title: Mechanisms of cardiac muscle insensitivity to a novel acetylcholinesterase inhibitor C-547.
abstract: We compared the effects of the novel acetylcholinesterase (AChE) inhibitor C-547 on action potential configuration and sinus rhythm in the isolated right atrium preparation of rat with those of armin and neostigmine. Both armin (10(-7), 10(-6), and 10(-5) M) and neostigmine (10(-7), 10(-6), and 5 x 10(-6) M) produced a marked decrease in action potential duration and slowing of sinus rate. These effects were abolished by atropine and are attributable to the accumulation of acetylcholine in the myocardium. The novel selective AChE inhibitor C-547 (10(-9) to 10(-7) M), an alkylammonium derivative of 6-methyluracil, had no such effects. The inhibition constant of C-547 on cardiac AChE is 40-fold higher than that on extensor digitorum longus muscle AChE. These results suggest that C-547 might be employed to treat diseases such as myasthenia gravis or Alzheimer disease, without having unwanted effects on the heart.
authors.affiliation: Institute of Experimental Cardiology, Laboratory of Heart Electrophysiology, Moscow, Russia. abram340@mail.ru
authors.forename: Denis V
authors.initials: DV
authors.lastname: Abramochkin
authors.forename: Konstantin A
authors.initials: KA
authors.lastname: Petrov
authors.forename: Vladimir V
authors.initials: VV
authors.lastname: Zobov
authors.forename: Lilia O
authors.initials: LO
authors.lastname: Yagodina
authors.forename: Eugen E
authors.initials: EE
authors.lastname: Nikolsky
authors.forename: Leonid V
authors.initials: LV
authors.lastname: Rosenshtraukh
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001138:Armin / Q000494:pharmacology; D016275:Atrial Function / Q000187:drug effects; D001285:Atropine / Q000494:pharmacology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D009388:Neostigmine / Q000494:pharmacology; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology*; D051381:Rats; D012849:Sinoatrial Node / Q000187:drug effects / Q000502:physiology; D014498:Uracil / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: C449662:C-547 compound; D002800:Cholinesterase Inhibitors; D000644:Quaternary Ammonium Compounds; D009388:Neostigmine; D014498:Uracil; D001285:Atropine; D001138:Armin