Anti-atherosclerotic activity of the calcium antagonist lacidipine in cholesterol-fed hamsters.
We have investigated the activity of the calcium antagonist lacidipine in male hamsters fed an atherogenic diet containing 2% cholesterol and 5% butter. Animals were examined at 14, 20 and 24 weeks of treatment. At 14 weeks, in hamsters fed the atherogenic diet and without lacidipine treatment, there were significant increases in serum levels of total cholesterol, triglycerides and lipoproteins; these values were approximately similar at week 24. Lacidipine treatment at 0.3, 1.0 and 3.0 mg/kg/d did not affect levels of serum cholesterol, triglycerides and lipoproteins. At 24 weeks, in hyperlipidemic hamsters fed the atherogenic diet, the area of the fatty streak in the aortic arch covered a mean area of 375 +/- 145 micron2 x 100, which accounted for 2.7% of the total surface area of the aortic arch. In hamsters fed the atherogenic diet and treated with lacidipine at 0.3, 1.0 and 3.0 mg/kg, at 24 weeks, the surface area of the aortic arch lesion was significantly reduced by 41 to 71%. In the thoracic aorta at 24 weeks, in lacidipine-treated animals, both the incidence and degree of severity of the lesions was reduced, the area of the fatty streak being lowered by 78 to 97% in comparison with non-lacidipine-treated control animals. Ultrastructural examination demonstrated that the early changes in the aorta in hamsters fed the atherogenic diet involved the intima and smooth muscle cells; lacidipine treatment reduced the severity of the intimal lesions significantly. With SEM, lacidipine administration was seen to reduce endothelial irregularity and the presence of crater-like lesions. At TEM, treatment with lacidipine reduced the number of foam cells and the presence of liposomes in the subendothelium. This investigation demonstrates that in the hyperlipidemic hamster, lacidipine treatment decreases atheromatous lesions without lowering serum lipids. It is suggested that lacidipine influences the atherogenic process by an unusual mechanism which may be related to a combination of both the long-lasting calcium antagonism of the drug and significant antioxidant activity.
Cristofori
P
P
GlaxoWellcome Research Laboratories, GlaxoWellcome SpA, Verona, Italy.
Lanzoni
A
A
Gaviraghi
G
G
Turton
J
J
Sbarbati
A
A
D000818:Animals; D001013:Aorta, Thoracic / Q000648:ultrastructure; D001161:Arteriosclerosis / Q000188:drug therapy*; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000627:therapeutic use*; D002784:Cholesterol / Q000097:blood; D002791:Cholesterol, Dietary / Q000009:adverse effects; D006224:Cricetinae; D004095:Dihydropyridines / Q000008:administration & dosage / Q000627:therapeutic use*; D004195:Disease Models, Animal; D008055:Lipids / Q000097:blood; D008074:Lipoproteins / Q000097:blood; D008297:Male; D008647:Mesocricetus
D002121:Calcium Channel Blockers; D002791:Cholesterol, Dietary; D004095:Dihydropyridines; D008055:Lipids; D008074:Lipoproteins; C030104:lipoprotein cholesterol; C060285:lacidipine; D002784:Cholesterol