Blockade of cardiac nicotinic responses by anticholinesterases.
1. Tacrine (10 microM) and physostigmine (10 microM) completely inhibited the positive chronotropic and inotropic actions of acetylcholine (ACh) or nicotine in the atropinized guinea pig right atria. 2. Edrophonium (6 microM) and soman (0.1 microM) completely inhibited these nicotinic responses, as well as the associated increase in pyridine nucleotide fluorescence and vasodilation induced by ACh in the atropinized guinea pig perfused heart. 3. The 200-fold increase in noradrenaline release induced by ACh in the perfused heart was blocked by 10 microM tacrine and 6 microM edrophonium. 4. Tacrine (10 microM) significantly (16-32%) reduced the basal heart rate of both preparations. 5. Edrophonium (6 microM) induced a five- to sixfold increase in basal 3,4-dihydroxyphenyl-(ethylene) glycol (DOPEG) release. 6. The inhibition of nicotinic receptor activation in the atria by the anticholinesterases appears mainly non-competitive. IC50 values range from 0.1 to 10 microM in the perfused heart to 1 to 100 microM in atria (in either case tacrine about 2 microM). 7. The possibility that these compounds have a direct action at nicotinic receptors is discussed.
Paddle
B M
BM
Department of Defence, DSTO, Aeronautical and Maritime Research Laboratory, Melbourne VIC, Australia.
Dowling
M H
MH
D000109:Acetylcholine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D002219:Carbamates / Q000494:pharmacology; D002395:Catecholamines / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D004491:Edrophonium / Q000494:pharmacology; D005260:Female; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D006325:Heart Atria / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D009200:Myocardial Contraction / Q000187:drug effects; D009538:Nicotine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000494:pharmacology*; D012999:Soman / Q000494:pharmacology; D013619:Tacrine / Q000494:pharmacology
D002219:Carbamates; D002395:Catecholamines; D002800:Cholinesterase Inhibitors; D018733:Nicotinic Antagonists; D013619:Tacrine; D009538:Nicotine; D004491:Edrophonium; D001285:Atropine; D012999:Soman; D000109:Acetylcholine