We have developed a new model to study the interaction between diet and genetics in atherogenesis, the cholesterol-fed heterozygous WHHL rabbit. To determine the effects of calcium blockers on atherosclerosis in this model, two groups of heterozygous WHHL rabbits were fed 0.25% cholesterol and 2% peanut oil with (n = 6) and without (n = 6) oral nifedipine (40 mg/kg/day) for 16 weeks. Body weights, serum cholesterol, triglycerides and calcium, and blood pressures were not significantly different between the 2 groups during the study period. Heterozygous WHHL rabbits in the nifedipine group had less aortic surface area with sudanophilic lesions (23 +/- 15% vs. 62 +/- 18%, P less than 0.01) and fewer segments of coronary arteries with lesions (19 +/- 9% vs. 35 +/- 8%, P less than 0.02). Total aortic cholesterol, phospholipid, and calcium were also reduced in nifedipine-treated rabbits compared with untreated animals. We conclude that nifedipine reduced atherosclerosis in this model. Although the mechanism is unknown, it is apparent that nifedipine acts independently of changes in plasma lipids and blood pressure.