Antifibrillatory effects of clofilium in the rabbit isolated heart.
1. This study was designed to determine whether clofilium exhibits antifibrillatory activity in a pinacidil + hypoxia-induced model of ventricular fibrillation (VF) in Langendorff-perfused hearts. 2. Ten minutes after exposure to vehicle or clofilium (0.1, 1.0 and 10.0 microM), hearts were exposed to pinacidil (1.25 microM), then subjected to 12 min of hypoxia and reoxygenated. Onset to VF was recorded. Additional groups of hearts were pretreated with UK-68,798 (1.0, 3.0 and 10.0 microM), a delayed rectifier channel blocker, and 5-hydroxydecanoate (10 microM), a known ATP-dependent K+ channel blocker, and subjected to an identical protocol. 3. Clofilium decreased the incidence of VF in a concentration-dependent manner; 7/9 control hearts developed VF vs 1/9 hearts (P = 0.007, Fisher's Exact) treated with 10.0 microM clofilium. In addition, 5-hydroxydecanoate protected hearts from VF, while UK-68,798 pretreatment did not. 4. In a separate group of hearts, electrically-induced VF was converted to sinus rhythm in 10/11 hearts after clofilium was introduced as a bolus. 5. Clofilium is capable of preventing VF in the rabbit isolated heart in a concentration-dependent manner. We have data to suggest that the ability of clofilium to attenuate the effects of pinacidil+hypoxia in our model may include blockade of metabolically active K+ channels, i.e., KATP (glibenclamide-sensitive) channel.
Friedrichs
G S
GS
University of Michigan Medical School, Department of Pharmacology, Ann Arbor 48109-0626.
Chi
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Green
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Lucchesi
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BR
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D003652:Decanoic Acids / Q000494:pharmacology; D004195:Disease Models, Animal; D005905:Glyburide / Q000494:pharmacology; D006321:Heart / Q000187:drug effects*; D006880:Hydroxy Acids / Q000494:pharmacology; D066298:In Vitro Techniques; D009206:Myocardium / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects; D018408:Patch-Clamp Techniques; D010627:Phenethylamines / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology*; D011817:Rabbits; D012032:Refractory Period, Electrophysiological / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology; D014693:Ventricular Fibrillation / Q000188:drug therapy* / Q000503:physiopathology; D017725:Ventricular Pressure / Q000187:drug effects
D000889:Anti-Arrhythmia Agents; D003652:Decanoic Acids; D006880:Hydroxy Acids; D010627:Phenethylamines; D015221:Potassium Channels; D000644:Quaternary Ammonium Compounds; D013449:Sulfonamides; C052853:5-hydroxydecanoic acid; C022799:clofilium; C063533:dofetilide; D005905:Glyburide