Cellular electrophysiologic effects of vertebrate digitalis-like substances.
Substances structurally and functionally similar to digitalis glycosides are produced by several vertebrate species. There also is evidence for a digitalis-like substance of human origin. Standard microelectrode techniques were used to study the direct effects on the cellular electrophysiology of canine Purkinje fibers of 1) bufalin, an unconjugated cardiotonic steroid molecule that is produced by the toad Bufo marinus, and 2) an extract of human bile that showed digitalis-like immunoreactivity on radioimmunoassay. The goal of this study was to determine whether these substances have arrhythmogenic effects comparable with those seen with toxic doses of digitalis glycosides. Bufalin, 2 x 10(-8) M, significantly (p less than 0.05) reduced maximal diastolic potential, action potential amplitude and duration and maximal rate of rise of phase 0 (Vmax) within 40 min of onset of exposure. All six fibers developed delayed afterdepolarizations and two developed triggered rhythms. Ouabain was less potent, in that a 2 x 10(-7) M concentration was required to comparably reduce maximal diastolic potential, action potential amplitude and duration and Vmax within 30 min. These Purkinje fibers also developed delayed afterdepolarizations and triggered rhythms. A sample of an extract of human bile that showed digitalis-like immunoreactivity with an antibufalin serum also reduced maximal diastolic potential, action potential amplitude and duration and Vmax, and produced delayed afterdepolarizations and triggered activity. In contrast, immunologically unreactive bile extracts had no appreciable effect on the action potential. In summary, the cardiac toxicity of digitalis substances produced by lower vertebrates is comparable with that induced by the glycosides. Moreover, it appears that humans may produce digitalis-like substances that may be cardiotoxic.
Kieval
R S
RS
Department of Pharmacology, College of Physicians and Surgeons, Columbia University, New York, New York 10032.
Butler
V P
VP
Derguini
F
F
Bruening
R C
RC
Rosen
M R
MR
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001646:Bile / Q000276:immunology; D001798:Blood Proteins / Q000494:pharmacology*; D002018:Bufanolides / Q000276:immunology / Q000494:pharmacology*; D002298:Cardenolides; D004077:Digoxin; D004285:Dogs; D004594:Electrophysiology; D005260:Female; D006329:Heart Conduction System / Q000187:drug effects*; D006801:Humans; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D010042:Ouabain / Q000494:pharmacology; D011690:Purkinje Fibers / Q000187:drug effects* / Q000502:physiology; D011863:Radioimmunoassay; D012503:Saponins; D000254:Sodium-Potassium-Exchanging ATPase / Q000494:pharmacology*
D001798:Blood Proteins; D002018:Bufanolides; D002298:Cardenolides; D012503:Saponins; C034504:digoxin-like factors; D010042:Ouabain; D004077:Digoxin; D000254:Sodium-Potassium-Exchanging ATPase; C022777:bufalin