nitrite / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects
D002791:Cholesterol, Dietary; D015737:Nisoldipine; D002784:Cholesterol; D012977:Sodium Nitrite; D000109:Acetylcholine; D009638:Norepinephrine