In order to study the contribution of the nitric oxide (NO)-pathway to cholinergic vasodilatation in the resistance vessels of the human forearm, we infused acetylcholine (ACh; 0.1 1000 ng/kg/min) or methacholine (MCh; 0.1 A 100 ng/kg/min) in the presence of saline, the NO-scavenger and guanylate cyclase inhibitor methylene blue (MB; 1000 ng/kg/min), or the NO-synthase inhibitor NG-monomethyl-L-arginine (L-NMMA; 30 micrograms/kg/min) into the brachial artery of normotensive volunteers (n = 32), using venous occlusion plethysmography. We calculated the plasma concentrations of the infused compounds to obtain EC50-values (-log mol/l). ACh and MCh both caused concentration-dependent vasodilatation (EC50-values of 6.43 +/- 0.05 and 7.24 +/- 0.08, respectively). MB (13 mumol/l) did not change basal forearm blood flow (FBF) when administered alone, but it markedly potentiated the vasodilator response to ACh, shifting the concentration-response curve (CRC) leftwards by 1.5 log-step (p < 0.001). MB did not affect MCh-induced vasodilatation. L-NMMA (1 mmol/l) alone caused dose-dependent vasoconstriction that was subject to tachyphylaxis. In addition, L-NMMA caused a steepening of the slopes of the CRCs of ACh, and MCh L-NMMA attenuated the ACh-/MCh-induced vasodilator responses in the lowest concentration ranges (p < 0.05) only, but did not alter the response at higher concentrations. The 10-fold higher potency of MCh compared to ACh can be explained by the more rapid degradation of ACh by cholinesterases. The observation that high concentrations of L-NMMA only affect vasodilation mediated by low concentrations of ACh or MCh, suggests a second mechanism in cholinergic vasodilatation, such as a direct effect on smooth muscle cells or the release of a relaxing factor other than NO.

Objective: To evaluate whether acute elevations of local plasma glucose concentrations could influence forearm blood flow (FBF) and how this interacts with local hyperinsulinaemia in healthy volunteers. Methods: Using the perfused forearm technique, in random order, glucose 20% or saline 0.9% as a control was infused in three dose steps (0.3, 1.0, and 3.0 ml/min) for 5 min each in eight healthy men. The infusion experiments were repeated, in random order, during local hyperinsulinaemia by intra-arterial infusion of insulin 0.05 mU/kg/min. The ratio of FBF of the infused over the FBF in the control arm (FR) was measured at 15-sec intervals during the infusions. Results: Glucose infusion increased the FR dosedependently by 172% ± 39% (M ± SE) at the highest dose (P Ͻ 0.01). During hyperinsulinaemia the glucoseinduced increase in FR was significantly (P Ͻ 0.01) less, 96% ± 26%, however, when changes in FR or forearm

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In arterioles, acetylcholine (ACh) is a well known vasodilator. However, in veins a wide variation in responses to ACh has been reported. In the present study the effects of the cholinergic agonists acetylcholine and methacholine (MCh) were determined simultaneously both in arterial and venous vasculature in the forearm vascular bed of healthy volunteers by means of venous occlusion plethysmography. The vasodilator sodium nitroprusside (SNP) served as an endothelium-independent control agent. The vascular beds were preconstricted by the selective alpha 1-adrenoceptor agonist methoxamine. Atropine, a non-selective muscarinic receptor antagonist, was used to antagonize the dilator effect of MCh. Overall we observed a weaker relaxant effect of ACh, MCh and SNP in the veins compared with their dilator responses in the arteries. ACh, which is highly sensitive to the hydrolytic inactivation by choline esterases, failed to induce a significant vasodilation in the venous vascular bed. Atropine blocked the dilator effects of MCh, indicating the involvement of muscarinic receptors. In arteries, MCh did not induce a significantly stronger vasodilatation than SNP on a molar basis. However, in veins, MCh had a weaker relaxant effect (p < 0.05).