Effect of a neuroprotective drug, eliprodil on cardiac repolarisation: importance of the decreased repolarisation reserve in the development of proarrhythmic risk.
1. The aim of this study was to analyse the effects of eliprodil, a noncardiac drug with neuroprotective properties, on the cardiac repolarisation under in vitro circumstances, under normal conditions and after the attenuation of the 'repolarisation reserve' by blocking the inward rectifier potassium current (I(K1)) current with BaCl(2). 2. In canine right ventricular papillary muscle by applying the conventional microelectrode technique, under normal conditions, eliprodil (1 microm) produced a moderate reverse rate-dependent prolongation of the action potential duration (7.4+/-1.5, 8.9+/-2.1 and 9.9+/-1.8% at cycle lengths of 300, 1000 and 5000 ms, respectively; n=9). 3. This effect was augmented in preparations where I(K1) was previously blocked by BaCl(2) (10 microm). BaCl(2) alone lengthened APD in a reverse frequency-dependent manner (7.0+/-1.3, 14.2+/-1.6 and 28.1+/-2.1% at cycle lengths of 300, 1000 and 5000 ms, respectively; n=8). When eliprodil (1 microm) was administered to these preparations, the drug induced a marked further lengthening relative to the APD values measured after the administration of BaCl(2) (12.5+/-1.0, 17.6+/-1.5 and 20.5+/-0.9% at cycle lengths of 300, 1000 and 5000 ms, respectively; n=8). 4. In the normal Langendorff-perfused rabbit heart, eliprodil (1 microm) produced a significant QT(c) prolongation at 1 Hz stimulation frequency (12.7+/-1.8%, n=9). After the attenuation of the 'repolarisation reserve' by the I(K1) blocker BaCl(2) (10 microm), the eliprodil-evoked QT(c) prolongation was greatly enhanced (28.5+/-7.9%, n=6). In two out of six Langendorff preparations, this QT(c) lengthening degenerated into torsade de pointes ventricular tachycardia. 5. Eliprodil significantly decreased the amplitude of rapid component of the delayed rectifier potassium current (I(Kr)), but slow component (I(Ks)), transient outward current (I(to)) and I(K1) were not considerably affected by the drug when measured in dog ventricular myocytes by applying the whole-cell configuration of the patch-clamp technique. 6. The results indicate that eliprodil, under normal conditions, moderately lengthens cardiac repolarisation by inhibition of I(Kr). However, after the attenuation of the normal 'repolarisation reserve', this drug can induce marked QT interval prolongation, which may result in proarrhythmic action.
Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Szeged, Dóm tér 12, PO Box 427, Szeged H-6701, Hungary.
Csaba
C
Lengyel
László
L
Dézsi
Péter
P
Biliczki
Csilla
C
Horváth
László
L
Virág
Norbert
N
Iost
Miklós
M
Németh
László
L
Tálosi
Julius Gy
JG
Papp
András
A
Varró
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000503:physiopathology*; D017609:Barium Compounds / Q000494:pharmacology; D002712:Chlorides / Q000494:pharmacology; D004285:Dogs; D004562:Electrocardiography / Q000187:drug effects; D004594:Electrophysiology; D005260:Female; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology*; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008839:Microelectrodes; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010210:Papillary Muscles / Q000187:drug effects; D018408:Patch-Clamp Techniques; D010880:Piperidines / Q000494:pharmacology*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D024661:Potassium Channels, Inwardly Rectifying / Q000187:drug effects; D011817:Rabbits
D017609:Barium Compounds; D002712:Chlorides; D018696:Neuroprotective Agents; D010880:Piperidines; D026902:Potassium Channel Blockers; D024661:Potassium Channels, Inwardly Rectifying; C024986:barium chloride; C058083:eliprodil