A role for endogenous endothelin-1 in neointimal formation after rat carotid artery balloon angioplasty. Protective effects of the novel nonpeptide endothelin receptor antagonist SB 209670.
A role for endogenous endothelin-1 in neointimal formation after rat carotid artery balloon angioplasty. Protective effects of the novel nonpeptide endothelin receptor antagonist SB 209670.
复制标题
内源性内皮素-1 在大鼠颈动脉球囊血管成形术后新内膜形成中的作用。
作者：
Stephen A. Douglas;C. Louden;L. Vickery;B. Storer;Timothy Hart;G. Feuerstein;John D. Elliott;E. Ohlstein
经皮腔内冠状动脉成形术（PTCA）后，人冠状窦中促有丝分裂肽内皮素-1水平升高的观察结果表明，内皮素-1与血管再狭窄的病因有关。本研究使用新型非肽类内皮素受体拮抗剂SB 209670在新生内膜形成的体外和体内大鼠模型中验证了这一假设。在体外，内皮素-1（1 nmol/L）诱导大鼠主动脉血管平滑肌[3 H]胸苷掺入增加9倍。SB 209670可完全抑制内皮素A受体介导的作用（IC 50，6.2 +/- 2.2 nmol/L）。在体内，急性动脉内给予外源性内皮素-1（5 - 500 pmol/kg，血管成形术后30分钟内立即给药）剂量依赖性地增加了新生内膜形成的程度（术后14天评估时高达150%）。这种反应早在血管成形术后7天就很明显。血液动力学研究表明，这一行动是无关的肽的全身升压作用。SB 209670给药（2.5 mg/kg IP，每天两次，术前3天，术后2周）使新生内膜形成相对于对照动物减少约50%。因此，数据首次表明：（1）内皮素-1促进体内新生内膜形成，（2）内源性内皮素-1参与大鼠血管成形术诱导的病变形成的发病机制。因此，内皮素受体拮抗剂如SB 209670可作为PTCA的有效抑制剂，减轻血管壁损伤后观察到的血管再狭窄程度。
The observation that levels of the mitogenic peptide endothelin-1 are elevated in the human coronary sinus after percutaneous transluminal coronary angioplasty (PTCA) has implicated endothelin-1 in the etiology of vascular restenosis. The present study examined this hypothesis in both an in vitro and an in vivo rat model of neointimal formation by using the novel nonpeptide endothelin receptor antagonist SB 209670. In vitro, endothelin-1 (1 nmol/L) induced a ninefold increase in rat aortic vascular smooth muscle [3H]thymidine incorporation. This endothelin A receptor-mediated effect was completely inhibited by SB 209670 (IC50, 6.2 +/- 2.2 nmol/L). In vivo, acute intra-arterial administration of exogenous endothelin-1 (5 to 500 pmol/kg over a 30-minute period immediately after angioplasty) dose-dependently augmented the degree of neointimal formation (by up to 150% when assessed 14 days after surgery). This response was evident as early as 7 days after angioplasty. Hemodynamic studies indicated that this action was unrelated to a systemic pressor action of the peptide. Administration of SB 209670 (2.5 mg/kg IP, twice a day for 3 days before and for 2 weeks after surgery) reduced neointimal formation by approximately 50% relative to control animals. Thus, the data indicate for the first time that (1) endothelin-1 promotes neointimal formation in vivo and (2) endogenous endothelin-1 is involved in the pathogenesis of angioplasty-induced lesion formation in the rat. Endothelin receptor antagonists such as SB 209670 may therefore serve as useful adjuncts to PTCA, attenuating the degree of vascular restenosis observed after vascular wall injury.
影响因子：
19.9
作者：
Tong F
通讯作者：
Tong F
影响因子：
3
作者：
T. Scott‐Burden;T. Resink;A. Hahn;P. Vanhoutte
通讯作者：
T. Scott‐Burden;T. Resink;A. Hahn;P. Vanhoutte
影响因子：
20.1
作者：
KOHLER, TR;KIRKMAN, TR;CLOWES, AW
通讯作者：
CLOWES, AW