Antifibrillatory effects of clofilium in the rabbit isolated heart

Abstract

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 JIM), hearts were exposed to pinacidil (1.25 riM), 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 pLM), a delayed rectifier channel blocker, and 5-hydroxydecanoate (1O iM), 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 10.011M 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.

Adrenergic-dependent Effect of Adenosine-induced Ventricular Fibrillation in the Isolated Rabbit Heart

“…Two of the 10 control hearts developed ventricular fibrillation during hypoxia or reoxygenation. The incidence of ventricular fibrillation in this group of hearts is similar to vehicle treated groups in comparable (9) and related (19,20) investigations. Selected hemodynamic variables are shown in Table 1.…”

“…Our previous studies have demonstrated that the rabbit isolated heart subjected to 12 minutes of hypoxia followed by 40 minutes of reoxygenation and perfused with buffer containing 2.5 mM K+ is a suitable model for the study of profibrillatory and antifibrillatory agents (9,19,20,40,41). A period of 12 minutes of hypoxia causes significant metabolic and electrophysiologic changes, such as decreased tissue ATP content and shortening of action potential duration and ventricular refractory period, providing a susceptible substrate in the genesis of ventricular fibrillation when hearts are exposed to specific profibrillatory drugs (42,43).…”

Effects of tedisamil (KC‐8857) on cardiac electrophysiology and ventricular fibrillation in the rabbit isolated heart

“…Shortening of action potential duration, reduction of refractory period and initiation of re-entry are precursors to the onset of ventricular fibrillation Fagbemi et al, 1993). Several K+ channel blockers, such as glibenclamide, E-403 1, clofilium (Friedrichs et al, 1994) and ibutilide , effectively prevented the development of ventricular fibrillation in this model. In vivo studies reveal that tedisamil prevents regional ischaemiaand reperfusion-induced ventricular fibrillation in anaesthetized and conscious rats (Beatch et al, 1991;Adaikan et al, 1992;Bril et al, 1993).…”

RSD1019 suppresses ischaemia‐induced monophasic action potential shortening and arrhythmias in anaesthetized rabbits

“…While evidence for the antiarrhythmic efficacy of ischaemia‐selective AP prolongation is scarce, there is evidence from in vitro studies to support the hypothesis. Lucchesi's group ( Friedrichs et al ., 1994 ; Chi et al ., 1996 ) has shown that drugs which can be expected to prevent AP shortening under ‘simulated ischaemic’ conditions effectively prevent VF. The conditions they used to simulate ischaemia are of major importance when interpreting their results.…”