University of Tasmania
Browse

Vascular and metabolic effects of methacholine in relation to insulin action in muscle

Download (221.89 kB)
journal contribution
posted on 2023-05-16, 18:29 authored by Mahajan, H, Kolka, CM, Newman, JMB, Stephen RattiganStephen Rattigan, Stephen RichardsStephen Richards, Michael ClarkMichael Clark
Aims/hypothesis: Methacholine (MC) is a nitric oxide vasodilator, but unlike other vasodilators, it potentiates insulin-mediated glucose uptake by muscle. The present study aimed to resolve whether this action was the result of a vascular effect of MC leading to increased muscle perfusion or a direct effect of MC on the myocytes. We hypothesise that vascular-mediated insulin-stimulated glucose uptake responses to MC occur at lower doses than direct myocyte MC-mediated increases in glucose uptake. Methods: The vascular and metabolic effects of this vasodilator were examined in rats in vivo using a novel local infusion technique, and in the pump-perfused rat hindlimb under conditions of constant flow. Results: Local infusion of low-dose MC (0.3 μmol/l) into the epigastric artery of one leg (test) in vivo markedly increased femoral blood flow and decreased vascular resistance, without effects in the contra-lateral leg. Capillary recruitment, but not glucose uptake, was increased in the test leg. All increases caused by MC were confined to the test leg and blocked by local infusion into the test leg of Nω- nitro-L-arginine methyl ester (L-NAME), but not by infusion of N ω-nitro-D-arginine methyl ester (D-NAME). In the constant-flow pump-perfused rat hindlimb, infusion of 0.6 μmol/l MC vasodilated the pre-constriction effected by 70 nmol/l noradrenaline or 300 nmol/l serotonin, and this was blocked by 10 μmol/l L-NAME. 2-Deoxyglucose in muscle was increased by 30 μmol/l MC (p<0.05), but was unaffected by 3 μmol/l MC. All increases in 2-deoxyglucose uptake by 30 μmol/l MC were blocked by 10 μmol/l L-NAME. Conclusions/interpretation: MC has dose-dependent effects both on the vasculature and on muscle metabolism. At low dose (0.3-3 μmol/l), MC is a potent vasodilator in muscle, both in vivo and in vitro, without metabolic effects; at higher doses (≥30 μmol/l) MC has a direct metabolic effect leading to increased glucose uptake. Both the vascular and metabolic effects are sensitive to L-NAME. The low-dose enhancement of insulin action in vivo by MC, which has been reported previously, thus seems to be attributable to vascular effects. © Springer-Verlag 2006.

History

Publication title

Diabetologia

Volume

49

Issue

4

Pagination

713-723

ISSN

0012-186X

Department/School

Tasmanian School of Medicine

Publisher

Springer-Verlag

Place of publication

New York

Repository Status

  • Restricted

Socio-economic Objectives

Clinical health not elsewhere classified

Usage metrics

    University Of Tasmania

    Categories

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC