Antifibrillatory effects of ibutilide in the rabbit isolated heart: mediation via ATP-dependent potassium channels.
This study determined if ibutilide, a drug with class III activity, exhibited antifibrillatory effects in an isolated heart model of ventricular fibrillation (VF). Langendorff-perfused hearts were randomized among six groups. Group I (n = 9) served as the vehicle-treated control group. Groups II (n = 6), III (n = 10) and IV (n = 9) were pretreated with ibutilide 0.1; 1.0 or 3.0 microM, respectively. Ten minutes after perfusion in the presence of vehicle or ibutilide, hearts were perfused with the ATP-dependent potassium channel opener, pinacidil (1.25 microM) and subjected to a 12-min hypoxic period followed by 40 min of reoxygenation, or until the onset of VF. Groups V and VI were used to investigate electrophysiological effects of ibutilide (n = 12), as well as its chemical defibrillatory activity (n = 9), respectively. Additional experiments involved isometric tension recordings from canine atrial pectinate muscle exposed to increasing concentrations of pinacidil (3-300 microM) in the presence of ibutilide (3-30 microM). Ibutilide decreased the incidence of VF in a concentration-dependent manner; eight of nine control hearts developed VF vs. two of nine hearts (P = .018 chi 2) treated with 3.0 microM ibutilide. In atrial pectinate tissue, ibutilide attenuated the negative inotropic effect of pinacidil. An unexpected finding was the ability of ibutilide to achieve chemical defibrillation when added to the perfusion medium after the electrical induction of ventricular fibrillation in the isolated heart. The antifibrillatory effect of ibutilide may result from inhibition of the ATP-dependent potassium channel made susceptible to opening by pinacidil during hypoxia.
Friedrichs
G S
GS
Department of Pharmacology, University of Michigan Medical School, Ann Arbor.
Chi
L
L
Black
S C
SC
Manley
P J
PJ
Oh
J Y
JY
Lucchesi
B R
BR
D000255:Adenosine Triphosphate / Q000502:physiology*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D016275:Atrial Function; D003864:Depression, Chemical; D004594:Electrophysiology; D006146:Guanidines / Q000037:antagonists & inhibitors; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006325:Heart Atria / Q000187:drug effects; D066298:In Vitro Techniques; D008954:Models, Biological; D009200:Myocardial Contraction / Q000187:drug effects; D010477:Perfusion; D020110:Pinacidil; D015221:Potassium Channels / Q000187:drug effects* / Q000502:physiology*; D011817:Rabbits; D013449:Sulfonamides / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000037:antagonists & inhibitors; D014693:Ventricular Fibrillation / Q000188:drug therapy*
D000889:Anti-Arrhythmia Agents; D006146:Guanidines; D015221:Potassium Channels; D013449:Sulfonamides; D014665:Vasodilator Agents; C067192:ibutilide; D020110:Pinacidil; D000255:Adenosine Triphosphate