This study explored the intrinsic vasorelaxant and inotropic effects of the mixed potassium and sodium channel blocker atrial antiarrhythmic vernakalant and the class IC antiarrhythmic agent flecainide in human isolated subcutaneous resistance artery and in ventricular trabecular muscle preparations. At test concentrations encompassing free plasma concentrations associated with clinical efficacy for conversion of atrial fibrillation, vernakalant (1–10 μM) displayed no significant direct effects on human resistance artery tone or ventricular contractility. In contrast, tested at equimolar concentrations, flecainide significantly reduced peak isometric contractile force (10 μM) and maximal rates of force development and decline (3 and 10 μM) in the human ventricular muscle preparation while displaying no significant effect on human resistance artery tone. The lack of effects of vernakalant on human resistance artery tone and ventricular muscle contractile function suggests that direct vasorelaxant and inotropic effects do not underlie the rare hypotensive events observed clinically with vernakalant, raising the possibility that secondary (eg, reflex) effects may mediate these events. The demonstration of negative inotropic effects with flecainide in the human ventricular muscle preparations in the absence of an effect on resistance artery tone suggests that the hemodynamic effects of flecainide observed clinically result primarily from direct negative inotropic effects.
*Department of Hypertension, Merck Research Laboratories, Rahway, NJ
†Department of Safety and Exploratory Pharmacology, Merck Research Laboratories, West Point, PA
‡Cardiome Pharma Corp, Vancouver, British Columbia, Canada
§Department of Cardiovascular Disease, Merck Research Laboratories, Rahway, NJ.
Reprints: Joseph J. Lynch, Jr, PhD, Merck Research Laboratories, WP46-300, West Point, PA 19486 (e-mail: firstname.lastname@example.org).
The authors are employees of Merck Research Laboratories and Cardiome Pharma.
Received September 25, 2012
Accepted October 25, 2012