Inhibition of acetylcholinesterase selectively potentiates NG-monomethyl-L-arginine-resistant actions of acetylcholine in human forearm vasculature.
1. NG-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 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), 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 mumol/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 mumol/min).(ABSTRACT TRUNCATED AT 250 WORDS)
Chowienczyk
P J
PJ
Department of Clinical Pharmacology, UMDS, Guy's Hospital, London, U.K.
Cockcroft
J R
JR
Ritter
J M
JM
D000109:Acetylcholine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000328:Adult; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004491:Edrophonium / Q000494:pharmacology*; D005542:Forearm / Q000098:blood supply; D006801:Humans; D007700:Kinetics; D016210:Methacholine Chloride / Q000494:pharmacology; D008875:Middle Aged; D009569:Nitric Oxide / Q000037:antagonists & inhibitors*; D012039:Regional Blood Flow / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects*; D019323:omega-N-Methylarginine
D016210:Methacholine Chloride; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D004491:Edrophonium; D001120:Arginine; D000109:Acetylcholine