Inhibition of acetylcholinesterase selectively potentiates N(G)-monomethyl-L-arginine-resistant actions of acetylcholine in human forearm vasculature

1. N(G)-monomethyl-L-arginine (L-NMMA, a nitric oxide synthase inhibitor) inhibits vasodilator responses to acetylcholine but not methacholine in human forearm vasculature. To investigate whether this difference results from the relative susceptibility of these agonists to hydrolysis by acetylcholinesterase, we studied vasodilator responses to brachial artery administration of acetylcholine alone and in the presence of the acetylcholinesterase inhibitor edrophonium. 2. Vasodilator responses to constant-rate brachial artery infusions of acetylchotine were biphasic, with an initial peak response fading over 2min to a plateau. Fade C(peak-plateau)/peak x 100%] was dose dependent (P<0.02), ranging from 43±7% (mean ±SEM) at low dose (16 nmol/min) to 9±8% at high dose (83 nmol/min). 3. Edrophonium (0.5 μmol/min intra-arterially) alone produced no change in forearm blood flow but increased blood flow responses to acetylcholine (P<0.01), causing an approximately 10-fold reduction in the dose required to increase plateau blood flow by 10 ml min^-1 100 ml^-1. 4. Responses to low doses of acetylcholine alone (16 and 41 nmol/min) faded more (P<0.01) than those to doses of acetylcholine with edrophonium chosen to produce similar plateau blood flows. Responses to acetylcholine (41 nmol/min) also faded more (P<0.01) than those to methacholine (5 nmol/min), producing matched plateau flows. 5. Peak and plateau responses to acetylcholine (41 nmol/min) were reduced (P<0.01) by similar amounts (47 ± 15% and 37 ± 13% respectively, P= 0.39) by coinfusion of L-NMMA (4 μmol/min). L-NMMA inhibited responses to acetylcholine more than matched responses to acetylcholine with edrophonium (P<0.01). 6. These results suggest that the actions of acetylcholine in human forearm resistance vessels are mediated both through an L-NMMA-sensitive pathway (L-arginine/nitric oxide pathway) that exhibits biphasic characteristics and through an L-NMMA-resistant pathway. The L-NMMA-resistant pathway is selectively potentiated by edrophonium. Inhibition of acetylcholinesterase by edrophonium may increase concentrations of acetylcholine deep to the endothelium and favour NO-independent actions on smooth muscle or sensory nerve endings mediating vasodilatation.