The role of endothelin receptor antagonism in collar-induced intimal thickening and vascular reactivity changes in rabbits.

Reel B., Ozkal S., İŞLEKEL G. H., Ozer E., Oktay G., Sozer G., ...More

The Journal of pharmacy and pharmacology, vol.57, no.12, pp.1599-608, 2005 (SCI-Expanded) identifier identifier identifier


Intimal thickening, due to smooth muscle cell migration and proliferation, is considered to be one of the major components of vascular proliferative disorders such as atherosclerosis and restenosis. One experimental model, resulting in intimal thickening in the rabbit, involves placing a silicon collar around the carotid artery, and is used in this study. Endothelia is known to act as a strong mitogen and to stimulate smooth muscle cell proliferation and migration. We investigated the contribution of endothelia to the development of collar-induced intimal thickening and the effects of TAK-044, (5mg kg(-1) daily, s.c.), a non-selective ETA/ETB receptor antagonist, on intimal thickening and vascular reactivity changes in the collared rabbit carotid artery. Endothelia levels and the intimal cross-sectional area, as well as the ratio of intimal area to media (index), increased significantly in collared arteries as compared with those in sham-operated arteries. TAK-044 significantly inhibited intimal thickening and also decreased the index without affecting increased endothelia levels in collared arteries. Vascular reactivity changes in response to collaring produced predictable effects, such as decreased contractile responses to vasoconstrictor agents and increased sensitivity to serotonin (5-hydroxytryptamine, 5-HT). In terms of contractile responses in this model, TAK-044, in particular, did not affect collar-induced vascular reactivity changes. These results suggest that endothelia may be involved in the pathogenesis of collar-induced intimal thickening. As an endothelia receptor antagonist, TAK-044 may potentially be beneficial in the treatment of atherosclerosis.