The responses to vasoactive agents and the fine structure of hepatic arterial ring segments from male and female Watanabe heritable hyperlipidaemic (WHHL) rabbits (4, 6, and 12 months) were compared with those of age- and sex-matched New Zealand White (NZW) rabbits. In males only, KCl-induced contractions were reduced in WHHL rabbits compared with NZW rabbits. In male and female WHHL rabbits, maximum noradrenaline-induced contractions and sensitivity to noradrenaline were greater than those of male and female NZW rabbits. In female WHHL and NZW rabbits only, maximum noradrenaline-induced contractions and the EC50 values were reduced at 6 months. Endothelium-dependent relaxation: In females only, maximum relaxant responses and the sensitivity of WHHL rabbits to acetylcholine increased with age, while there was a decrease in NZW rabbits. Similarly, relaxation to substance P increased with age in WHHL rabbits and decreased in NZW rabbits, but this occurred in both male and female animals. In addition, substance P-induced relaxation in female WHHL rabbits was greater than in male WHHL rabbits. Endothelium-independent relaxation: In both male and female WHHL rabbits, calcitonin gene-related peptide-induced and vasoactive intestinal polypeptide-induced relaxation did not change with age. However, there was an age-related decrease in the response of NZW rabbits to these peptides. Electron microscopic evaluation of hepatic arteries from WHHL rabbits showed occasional ruptures in the internal elastic lamina at 4 months. At 6 months, widespread intimal thickening associated with smooth muscle cell migration was apparent, but this became less obvious at 12 months. No obvious differences in structure between male and female hepatic arteries were observed. It is suggested that a "compensatory vasodilatation" develops in atherosclerosis, initially at the level of the endothelium, and then with the progression of the disease extends to changes in the smooth muscle. This may occur in order to offset the thickening of the arterial wall. Sexual dimorphism in vascular reactivity has been demonstrated.