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

Abstract

1 The direct cardiac electrophysiological and antifibrillatory actions of tedisamil (KC-8857) were studied in rabbit isolated hearts.2 Tedisamil (1, 3, and 10 gM), prolonged the ventricular effective refractory period (VRP) from 120±18 ms (baseline) to 155 + 19, 171+20, and 205+14 ms, respectively. Three groups of isolated hearts (n = 6 each) were used to test the antifibrillatory action of tedisamil. Hearts were perfused with 1.25 Mm pinacidil, a KATP channel activator. Hearts were subjected to hypoxia for 12 min followed by 40 min of reoxygenation. Ventricular fibrillation (VF) developed during hypoxia and reoxygenation in both the control and 1 gM tedisamil-treated groups (5/6 and 4/6, respectively). Tedisamil (3 gM) reduced the incidence of VF (0/6, P= 0.007 vs. control). 3 In a separate group of hearts, VF was initiated by electrical stimulation. The administration of 0.3 ml of 10 mM tedisamil, via the aortic cannula, terminated VF in all hearts, converting them to normal sinus rhythm. 4 Tedisamil (3 gM) reversed pinacidil-induced negative inotropic effects in rabbit isolated atrial muscle which were equilibrated under normoxia, as well as in atrial muscle subjected to hypoxia and reoxygenation. 5 The results demonstrate a direct antifibrillatory action of tedisamil in vitro. The mechanism responsible for the observed effects may involve modulation by tedisamil of the cardiac ATP-regulated potassium channel, in addition to its antagonism of IK and Ith.

Tedisamil and dofetilide‐induced torsades de pointes, rate and potassium dependence

“…Tedisamil was obtained from Kali‐Chemi (Hanover, Germany) and dofetilide was obtained from Pfizer (Sandwich, U.K.). The test concentrations of tedisamil were selected on the basis of previous studies in our laboratory ( Chi et al ., 1996 ; Friedrichs et al ., 1998 ), as well as others ( Tsuchihashi & Curtis, 1991 ), which demonstrated that tedisamil had antiarrhythmic actions over this concentration range (0.3 – 3 μ M ) in vitro and in vivo . The lowest concentration of dofetilide (3 n M ) was selected on the basis of a literature report that demonstrated the antiarrhythmic activity of this drug in man ( Echt et al ., 1995 ).…”

“…Tedisamil is an experimental bradycardic agent being developed for the treatment of angina pectoris ( Fox et al ., 2000 ). The drug prolongs cardiac action potentials and the QT interval of the ECG in experimental animals ( Beatch et al ., 1991 ; Tsuchihashi & Curtis, 1991 ; Rees et al ., 1993 ; Wallace et al ., 1995 ; Chi et al ., 1996 ) and in man ( Bargheer et al ., 1994 ; Fox et al ., 2000 ). Tedisamil brings about these effects via blockade of several cardiac ion currents.…”

Different inhibition patterns of tedisamil for fast and slowly inactivating transient outward current in rat ventricular myocytes

“…Tedisamil has been described as an antiarrhythmic drug (Chi et al 1996), which in rat ventricular myocytes provokes marked prolongation of action potentials (Dukes and Morad 1989). This effect was explained by a selective inhibition of fast inactivating transient outward current (Dukes and Morad 1989).…”

Auswirkungen des K+-Kanalblockers Tedisamil auf Hämodynamik, Myokardischämie und neurohumorales System bei Patienten mit stabiler Angina pectoris.¶Ein Vergleich mit dem β-Blocker Atenolol

“…Die leichte Verlängerung der QT-und QT c -Dauer nach Gabe von Tedisamil als Indikator für eine verlängerte ventrikuläre Repolarisationsphase könnte einen antiarrhythmischen Effekt bewirken, wie dies bereits in tierexperimentellen Untersuchungen gezeigt werden konnte (1,2,4,6,11,31). Die Supprimierung von ischämiebedingten Arrhythmien, was nicht Gegenstand der vorliegenden Arbeit war, beruht bei Tedisamil primär wahrscheinlich auf der Wirkung auf ATPabhängige Kaliumkanäle.…”

“…Tedisamildihydrochlorid ist eine neuartige bradykardisierende Substanz mit nachweisbaren antiischämischen (7,14) und antiarrhythmischen Eigenschaften (1,2,4,6,11,31). Tedisamil führte nachweislich zur Inhibierung verschiedener repolarisierender (8,9,10) sowie zahlreicher neuronaler (9,10,21) und vaskulärer (17,22,23) K + -Kanäle.…”