Comparison of cholinergic vasodilator responses to acetylcholine and methacholine in the human forearm.
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.
Bruning
T A
TA
Department of Nephrology, University Hospital Leiden, The Netherlands.
Chang
P C
PC
Kemme
M J
MJ
Vermeij
P
P
Pfaffendorf
M
M
van Zwieten
P A
PA
D000109:Acetylcholine / Q000494:pharmacology*; D000328:Adult; D004305:Dose-Response Relationship, Drug; D005542:Forearm / Q000098:blood supply*; D006801:Humans; D008297:Male; D016210:Methacholine Chloride / Q000494:pharmacology*; D008833:Microcirculation / Q000187:drug effects* / Q000502:physiology; D009569:Nitric Oxide / Q000502:physiology; D010277:Parasympathomimetics / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects*
D010277:Parasympathomimetics; D016210:Methacholine Chloride; D009569:Nitric Oxide; D000109:Acetylcholine