Patients with coronary vasospasm appear to be supersensitive to the coronary constrictor effects of ergonovine. To determine whether atherosclerosis alters arterial reactivity and sensitizes arteries to ergonovine, contractile responses of isolated aortae from control rabbits and from rabbits fed a high-cholesterol diet were compared. Aortic strips were mounted in a myograph for the monitoring of isometric tension, equilibrated in oxygenated Krebs buffer, and exposed to graded concentrations of agonists and antagonists. The concentration-response relation for ergonovine in atherosclerotic arteries exhibited a markedly depressed constrictor threshold concentration (0.5 pM vs. 0.23 μM in controls), a significantly lowered one-half effective dose (ED₅₀) value, and an augmented maximal response. Furthermore, atherosclerotic arteries showed similar, although less pronounced changes in the concentration-response relation for serotonin. In contrast, responses to 34 mM KCl were virtually identical, and the concentration-response relation for phenylephrine were similar in the two groups. In control arteries, 0.1 μM phentolamine and 0.1 μM prazosin suppressed responses to 1 μM ergonovine by 71 and 90%, respectively. However, in atherosclerotic arteries α-blockers in the same concentration inhibited responses to 0.01 μM ergonovine by less than 10%. On the other hand, 0.1 μM cyproheptadine, a serotonergic antagonist, suppressed these responses by 82%. Thus, the supersensitivity to ergonovine appeared to be mediated predominantly by a serotonergic mechanism. These results indicate that smooth muscle in atherosclerotic arteries may be supersensitive to specific vasoconstricting stimuli, a change that might contribute to arterial dysfunction in vivo.