Watanabe heritable hypertlpldemlc (WHHL) rabbits have elevated concentrations of plasma cholesterol and develop progressive atherosclerosis. The present Investigation was undertaken to evaluate the vascular responses to vasoactive compounds of aorta from WHHL rabbits and normal New Zealand White (NZW) rabbits at 1 and 6 months of age. Rings of distal thoracic aorta were suspended under isometric tension in oxygenated Krebs buffer. Developed tension was measured In response to graded concentrations of agonists. Maximal responses to KCI (40 mM) were the same In aortas from the 1-month-old and 6-month-old WHHL and NZW rabbits. Aortas from 1-month-old animals were more sensitive to serotonin than aortas from 6-month-old animals. Aortas from WHHL rabbits exhibited an Increased maximal response to serotonin when compared with NZW controls. In contrast, the constrictor responses to norepinephrine were reduced In WHHL rabbits compared with NZW rabbits at both age groups. Methacholine decreased tension development In serotonin-contracted vessels. This relaxation was greatest In aortas from NZW rabbits. In 1-month-old NZW rabbits fed a high cholesterol diet, the constrictor responses to serotonin and the relaxation responses to methacholine did not differ from NZW rabbits Ingesting a normal diet However, the responses to norepinephrine were markedly attenuated In the hyperchotosterolemlc NZW rabbits. C oronary artery vasospasm has been proposed as one mechanism to account for the episodic reductions in myocardial oxygen delivery in patients with unstable angina pectoris. 1 ' 23 Atherosclerosis may contribute to the development of coronary artery vasospasm through several mechanisms. Atherosclerosis may result in altered responses of the epicardial coronary vessels to vasoactive stimuli by either augmenting responses to vasoconstrictors or diminishing the production of compensatory vasodilatory substances, such as prostacyclin. Also, ath- Received September 24,1987; revision accepted October 24, 1988. erosclerosis may promote the local accumulation of platelets, neutrophils, or macrophages. 45 These cells may release vasoconstrictors that may promote vascular spasm. Other investigators have suggested that hypercholesterotemia per se may augment the reactivity of blood vessels. 6 In the present investigation, we hypothesized that augmented vasoconstrictor responses occur in blood vessels obtained from hypercholesterolemic animals that are prone to devebp atherosclerosis.In these studies, we used the Watanabe heritable hyperiipidemic (WHHL) rabbit. 7 * Homozygous WHHL rabbtts produced by serial inbreeding have plasma cholesterol concentrations of 500 to 950 mg/dl, develop grossly visible aortic atherosclerosis by 5 months of age, 8 -1011 and have decreased numbers of functioning low density lipoprotein (LDL) receptors in several tissues. 812 Thus, this animal model exhibits many clinical and biochemical similarities to familial hypercholesterolemia. To test our hypothesis, we evaluated the vasoconstrictor responses o...