title: Comparison of the intrinsic vasorelaxant and inotropic effects of the antiarrhythmic agents vernakalant and flecainide in human isolated vascular and cardiac tissues.
abstract: 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.
authors.affiliation: Department of Hypertension, Merck Research Laboratories, Rahway, NJ, USA. joseph_lynch@merck.com
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Lynch
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Regan
authors.forename: Gregory N
authors.initials: GN
authors.lastname: Beatch
authors.forename: Gilbert W
authors.initials: GW
authors.lastname: Gleim
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Morabito
mesh_terms: D000840:Anisoles / Q000494:pharmacology*; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001158:Arteries / Q000187:drug effects*; D002316:Cardiotonic Agents / Q000494:pharmacology; D054715:Cardiotoxins / Q000494:pharmacology; D005424:Flecainide / Q000494:pharmacology*; D006352:Heart Ventricles / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D009200:Myocardial Contraction / Q000187:drug effects; D009994:Osmolar Concentration; D011759:Pyrrolidines / Q000494:pharmacology*; D012867:Skin / Q000098:blood supply; D049994:Sodium Potassium Chloride Symporter Inhibitors / Q000494:pharmacology*; D014655:Vascular Resistance / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D000840:Anisoles; D000889:Anti-Arrhythmia Agents; D002316:Cardiotonic Agents; D054715:Cardiotoxins; D011759:Pyrrolidines; D049994:Sodium Potassium Chloride Symporter Inhibitors; D014665:Vasodilator Agents; C524581:vernakalant; D005424:Flecainide