Vernakalant selectively prolongs atrial refractoriness with no effect on ventricular refractoriness or defibrillation threshold in pigs.
Vernakalant is a novel antiarrhythmic agent that has demonstrated clinical efficacy for the treatment of atrial fibrillation. Vernakalant blocks, to various degrees, cardiac sodium and potassium channels with a pattern that suggests atrial selectivity. We hypothesized, therefore, that vernakalant would affect atrial more than ventricular effective refractory period (ERP) and have little or no effect on ventricular defibrillation threshold (DFT). Atrial and ventricular ERP and ventricular DFT were determined before and after treatment with vernakalant or vehicle in 23 anesthetized male mixed-breed pigs. Vernakalant was infused at a rate designed to achieve stable plasma levels similar to those in human clinical trials. Atrial and ventricular ERP were determined by endocardial extrastimuli delivered to the right atria or right ventricle. Defibrillation was achieved using external biphasic shocks delivered through adhesive defibrillation patches placed on the thorax after 10 seconds of electrically induced ventricular fibrillation. The DFT was estimated using the Dixon "up-and-down" method. Vernakalant significantly increased atrial ERP compared with vehicle controls (34 ± 8 versus 9 ± 7 msec, respectively) without significantly affecting ventricular ERP or DFT. This is consistent with atrial selective actions and supports the conclusion that vernakalant does not alter the efficacy of electrical defibrillation.
Cardiome Pharma Corp. Vancouver, British Columbia, Canada. jbechard@cardiome.com
Jeff
J
Bechard
John Ken
JK
Gibson
Cheryl R
CR
Killingsworth
Jeffery J
JJ
Wheeler
Marlowe J
MJ
Schneidkraut
Jian
J
Huang
Raymond E
RE
Ideker
Donald A
DA
McAfee
D000818:Animals; D000840:Anisoles / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D000889:Anti-Arrhythmia Agents / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004554:Electric Countershock; D006325:Heart Atria / Q000187:drug effects* / Q000473:pathology; D006801:Humans; D008297:Male; D015221:Potassium Channels / Q000187:drug effects*; D011759:Pyrrolidines / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D012032:Refractory Period, Electrophysiological / Q000187:drug effects*; D015222:Sodium Channels / Q000187:drug effects*; D013552:Swine; D016276:Ventricular Function / Q000187:drug effects* / Q000502:physiology
D000840:Anisoles; D000889:Anti-Arrhythmia Agents; D015221:Potassium Channels; D011759:Pyrrolidines; D015222:Sodium Channels; C524581:vernakalant