Activation of the Sodium-Potassium Pump Contributes to Insulin-Induced Vasodilation in Humans

Abstract

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 N G -monomethyl- l -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.