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 (INaL) 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 INaL 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 INaL in the range of test potentials between –50 mV and +10 mV was observed and similar effects were obtained on LPC-induced INaL. Thus, the quantity of charge carried by LPC-induced INaL 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 INaL 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.