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(Hypertension. 1996;28:426-432.)
© 1996 American Heart Association, Inc.

Articles

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

Cees J.J. Tack; Jos A. Lutterman; Gerald Vervoort; Theo Thien; Paul Smits

the Department of Internal Medicine, Division of General Internal Medicine (C.J.J.T., J.A.L., G.V., T.T., P.S.), and Department of Pharmacology (P.S.), University Hospital Nijmegen (The Netherlands).

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.

Key Words: insulin • vasodilation • sodium-potassium pump • ouabain • nitric oxide • endothelium

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