Anti-ischemic compound KC 12291 prevents diastolic contracture in isolated atria by blockade of voltage-gated sodium channels.

Abstract

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.

• Authors: Sophie Tamareille, Bruno Le Grand, Gareth W John, Danielle Feuvray, Alain Coulombe
• Journal: Journal of cardiovascular pharmacology (J Cardiovasc Pharmacol) Vol. 40 Issue 3 Pg. 346-55 (Sep 2002) ISSN: 0160-2446 [Print] United States
• PMID: 12198320 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 3-(3-(N-(2-(3,4-dimethoxyphenyl)ethyl)-N-methylamino)propyloxy)-5-phenyl-1,2,4-thiadiazole
• Sodium Channel Blockers
• Sodium Channels
• Thiadiazoles

Topics

• Animals
• Diastole (drug effects, physiology)
• Dose-Response Relationship, Drug
• Guinea Pigs
• Heart Atria (cytology, drug effects)
• In Vitro Techniques
• Male
• Membrane Potentials (drug effects, physiology)
• Myocardial Contraction (drug effects, physiology)
• Myocytes, Cardiac (drug effects, physiology)
• Sodium Channel Blockers (pharmacology)
• Sodium Channels (physiology)
• Thiadiazoles (pharmacology)