We studied the effects of nifedipine, a calcium antagonist, on atherosclerosis in cholesterol-fed rabbits and Watanabe heritable hyperlipidemic rabbits (WHHL rabbits). Japanese White rabbits were fed 120g of 2% cholesterol rabbit chow daily, and WHHL rabbits were fed standard rabbit chow. In each experiment, the rabbits were divided into two groups. Twenty milligrams of nifedipine was given orally twice a day to the nifedipine group, and the control group was given a placebo in the same way. The rabbits were sacrificed at the end of the 12th week in the case of cholesterol-fed rabbits, and the 20th week in the case of WHHL rabbits. Among the cholesterol-fed rabbits, the percentage of aortic intimal surface area covered by atherosclerotic lesions (AS%) was 25.9 +/- 7.6% (mean +/- S.D.) in the nifedipine group (n = 7), and 55.6 +/- 22.8% in the placebo group (n = 8) (p less than 0.01). The cholesterol content of thoracic and abdominal aorta in the nifedipine group was lower than those in the placebo group (p less than 0.05). Among the WHHL rabbits, the AS% was 33.4 +/- 14.1% in the nifedipine group (n = 5), and 27.0 +/- 11.7% in the placebo group (n =6) (n.s.). The aortic cholesterol and calcium contents also showed no significant differences between the two groups. We concluded that nifedipine suppressed atherosclerosis in cholesterol-fed rabbits but not in WHHL rabbits. The different responses suggest that the effect of nifedipine could be mediated by low density lipoprotein receptors or that the early exposure to hyperlipidemic serum from birth might affect cell functions of WHHL rabbits.