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 voltagegated 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 μM veratridine and 10 μM 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 μM 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 IC₅₀ of 0.55 μM and 0.79 μM, 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.