Reel Buket, Ozkal Sermin, Islekel Huray, Ozer Erdener, Oktay Gulgun, Sozer Gonen Ozsarlak, Tanriverdi Serpil, Turkseven Saadet, Kerry Zeliha
Ege University, Faculty of Pharmacy, Department of Pharmacology, Bornova, Izmir, Turkey.
J Pharm Pharmacol. 2005 Dec;57(12):1599-608. doi: 10.1211/jpp.57.12.0010.
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. Endothelin is known to act as a strong mitogen and to stimulate smooth muscle cell proliferation and migration. We investigated the contribution of endothelin to the development of collar-induced intimal thickening and the effects of TAK-044, (5 mg kg(-1) daily, s.c.), a non-selective ET(A)/ET(B) receptor antagonist, on intimal thickening and vascular reactivity changes in the collared rabbit carotid artery. Endothelin 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 endothelin 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 endothelin may be involved in the pathogenesis of collar-induced intimal thickening. As an endothelin receptor antagonist, TAK-044 may potentially be beneficial in the treatment of atherosclerosis.
由于平滑肌细胞迁移和增殖导致的内膜增厚被认为是血管增殖性疾病（如动脉粥样硬化和再狭窄）的主要组成部分之一。本研究采用一种可导致家兔内膜增厚的实验模型，即围绕颈动脉放置一个硅环。已知内皮素是一种强效有丝分裂原，可刺激平滑肌细胞增殖和迁移。我们研究了内皮素在硅环诱导的内膜增厚发展过程中的作用，以及非选择性ET(A)/ET(B)受体拮抗剂TAK-044（每日5 mg kg(-1)，皮下注射）对带环家兔颈动脉内膜增厚和血管反应性变化的影响。与假手术动脉相比，带环动脉中的内皮素水平、内膜横截面积以及内膜面积与中膜面积之比（指数）均显著增加。TAK-044显著抑制内膜增厚，并且降低了该指数，而不影响带环动脉中升高的内皮素水平。对套环产生的血管反应性变化产生了可预测的影响，例如对血管收缩剂的收缩反应降低以及对5-羟色胺（5-羟色胺，5-HT）的敏感性增加。就该模型中的收缩反应而言，TAK-044尤其不影响套环诱导的血管反应性变化。这些结果表明，内皮素可能参与了套环诱导的内膜增厚的发病机制。作为一种内皮素受体拮抗剂，TAK-044可能在动脉粥样硬化的治疗中具有潜在益处。
