Antiarrhythmic and electrophysiologic actions of clofilium in experimental canine models

Abstract

Clofilium was studied in three experimental models. In non-ischemic and chronically infarcted canine hearts, clofilium (0.5-2 mg/kg) produced a dose-dependent increase in electrical ventricular fibrillation threshold (VFT), but prolonged the effective refractory period (ERP) of normal myocardium in only the non-ischemic heart. When chronically infarcted hearts were subjected to programmed electrical stimulation, 1 mg/kg of clofilium inhibited the re-induction of either ventricular tachycardia or ventricular fibrillation in 5 of 6 animals and slowed the rate of the induced tachycardia in the sixth. Clofilium, however, failed to alter ventricular refractory periods of normal myocardium at either twice diastolic threshold current (176 +/- 5 ms control vs. 187 +/- 9 ms post-clofilium, P greater than 0.05) or at 10 mA (134 +/- 6 ms control vs. 137 +/- 13 ms post-clofilium, P greater than 0.05). In addition, chronic administration of clofilium (2 mg/kg, i.v., followed by 1 mg/kg every 12 h) was ineffective in decreasing mortality in a canine model of sudden coronary death. Of 10 saline-treated conscious animals subjected to an electrically-induced intimal lesion of the left circumflex coronary artery in the presence of a previous ischemic insult, all 10 died suddenly of ventricular fibrillation within 173 +/- 45 min after current application. Under similar conditions, 7 clofilium-treated animals died suddenly within 249 +/- 88 min (P greater than 0.05) after current application while 3 animals survived (P greater than 0.10). Clofilium did, however, elevate the effective refractory period in these animals (150 +/- 3 ms saline-treated vs. 195 +/- 7 ms clofilium-treated). It is concluded from our data that there is little relationship between clofilium's electrophysiologic actions in normal myocardium and antiarrhythmic effects. Furthermore, simple prolongation of refractoriness in normal non-ischemic myocardium may be insufficient for the prevention of ventricular fibrillation which develops in response to a transient ischemic event superimposed on a chronically injured myocardium.

Failure of Thromboxane Synthetase Inhibition to Protect the Postinfarcted Heart against the Induction of Ventricular Tachycardia and Ventricular Fibrillation in a Conscious Canine Model of Sudden Coronary Death

“…every 12 h (total of 3 doses administered at the time of post-treatment programming), 2 animals (18%) became noninducible while the re maining 9 developed the same pattern of VT as observed at the time of the control evalu ation. A similar incidence of inducibilily has been observed in vehicle-treated control groups from previous studies conducted in this laboratory (13% [27], 7% [26], 10% [28]). In general, the ease of induction of VT in the drug-treated animals was comparable before and after administration of CGS 12970.…”

Antifibrillatory effects of clofilium in the rabbit isolated heart

“…The role of clofilium as an antifibrillatory agent has been shown to be beneficial by lowering defibrillation requirements (Kopia et al, 1985;Dorian et al, 1991). To date, there has not been a report that systematically describes the chemical defibrillatory ability of clofilium.…”

“…Clofilium has been shown to prolong the effective refractory period or action potential duration in a number of animal models (Steinberg & Molley, 1975;Steinberg et al, 1981;Kowey et al, 1985;Wu et al, 1989;Li et al, 1990) as well as to increase the refractory period in the human ventricular myocardium without affecting conduction time or haemodynamics (Greene et al, 1983). An additional potential benefit of clofilium derives from its ability to decrease the electrical energy requirement for ventricular defibrillation (Kopia et al, 1985;Dorian et al, 1991). However, its reported mechanism of action varies with species and model employed.…”

Antiarrhythmic Effects of MS-551, a New Class III Antiarrhythmic Agent, on Canine Models of Ventricular Arrhythmia.

“…Thus, it was suggested that MS-551 might be effective in cardiac arrhythmias by a different mechanism from class l antiarrhyth mic drugs. Lucchesi et al suggested that ven tricular tachycardia (VT) in response to pro grammed electrical stimulation (PES) delivered to the ventricular septum of dogs with myocar dial infarction is an useful method for evaluat ing pharmacological interventions for the pre vention of life-threatening reentrant tachyar rhythmias (5)(6)(7)(8). They showed that a number of class III antiarrhythmic drugs prevented such VT.…”