Tack C J, Lutterman J A, Vervoort G, Thien T, Smits P
Department of Internal Medicine, University Hospital Nijmegen, The Netherlands.
Hypertension. 1996 Sep;28(3):426-32. doi: 10.1161/01.hyp.28.3.426.
Systemic hyperinsulinemia induces vasodilation in human skeletal muscle. This vasodilation contributes to insulin-stimulated glucose uptake and has been found to be reduced in various insulin-resistant states. The mechanism of the effect of insulin on vascular tone is not completely understood. We hypothesized that activation of the sodium-potassium pump (Na+, K(+)-ATPase) located in endothelial or smooth muscle cells would be involved in the insulin-mediated vasodilation. Therefore, in 24 healthy, nonsmoking, nonobese, normotensive volunteers, we infused ouabain, a specific inhibitor of Na+, K(+)-ATPase, into the brachial artery before and during euglycemic hyperinsulinemia. As expected, insulin (systemic concentrations, approximately 700 [low] and 1400 [high] pmol.L-1) induced vasodilation in the control arm (forearm blood flow [FBF, plethysmography] from 1.6 +/- 0.2 to 2.1 +/- 0.4 mL.dL-1.min-1 [low insulin] and from 1.6 +/- 0.2 to 2.1 +/- 0.2 [high insulin], P < .05 for both), but the increase in FBF was abolished in the ouabain-infused forearm (from 1.3 +/- 0.1 to 1.4 +/- 0.2 mL.dL-1.min-1 [low] and from 1.3 +/- 0.1 to 1.3 +/- 0.1 [high], P = NS). Ouabain-induced increases in forearm potassium release were partly reversed by insulin. To investigate whether the mechanism of action could be at the endothelial level, we infused NG-monomethyl-I-arginine (L-NMMA), an inhibitor of endothelial nitric oxide synthase (0.05, 0.1, and 0.2 mg.dL-1.min-1) intra-arterially in 12 subjects and induced a clear dose-dependent decrease of FBF from 1.7 +/- 0.2 to 1.2 +/- 0.1 mL.dL-1.min-1 (P < .01). In contrast, after ouabain (and continued insulin) infusion, L-NMMA had no effect on FBF (from 1.6 +/- 0.4 to 1.5 +/- 0.3 mL.dL-1.min-1, n = 6, P = .66). These results demonstrate that insulin induces vasodilation by stimulation of Na+, K(+)-ATPase. This activation of Na+, K(+)-ATPase could occur at the level of the endothelium rather than that of vascular smooth muscle and contributes to the endothelium-dependent vasodilator response to insulin.
全身性高胰岛素血症可诱导人体骨骼肌血管舒张。这种血管舒张有助于胰岛素刺激的葡萄糖摄取，并且已发现在各种胰岛素抵抗状态下该血管舒张作用减弱。胰岛素对血管张力的作用机制尚未完全阐明。我们推测，位于内皮细胞或平滑肌细胞中的钠钾泵（Na +，K（+）-ATP酶）的激活参与胰岛素介导的血管舒张。因此，在24名健康、不吸烟、非肥胖、血压正常的志愿者中，我们在正常血糖高胰岛素血症之前和期间向肱动脉内注入哇巴因（一种Na +，K（+）-ATP酶的特异性抑制剂）。正如预期的那样，胰岛素（全身浓度，约700 [低]和1400 [高] pmol.L-1）在对照臂中诱导血管舒张（前臂血流量[FBF，体积描记法]从1.6±0.2增加至2.1±0.4 mL.dL-1.min-1 [低胰岛素]和从1.6±0.2增加至2.1±0.2 [高胰岛素]，两者P <.05），但在注入哇巴因的前臂中FBF的增加被消除（从1.3±0.1增加至1.4±0.2 mL.dL-1.min-1 [低]和从1.3±0.1增加至1.3±0.1 [高]，P =无显著性差异）。哇巴因诱导的前臂钾释放增加部分被胰岛素逆转。为了研究作用机制是否可能在内皮水平，我们在12名受试者中动脉内注入内皮型一氧化氮合酶抑制剂NG-单甲基-L-精氨酸（L-NMMA，0.05、0.1和0.2 mg.dL-1.min-1），并诱导FBF从1.7±0.2明显剂量依赖性降低至1.2±0.1 mL.dL-1.min-1（P <.01）。相反，在注入哇巴因（和持续的胰岛素）后，L-NMMA对FBF无影响（从1.6±0.4至1.5±0.3 mL.dL-1.min-1，n = 6，P =.66）。这些结果表明，胰岛素通过刺激Na +，K（+）-ATP酶诱导血管舒张。Na +，K（+）-ATP酶的这种激活可能发生在内皮水平而非血管平滑肌水平，并有助于内皮依赖性血管舒张对胰岛素的反应。
