Comparison of Cholinergic Vasodilator Responses to Acetylcholine and Methacholine in the Human Forearm
AbstractIn 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; 0.1Ä100 ng/kg/min) in the presence of saline, the NO-scavener and guanylate cyclase inhibitor methylene blue (MB; 1000ng/kg/min), or the NO-synthase inhibitor N G -monomethyl-L-arginine (L-NMMA; 30 μg/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 EC 50 -values (-log mol/1). ACh and MCh both caused concentration-dependent vasodilatation (ECso-values of 6.43 & 0.05 and 7.24 * 0.08, respectively). MB (13 μmol/1) 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 mmo1/1) 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 vasodilatation 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.