title: Comparison of the in vivo hemodynamic effects of the antiarrhythmic agents vernakalant and flecainide in a rat hindlimb perfusion model.
abstract: A series of in vivo experiments were conducted to compare the hemodynamic actions of vernakalant (a novel, relatively atrial selective, antiarrhythmic drug) to flecainide after infusion into the peripheral vasculature. Anesthetized rats were surgically prepared to have an extracorporeal perfusion circuit whereby blood in the abdominal aorta (distal to the renal arteries) was diverted to a constant flow pump and returned to the abdominal aorta at the same level allowing measurement of hindlimb vascular resistance. The effects of cumulative, ascending doses of intravenous vernakalant and flecainide on vascular resistance, after arterial pressures, and heart rate were measured. Blood samples were drawn following each dose to determine drug plasma concentrations. Vernakalant had no significant vasomotor effects on peripheral or systemic vasculature. In contrast, flecainide decreased peripheral vascular resistance (15% at 0.8 μg/mL) and systemic pressures (32% mean arterial pressure at 0.8 μg/mL) in a dose-dependent manner. At therapeutic plasma concentrations, vernakalant (1 μg/mL) had little effect on heart rate (-24 beats/min) or QRS intervals (+3.4 msec), whereas flecainide (0.8 μg/mL) significantly decreased heart rate (55 beats/min) and increased QRS intervals (9.9 msec). In conclusion, vernakalant did not have negative hemodynamic effects at therapeutic plasma concentrations in a rat hindlimb perfusion model.
authors.affiliation: Cardiome Pharma Corp, Vancouver, British Columbia, Canada. ballison@cardiome.com
authors.forename: Beth
authors.initials: B
authors.lastname: Allison
authors.forename: Yi
authors.initials: Y
authors.lastname: Yang
authors.forename: Marc
authors.initials: M
authors.lastname: Pourrier
authors.forename: John K
authors.initials: JK
authors.lastname: Gibson
mesh_terms: D000818:Animals; D000840:Anisoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D001012:Aorta, Abdominal / Q000187:drug effects / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005424:Flecainide / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D006614:Hindlimb; D008297:Male; D011759:Pyrrolidines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014655:Vascular Resistance / Q000187:drug effects*
chemical_list: D000840:Anisoles; D000889:Anti-Arrhythmia Agents; D011759:Pyrrolidines; C524581:vernakalant; D005424:Flecainide