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

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 N ω -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 pumpperfused 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 lowdose enhancement of insulin action in vivo by MC, which has been reported previously, thus seems to be attributable to vascular effects.

Tadalafil increases muscle capillary recruitment and forearm glucose uptake in women with type 2 diabetes

“…Our observation of a strong correlation between ∆AUC PS glu and ∆AUC forearm glucose uptake in both study groups is consistent with previous studies showing that a microvascular response is critical for glucose uptake in skeletal muscle [4, 10]. Thus, it is possible that increased nutritive blood flow may enhance glucose delivery to insulin-resistant muscle in the postabsorptive state, too.…”

“…Recent evidence suggests that reduced synthesis of nitric oxide in endothelial cells contributes to the impaired action of insulin in the vasculature of patients with insulin resistance syndrome [3]. A recent study of the pump-perfused rat hindlimb showed that stimulation of nitric oxide production by methacholine induced positive effects on muscle metabolism [4], while we have previously demonstrated beneficial effects of methacholine on capillary recruitment and forearm glucose uptake in insulin-resistant obese humans [5]. However, as methacholine cannot be used therapeutically, alternative approaches would be required to promote nitric oxide signalling.…”