Pham Dung, Jeng Arco Y, Plante Sylvain, Escher Emanuel, Battistini Bruno
Laval Hospital Research Center, Department of Medicine, Laval University, Sainte-Foy, QC, Canada.
Can J Physiol Pharmacol. 2002 May;80(5):450-7. doi: 10.1139/y02-059.
Clinical success of percutaneous transluminal coronary angioplasty is limited by restenosis within months of the initial intervention. A number of vasoactive mediators and growth factors have been reported to participate in this process. The aim of the present experiments was to examine the effects of nonselective neutral endopeptidase (NEPi)/endothelin-converting enzyme (ECEi) inhibitors against neointimal proliferation (NIP) following balloon angioplasty of the left carotid artery of Sprague-Dawley rats with the right vessel serving as the uninjured control. The rats were divided in several groups: group 1, nontreated (vehicle); group 2, treated with a selective NEPi i.p.; groups 3-7, treated with nonselective NEPi/ECEi either i.p., s.c., i.v., or p.o. at various doses. After 2 weeks, cross-sectional histopathological and morphometrical examination of the left carotids revealed a severe NIP in vehicle-treated angioplastic rats compared with the control uninjured right carotid of the same rats. The selective NEPi CGS 24592 had no significant effect on restenosis, nor did the dual NEPi/ECEi CGS 26303 at 5 mg x kg(-1) x day(-1) i.p. Both s.c and i.v. NEPi/ECEi treatment (10 mg x kg(-1) x day(-1) b.i.d. s.c. or 10 mg x kg(-1) x day(-1) i.v.) reduced NIP by up to 35%. The prodrug CGS 26393 (p.o.) also attenuated NIP by 23%. Plasma concentrations of these compounds correlated with the degree of inhibition. These data support the participation of the endothelin system in the rat model of balloon angioplasty and suggest that selective ECEi may be effective.
经皮腔内冠状动脉成形术的临床成功率受到初次干预后数月内再狭窄的限制。据报道，多种血管活性介质和生长因子参与了这一过程。本实验的目的是研究非选择性中性内肽酶（NEPi）/内皮素转化酶（ECEi）抑制剂对Sprague-Dawley大鼠左颈动脉球囊血管成形术后新生内膜增殖（NIP）的影响，以右侧血管作为未损伤对照。大鼠被分为几组：第1组，未治疗（赋形剂）；第2组，腹腔注射选择性NEPi治疗；第3 - 7组，分别以不同剂量经腹腔、皮下、静脉或口服给予非选择性NEPi/ECEi治疗。2周后，对左颈动脉进行横断面组织病理学和形态计量学检查发现，与同一大鼠未损伤的右侧对照颈动脉相比，接受赋形剂治疗的血管成形术大鼠出现严重的NIP。选择性NEPi CGS 24592对再狭窄无显著影响，腹腔注射5 mg·kg⁻¹·d⁻¹的双重NEPi/ECEi CGS 26303也无显著影响。皮下和静脉注射NEPi/ECEi治疗（皮下注射10 mg·kg⁻¹·d⁻¹，每日两次或静脉注射10 mg·kg⁻¹·d⁻¹）均可使NIP减少高达35%。前体药物CGS 26393（口服）也可使NIP减少23%。这些化合物的血浆浓度与抑制程度相关。这些数据支持内皮素系统参与大鼠球囊血管成形术模型，并表明选择性ECEi可能有效。
