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

• Published in: Diabetologia 2006-04, Vol.49 (4), p.713-723
• Main Authors: MAHAJAN, H, KOLKA, C. M, NEWMAN, J. M. B, RATTIGAN, S, RICHARDS, S. M, CLARK, M. G
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Femoral Artery - drug effects; Femoral Artery - metabolism; Glucose; Glucose - pharmacology; Hindlimb - blood supply; Hindlimb - drug effects; Human subjects; Insulin - metabolism; Insulin resistance; Male; Medical sciences; Metabolism; Methacholine Chloride - metabolism; Methacholine Chloride - pharmacology; Muscles - drug effects; Muscles - metabolism; Nitric Oxide - biosynthesis; Rats; Rats, Wistar; Regional Blood Flow - drug effects; Vasodilation - drug effects
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-005-0110-6

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. 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. Local infusion of low-dose MC (0.3 micromol/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 N-nitro-L-arginine methyl ester (L-NAME), but not by infusion of N-nitro-D-arginine methyl ester (D-NAME). In the constant-flow pump-perfused rat hindlimb, infusion of 0.6 micromol/l MC vasodilated the pre-constriction effected by 70 nmol/l noradrenaline or 300 nmol/l serotonin, and this was blocked by 10 micromol/l L-NAME. 2-Deoxyglucose in muscle was increased by 30 micromol/l MC (p or =30 micromol/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.