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 inhibito r) inhibits vasodilator responses to acetylcholine but not methacholin e in human forearm vasculature. To investigate whether this difference results from the relative susceptibility of these agonists to hydroly sis by acetylcholinesterase, we studied vasodilator responses to brach ial artery administration of acetylcholine alone and in the presence o f the acetylcholinesterase inhibitor edrophonium. 2. Vasodilator respo nses to constant-rate brachial artery infusions of acetylcholine were biphasic, with an initial peak response fading over 2 min to a plateau , Fade [(peak-plateau)/peak x 100%] was dose dependent (P<0.02), rangi ng from 43 +/- 7% (mean +/- SEM) at low dose (16 nmol/min) to 9 +/- 8% at high dose (83 nmol/min). 3. Edrophonium (0.5 mu mol/min intra-arte rially) alone produced no change in forearm blood flow but increased b lood flow responses to acetylcholine (P<0.01), causing an approximatel y 10-fold reduction in the dose required to increase plateau blood flo w by 10 ml min(-1) 100 ml(-1). 4. Responses to low doses of acetylchol ine alone (16 and 41 nmol/min) faded more (P<0.01) than those to doses of acetylcholine with edrophonium chosen to produce similar plateau b lood flows. Responses to acetylcholine (41 nmol/min) also faded more ( P<0.01) than those to methacholine (5 nmol/min), producing matched pla teau flows. 5. Peak and plateau responses to acetylcholine (41 nmol/mi n) were reduced (P<0.01) by similar amounts (47 +/- 15% and 37 +/- 13% respectively, P=0.39) by coinfusion of L-NMMA (4 mu mol/min). L-NMMA inhibited responses to acetylcholine more than matched responses to ac etylcholine with edrophonium (P<0.01). 6. These results suggest that t he actions of acetylcholine in human forearm resistance vessels are me diated both through an L-NMMA-sensitive pathway (L-arginine/nitric oxi de pathway) that exhibits biphasic characteristics and through an L-NM MA-resistant pathway. The L-NMMA-resistant pathway is selectively pote ntiated by edrophonium. Inhibition of acetylcholinesterase by edrophon ium may increase concentrations of acetylcholine deep to the endotheli um and favour NO-independent actions on smooth muscle or sensory nerve endings mediating vasodilatation.