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The neuroprotective agent sipatrigine blocks multiple cardiac ion channels and causes triangulation of the ventricular action potential.
Clin Exp Pharmacol Physiol. 2005 Dec; 32(12):1088-96.CE

Abstract

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.

Authors+Show Affiliations

Gao Z
Department of Physiology and Cardiovascular Research Laboratories, School of Medical Sciences, University of Bristol, Bristol, UK.
Milnes JT
No affiliation info available
Choisy SC
No affiliation info available
Leach MJ
No affiliation info available
Hancox JC
No affiliation info available
James AF
No affiliation info available

MeSH

Action PotentialsAnimalsCalcium Channel BlockersCell SeparationElectrophysiologyGuinea PigsHeartHeart VentriclesIn Vitro TechniquesIon ChannelsMaleMyocytes, CardiacNeuroprotective AgentsPiperazinesPotassium Channel BlockersPyrimidinesSodium Channel Blockers

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16445575

Citation

Gao, Zhan, et al. "The Neuroprotective Agent Sipatrigine Blocks Multiple Cardiac Ion Channels and Causes Triangulation of the Ventricular Action Potential." Clinical and Experimental Pharmacology & Physiology, vol. 32, no. 12, 2005, pp. 1088-96.
Gao Z, Milnes JT, Choisy SC, et al. The neuroprotective agent sipatrigine blocks multiple cardiac ion channels and causes triangulation of the ventricular action potential. Clin Exp Pharmacol Physiol. 2005;32(12):1088-96.
Gao, Z., Milnes, J. T., Choisy, S. C., Leach, M. J., Hancox, J. C., & James, A. F. (2005). The neuroprotective agent sipatrigine blocks multiple cardiac ion channels and causes triangulation of the ventricular action potential. Clinical and Experimental Pharmacology & Physiology, 32(12), 1088-96.
Gao Z, et al. The Neuroprotective Agent Sipatrigine Blocks Multiple Cardiac Ion Channels and Causes Triangulation of the Ventricular Action Potential. Clin Exp Pharmacol Physiol. 2005;32(12):1088-96. PubMed PMID: 16445575.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The neuroprotective agent sipatrigine blocks multiple cardiac ion channels and causes triangulation of the ventricular action potential. AU - Gao,Zhan, AU - Milnes,James T, AU - Choisy,Stéphanie C M, AU - Leach,Michael J, AU - Hancox,Jules C, AU - James,Andrew F, PY - 2006/2/1/pubmed PY - 2006/3/18/medline PY - 2006/2/1/entrez SP - 1088 EP - 96 JF - Clinical and experimental pharmacology & physiology JO - Clin Exp Pharmacol Physiol VL - 32 IS - 12 N2 - 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. SN - 0305-1870 UR - https://www.unboundmedicine.com/medline/citation/16445575/The_neuroprotective_agent_sipatrigine_blocks_multiple_cardiac_ion_channels_and_causes_triangulation_of_the_ventricular_action_potential_ DB - PRIME DP - Unbound Medicine ER -