SUPERSENSITIVITY TO VASOCONSTRICTOR ACTION OF SEROTONIN PRECEDES THE DEVELOPMENT OF ATHEROMA-LIKE LESIONS IN THE RABBIT

We have studied the relationship between the early morphological changes and arterial responsiveness to vasoactive agents in a new animal model that is proposed to mimic the events of early human atherosclerosis. Atheroma-like lesions were produced by positioning a hollow Silastic collar (referred to as a cuff) around the common carotid arteries of rabbits. Following a period of either 48 h or 1, 2, or 4 weeks after surgery, vessels from both cuffed and sham-operated animals were removed, and vascular reactivity to cumulative concentrations of agonists were studied in isolated rings in organ baths. The contralateral arteries were perfused and fixed, studied by light microscopy, and the degree of intimal thickening was quantified by computer-assisted morphometric analysis and expressed as changes in the ratios of the cross-sectional areas of the intima and media in each artery. At 48 h, rings prepared from cuffed arteries were sixfold more sensitive to the contractile effects of serotonin (5-HT) than the corresponding controls. Histologically, such vessels showed some perivascular inflammation but no other morphological abnormality. At 7 days, cuffed vessels were again sixfold more sensitive to 5-HT than controls, and showed a thickened intima with marked smooth muscle proliferation and some infiltration by monocytes. Intimal/medial cross-sectional area ratios remained elevated at 2 and 4 weeks, but the supersensitivity to 5-HT diminished by 2 weeks to threefold and was absent at 4 weeks. The augmented reactivity to 5-HT at 48 h was specific, in that it did not occur for the α-adrenoceptor agonist, phenylephrine. Although the endothelium appeared normal in all sections examined, the maximum vasorelaxant response to acetylcholine in 5-HT-contracted rings was reduced from 74 ± 5% in controls to 15 ± 4% (mean ± SEM, n = 10) in cuffed arteries at 7 days after surgery. Relaxations produced by the directly acting nitrovasodilator, sodium nitroprusside, were similar in control and cuffed arteries. These data suggest that the acetylcholine-induced release of nitric oxide from the endothelium, or the access of nitric oxide to the vascular smooth muscle, may be compromised during the development of these lesions. The mechanisms involved in the supersensitivity could be similar to those initiating coronary vasospasm in humans. © 1990 Raven Press, Ltd., New York.