Cholesterol-Diet Induced Atherosclerosis in Rabbits and Other Species

Cholesterol-Diet Induced Atherosclerosis in Rabbits and Other Species 

The additional anti-atherosclerotic potential of a candidate compound with a different primary indication does not represent a safety concern. In contrast, the atherogenic potential of a candidate compound, identified during safety pharmacological evaluation, represents a serious safety issue. Development of atherosclerosis needs time and therefore multiple dose studies are necessary to detect a putative anti-atherosclerotic or atherogenic side effect potential of a candidate compound. 

Experimental atherosclerosis was first successfully induced in rabbits by Saltykow (1908) and Ignatowski (1909). During the following years, various scientists found that dietary cholesterol was the responsible stimulus for development of atherosclerosis. Other species are also susceptible to diet-induced atherosclerosis (Reviews by Kritchevsky 1964 Hadjiinky et al. 1991). A unifying hypothesis of the pathogenesis of atherosclerosis has been proposed by Schwartz et al. (1991). 

PURPOSE AND RATIONALE Rabbits are known to be susceptible to hypercholesterolemia and arteriosclerosis after excessive cholesterol feeding (supplemented with 0.3-2% cholesterol in the diet). Therefore, this approach has been chosen by many authors to study the effect of potential anti-atherosclerotic drags. For studying the atherogenic potential of a candidate compound a low cholesterol concentration in the diet (0.1-0.3%) is recommended (pro-atherogenic). 

The animals are sacrificed and the thoracic aorta is removed, cleaned of surrounding tissues, and longitudinally cut and opened for fixation with formaldehyde. The tissue is stained with oil red. The percentage of the intimal surface covered by the oil red positive lesions is calculated with a computerized planimeter. In animals fed a normal diet, the aorta does not show any staining, whereas in cholesterol-fed rabbits the aorta shows severe atherogenic lesions. 

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