KC 12291: An Atypical Sodium Channel Blocker with Myocardial Antiischemic Properties

• Published in: Cardiovascular drug reviews 2004-03, Vol.22 (1), p.17-26
• Main Authors: John, Gareth W., Létienne, Robert, Grand, Bruno, Pignier, Christophe, Vacher, Bernard, Patoiseau, Jean‐Francois, Colpaert, Francis C., Coulombe, Alain
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Calcium overload; Cardioprotection; Cardiotonic Agents - chemistry; Cardiotonic Agents - pharmacokinetics; Cardiotonic Agents - pharmacology; Cardiovascular system; In Vitro Techniques; Ion Channel Gating; KC 12291; Medical sciences; Myocardial ischemia; Myocardial Ischemia - drug therapy; Pharmacology. Drug treatments; Sodium Channel Blockers - chemistry; Sodium Channel Blockers - pharmacokinetics; Sodium Channel Blockers - pharmacology; Sodium channels; Sodium loading; Sustained Na+ current; Thiadiazoles - chemistry; Thiadiazoles - pharmacokinetics; Thiadiazoles - pharmacology
• ISSN: 0897-5957; 1527-3466
• DOI: 10.1111/j.1527-3466.2004.tb00129.x

ABSTRACT KC 12291 was designed as a voltage‐gated sodium channel (VGSC) blocker with cardioprotective properties. KC 12291 has moderate inhibitory effects on peak (or rapid) Na+ current, and markedly reduces sustained (or slowly or non‐inactivating) Na+ current. This distinguishes KC 12291 from conventional VGSC blockers such as local anesthetics or antiarrhythmics, which have little or no cardioprotective properties. Since VGSCs represent the main pathway for ischemic Na+ loading by failing to inactivate fully, KC 12291 exerts pronounced antiischemic activity principally by reducing the amplitude of sustained Na+ current. In isolated atria and Langendorff‐perfused hearts, KC 12291 inhibits diastolic contracture, renowned for its resistance to pharmacological inhibition, reduces ischemic Na+ loading and preserves cardiac energy status. KC 12291 exerts oral antiischemic activity in vivo in the absence of major hemodynamic effects. Cardiac VGSC blockers such as KC 12291, which block cardiac VGSCs in atypical fashion by effectively inhibiting the sustained component of Na+ current, represent, therefore, promising potential antiischemic and cardioprotective drugs.