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

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 conv...

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Bibliographic Details
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
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Summary: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.
ISSN:0897-5957
1527-3466
DOI:10.1111/j.1527-3466.2004.tb00129.x