Kauffman R F, Bean J S, Zimmerman K M, Brown R F, Steinberg M I
Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, IN 46285.
Life Sci. 1991;49(25):PL223-8. doi: 10.1016/0024-3205(91)90298-p.
Angiotensin-converting enzyme inhibitors have been shown to inhibit intimal thickening following balloon catheterization of rat carotid arteries. To assess the role of the renin-angiotensin pathway and the angiotensin type-I (AT1) receptor in this effect, the nonpeptide Ang II antagonist losartan (DuP 753) or vehicle was infused continuously i.v. in rats from two days before to two weeks after balloon injury to the left common carotid artery; drug effects upon intimal thickening were examined histologically. Losartan produced a dose-dependent reduction in cross-sectional area of intimal lesions determined two weeks post balloon injury. At 5 mg/kg/day a nonsignificant 23% reduction of intimal area was observed. At the higher dose of 15 mg/kg/day, losartan produced a 48% reduction in intimal area (P less than 0.05) compared to the vehicle-infused group. The cellular density of the neointima was not affected by losartan, indicating a probable effect of the drug upon migration and/or proliferation of smooth muscle cells. In separate groups of non-ballooned rats, losartan infusions of 5 and 15 mg/kg/day produced significant rightward shifts (averaging 6.4- and 55-fold, respectively) in curves relating increases in blood pressure to intravenous Ang II in pithed rats determined between 2 and 16 days following initiation of losartan infusion. Mean arterial blood pressure (determined under alpha-chloralose anesthesia) was reduced following continuous losartan infusion for 6 days from 128 +/- 8 mm Hg (vehicle) to 105 +/- 8 mm Hg at 5 mg/kg/day (P less than 0.05), and 106 +/- 4 mm Hg at 15 mg/kg/day (P less than 0.05). Thus, losartan attenuated the vascular response to balloon catheter injury, and this effect was associated with functional block of vascular AT1 receptors. The results support a role for Ang II, acting via AT1 receptors, in myointimal thickening subsequent to balloon injury of rat carotid arteries.
血管紧张素转换酶抑制剂已被证明可抑制大鼠颈动脉球囊导管插入术后的内膜增厚。为了评估肾素 - 血管紧张素途径及血管紧张素I型（AT1）受体在此效应中的作用，从左颈总动脉球囊损伤前2天至损伤后2周，对大鼠持续静脉输注非肽类血管紧张素II拮抗剂氯沙坦（DuP 753）或赋形剂；通过组织学检查药物对内膜增厚的影响。氯沙坦使球囊损伤后2周测定的内膜病变横截面积呈剂量依赖性减小。在5毫克/千克/天的剂量下，观察到内膜面积有23%的减小，但无统计学意义。在15毫克/千克/天的较高剂量下，与输注赋形剂的组相比，氯沙坦使内膜面积减小了48%（P小于0.05）。氯沙坦不影响新生内膜的细胞密度，表明该药物可能对平滑肌细胞的迁移和/或增殖有作用。在单独的未进行球囊损伤的大鼠组中，在开始输注氯沙坦后2至16天测定，输注5毫克/千克/天和15毫克/千克/天的氯沙坦使去大脑大鼠静脉注射血管紧张素II后血压升高曲线显著右移（分别平均右移了6.4倍和55倍）。持续输注氯沙坦6天后，平均动脉血压（在α - 氯醛糖麻醉下测定）从128±8毫米汞柱（赋形剂组）降至5毫克/千克/天剂量下的105±8毫米汞柱（P小于0.05），以及15毫克/千克/天剂量下的106±4毫米汞柱（P小于0.05）。因此，氯沙坦减弱了血管对球囊导管损伤的反应性，且这种效应与血管AT1受体的功能阻断有关。这些结果支持血管紧张素II通过AT1受体在大鼠颈动脉球囊损伤后的肌内膜增厚中起作用。
