Anti-ischemic compound KC 12291 prevents diastolic contracture in isolated atria by blockade of voltage-gated sodium channels.
Several lines of evidence support a fundamental role for voltage-gated sodium channels in mediating ischemic Na rise. We examined the effect of the novel anti-ischemic compound KC 12291 on veratridine-stimulated and lysophosphatidylcholine (LPC)-induced sustained sodium current (I(NAL)) mediated by sodium channels in isolated myocytes obtained from guinea-pig atria, by using the whole-cell patch-clamp technique. We also analyzed the effect of KC 12291 on veratridine- and LPC-induced contractures in isolated guinea-pig atria. Veratridine as well as LPC increased I(NAL) measured at 20 ms of a 2 s pulse evoked from -100 to -30 mV (47.5 and 12 pA/pF in the presence of 40 microM veratridine and 10 microM LPC, respectively, vs. 6.7 pA/pF under control conditions). A significant reduction by KC 12291 in the quantity of charge carried by veratridine-stimulated I(NAL) in the range of test potentials between -50 mV and +10 mV was observed and similar effects were obtained on LPC-induced I(NAL). Thus, the quantity of charge carried by LPC-induced I(NAL) over a 2 s pulse to -30 mV was reduced by 48% in the presence of 10 microM KC 12291 vs. a reduction by 50% of veratridine-stimulated I(NAL) at the same test potential. Veratridine- and LPC-induced submaximal contractures in isolated atria were significantly inhibited by KC 12291 in a concentration-dependent manner, with an IC of 0.55 microM and 0.79 microM, respectively. The data indicate that veratridine- and LPC-induced increases in diastolic tension are inhibited by KC 12291 by a mechanism that involves blockade of voltage-gated sodium channels mediating sustained sodium current.
Tamareille
Sophie
S
Hôpital Marie Lannelongue, Université Paris Sud XI, Paris, France.
Le Grand
Bruno
B
John
Gareth W
GW
Feuvray
Danielle
D
Coulombe
Alain
A
D000818:Animals; D003971:Diastole / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006325:Heart Atria / Q000166:cytology / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000502:physiology; D026941:Sodium Channel Blockers / Q000494:pharmacology*; D015222:Sodium Channels / Q000502:physiology*; D013830:Thiadiazoles / Q000494:pharmacology*
C111116:3-(3-(N-(2-(3,4-dimethoxyphenyl)ethyl)-N-methylamino)propyloxy)-5-phenyl-1,2,4-thiadiazole; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D013830:Thiadiazoles