Mechanism of sodium channel blockade in the cardiotoxic action of emetine dihydrochloride in isolated cardiac preparations and ventricular myocytes of guinea pigs.
Emetine is used in the therapy of special forms of amebiasis and is abused as syrup of ipecac by persons with bulimia. Severe cardiac side effects were reported. Thus the intracellular microelectrode technique and the patch-clamp technique in the cell-attached mode were used to study the effects of emetine on the action potential and upstroke velocity (Vmax) in papillary muscles and Purkinje fibers of guinea pigs as well as on macroscopic and (S)-DPI 201-106-modified and unmodified single-sodium-channel current (I(Na)) of guinea-pig ventricular myocytes. Emetine caused a tonic block of Vmax and reduced I(Na) independent of frequency. Hill plots were linear, with slopes ranging from 0.96 to 1.06, suggestive of a first-order reaction. The current-voltage relation was not influenced, indicating a voltage-independent blockade of the sodium channels. The most prominent effects were an increase of sweeps without activity, a decrease of the fast component of the open-time distribution, an increase of the slow component of the closed-time distribution, and a reduction in the number of bursts per record. The amplitude of the unitary current was not changed. From the results, we conclude that I(Na) blockade contributes to the cardiotoxicity of emetine.
Lemmens-Gruber
R
R
Institute of Pharmacology and Toxicology, University of Vienna, Pharmazie-Zentrum, Austria.
Studenik
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C
Karkhaneh
A
A
Heistracher
P
P
D000200:Action Potentials / Q000187:drug effects; D000563:Amebicides / Q000633:toxicity*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004640:Emetine / Q000633:toxicity*; D005260:Female; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D008839:Microelectrodes; D010210:Papillary Muscles / Q000187:drug effects* / Q000502:physiology; D018408:Patch-Clamp Techniques; D011689:Purkinje Cells / Q000187:drug effects* / Q000502:physiology; D026941:Sodium Channel Blockers; D015222:Sodium Channels / Q000502:physiology
D000563:Amebicides; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D004640:Emetine