Igarashi M, Hirata A, Yamaguchi H, Tsuchiya H, Ohnuma H, Tominaga M, Daimon M, Kato T
Third Department of Internal Medicine, Yamagata University School of Medicine, Yamagata, Japan.
Hypertension. 2001 Dec 1;38(6):1255-9. doi: 10.1161/hy1101.095537.
This study investigates the effects of candesartan, an angiotensin II type 1 receptor blockade, on carotid arterial intimal thickening and glucose tolerance in balloon-injured male Wistar fatty rats and their littermates (Wistar lean rats). Candesartan was orally administered to 12-week-old rats for 21 days, and age-matched rats without the agent were used as the respective controls. Balloon catheterization in the left common carotid artery was performed on day 7, and the artery was removed on day 14 for histological analysis. Compared with the area ratios of the neointima/media in fatty rats without treatment, the ratios in fatty rats treated with candesartan at 1 mg. kg(-1). d(-1) and lean rats without treatment were significantly decreased to 65%; on the other hand, the ratios of fatty rats treated with candesartan at 10 mg. kg(-1). d(-1) and lean rats treated with 1 mg. kg(-1). d(-1) were reduced to 35%, and those of lean rats treated with 10 mg. kg(-1). d(-1) were reduced to 28%. The administration of candesartan also decreased the level of plasma glucose time- and dose-dependently in fatty rats. In an intragastric glucose load, the levels of both glucose and insulin at 30 and 60 minutes were significantly decreased when fatty rats were treated with candesartan at 10 mg. kg(-1). d(-1). In cultured vascular smooth muscle cells from fatty rats, insulin-stimulated Akt (New England Biolabs) phosphorylation and 2-deoxy-D-glucose uptake were inhibited to 59% and 68%, respectively, by angiotensin II, but the effects were ameliorated by the addition of 10(-7) mol/L candesartan. We conclude that candesartan could be effective for the suppression of vascular smooth muscle cell growth dose-dependently in Wistar fatty and lean rats. Furthermore, the agent could improve insulin resistance in Wistar fatty rats.
本研究调查了血管紧张素II 1型受体阻滞剂坎地沙坦对雄性Wistar肥胖大鼠及其同窝仔鼠（Wistar瘦鼠）颈动脉内膜增厚和葡萄糖耐量的影响。将坎地沙坦口服给予12周龄大鼠，持续21天，未给予该药物的年龄匹配大鼠作为各自的对照。在第7天对左颈总动脉进行球囊导管插入术，并在第14天取出动脉进行组织学分析。与未治疗的肥胖大鼠相比，给予1mg·kg⁻¹·d⁻¹坎地沙坦的肥胖大鼠以及未治疗的瘦鼠的新生内膜/中膜面积比显著降低至65%；另一方面，给予10mg·kg⁻¹·d⁻¹坎地沙坦的肥胖大鼠以及给予1mg·kg⁻¹·d⁻¹坎地沙坦的瘦鼠的该比值降至35%，给予10mg·kg⁻¹·d⁻¹坎地沙坦的瘦鼠的该比值降至28%。坎地沙坦的给药还能使肥胖大鼠的血浆葡萄糖水平随时间和剂量呈依赖性降低。在胃内葡萄糖负荷试验中，当肥胖大鼠给予10mg·kg⁻¹·d⁻¹坎地沙坦时，30分钟和60分钟时的葡萄糖和胰岛素水平均显著降低。在来自肥胖大鼠的培养血管平滑肌细胞中，血管紧张素II可将胰岛素刺激的Akt（新英格兰生物实验室）磷酸化和2-脱氧-D-葡萄糖摄取分别抑制至59%和68%，但添加10⁻⁷mol/L坎地沙坦可改善这些作用。我们得出结论，坎地沙坦可有效剂量依赖性地抑制Wistar肥胖和瘦鼠的血管平滑肌细胞生长。此外，该药物可改善Wistar肥胖大鼠的胰岛素抵抗。
