The neuroprotective agent sipatrigine blocks multiple cardiac ion channels and causes triangulation of the ventricular action potential.
Sipatrigine (BW 619C89), a blocker of neuronal Na+ and Ca2+ channels that is structurally related to lamotrigine, has been shown to be neuroprotective in models of cortical ischaemia. Although associated with cardiovascular effects in animal models in vivo, there is no published information concerning the effects of sipatrigine on cardiac ion currents and action potentials (AP). The aim of the present study was to examine the effects of sipatrigine on the delayed rectifier currents (I(Kr) and I(Ks)), the inward rectifier current (I(K1)), the L-type Ca2+ current (I(Ca,L)) and the fast Na+ current (I(Na)), as well as on AP duration at 30% (APD30) and 90% (APD90) repolarization, in guinea-pig isolated ventricular myocytes. Each of the currents was inhibited by sipatrigine, demonstrating the drug to be a relatively broad-spectrum blocker of cation channels in the heart. However, sipatrigine was a comparatively more potent inhibitor of I(Kr) (IC50 = 0.85 micromol/L) and I(Ks) (IC50 = 0.92 micromol/L) than of I(K1) (IC50 = 5.3 micromol/L), I(Ca,L) (IC50 = 6.0 micromol/L) and I(Na) (IC50 = 25.5 micromol/L). Consistent with block of I(Kr), I(Ks) and I(K1), sipatrigine (1-30 micromol/L) produced a concentration-dependent prolongation of APD90. Although lower concentrations of sipatrigine (< or = 3 micromol/L) caused APD(30) prolongation, higher concentrations (> or = 10 micromol/L) shortened APD30, consistent with an involvement of I(Ca,L) blockade. The contrasting effects of sipatrigine on APD30 and APD90 at higher concentrations resulted in a marked concentration-dependent triangulation of the AP. 5. The results of the present study demonstrate that sipatrigine, at concentrations previously shown to be neuroprotective in vitro, modulates cardiac K+, Ca2+ and Na+ currents and repolarization of the cardiac ventricular action potential.
Gao
Zhan
Z
Department of Physiology and Cardiovascular Research Laboratories, School of Medical Sciences, University of Bristol, Bristol, UK.
Milnes
James T
JT
Choisy
Stéphanie C M
SC
Leach
Michael J
MJ
Hancox
Jules C
JC
James
Andrew F
AF
D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002469:Cell Separation; D004594:Electrophysiology; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D006352:Heart Ventricles / Q000187:drug effects; D066298:In Vitro Techniques; D007473:Ion Channels / Q000187:drug effects*; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology*; D026941:Sodium Channel Blockers / Q000494:pharmacology
D002121:Calcium Channel Blockers; D007473:Ion Channels; D018696:Neuroprotective Agents; D010879:Piperazines; D026902:Potassium Channel Blockers; D011743:Pyrimidines; D026941:Sodium Channel Blockers; C081980:sipatrigine