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

Citation

Mahajan, H and Kolka, CM and Newman, JMB and Rattigan, S and Richards, SM and Clark, MG, Vascular and metabolic effects of methacholine in relation to insulin action in muscle, Diabetologia, 49, (4) pp. 713-723. ISSN 0012-186X (2006) [Refereed Article]

DOI: doi:10.1007/s00125-005-0110-6

Abstract

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.

Item Details

Item Type:Refereed Article
Research Division:Medical and Health Sciences
Research Group:Clinical Sciences
Research Field:Endocrinology
Objective Division:Health
Objective Group:Clinical Health (Organs, Diseases and Abnormal Conditions)
Objective Field:Diabetes
Author:Mahajan, H (Dr Hema Mahajan)
Author:Kolka, CM (Miss Cathryn Kolka)
Author:Newman, JMB (Dr John Newman)
Author:Rattigan, S (Professor Stephen Rattigan)
Author:Richards, SM (Dr Stephen Richards)
Author:Clark, MG (Professor Michael Clark)
ID Code:41916
Year Published:2006
Web of Science® Times Cited:3
Deposited By:Biochemistry
Deposited On:2006-08-01
Last Modified:2011-10-03
Downloads:0

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