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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1995;15:1152-1160.)
© 1995 American Heart Association, Inc.

Articles

Development and Progression of Atherosclerosis in Aorta From Heterozygous and Homozygous WHHL Rabbits

Effects of Simvastatin Treatment

Presented in part to the British Pharmacological Society, September 1993, Rome, Italy.

F. J. Dowell; C. A. Hamilton; G. B. M. Lindop; J. L. Reid

From the Department of Medicine and Therapeutics and the Department of Pathology (G.B.M.L.), Western Infirmary, Glasgow, UK.

Correspondence to F.J. Dowell, Clinical Research Initiative, West Medical Building, University of Glasgow, G12 8QQ, UK.

Abstract This study was conducted to define progression of atherosclerosis in both homozygous and heterozygous Watanabe heritable hyperlipidemic (WHHL) rabbits and to investigate the ability of the HMG CoA reductase inhibitor simvastatin to attenuate progression of the disease. We examined contractile responses to phenylephrine and endothelium-dependent relaxation in response to carbachol in thoracic aorta at 3, 6, 9, and 12 months in control New Zealand White (NZW) rabbits, homozygous WHHL rabbits, and heterozygous WHHL rabbits. Homozygous and heterozygous rabbits were treated with simvastatin (10 mg/kg per day) from 3 to 6 months and from 9 to 12 months of age. Simvastatin significantly reduced serum cholesterol levels in young heterozygotes, with a nonsignificant trend toward a reduction in older heterozygotes. In homozygotes, no significant fall was observed. Contractile function declined progressively with age in all groups-most in homozygotes and least in NZW rabbits. Relaxation was unaffected by age in NZW rabbits; relaxation declined in the heterozygotes and declined to a greater extent in homozygotes. Simvastatin retarded the loss of function in the young heterozygotes. Similar trends were observed in young homozygotes and older heterozygotes, with no effect in older homozygotes. Histological studies revealed the progressive development of early atherosclerosis in heterozygotes, and more advanced atherosclerosis was observed in homozygotes. Simvastatin did not inhibit development of atheroma. A correlation was observed between vascular function and structure. However, functional changes preceded the development of atheroma. In addition, we have demonstrated that simvastatin can help to reduce the loss of vascular function associated with the progression of atherosclerosis in the heterozygous WHHL rabbit.

Key Words: endothelium • simvastatin • aorta • atherosclerosis • WHHL rabbits

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