In vivo and in vitro characterization of the novel antiarrhythmic agent SSR149744C: electrophysiological, anti-adrenergic, and anti-angiotensin II effects.
SSR149744C (SSR, 2-butyl-3-[4-[3-(dibutylamino)pro-pyl]benzoyl]-1-benzofuran-5-carboxylate isopropyl fumarate), is a new non-iodinated benzofuran derivative. The aim of this study was to evaluate in vivo its electrophysiological, hemodynamic, and anti-adrenergic properties and to determine its mechanism of action using in vitro studies. In chloralose-anesthetized dogs, SSR149744C (1-10 mg/kg i.v.) prolonged the sinus cycle length, A-H interval, Wenckebach cycle length, atrial effective refractory period (ERP), and atrio-ventricular node ERP in a dose-dependent manner without change of ventricular ERP and HV, QRS, or QTc intervals. Arterial blood pressure and ventricular inotropism were slightly decreased. SSR149744C, which has no or low affinity for alpha 1 and beta 1 adrenergic and angiotensin II AT1 receptors, reduced isoproterenol-induced tachycardia and phenylephrine- or angiotensin II-induced hypertension in anaesthetized dogs. In guinea pig papillary muscle, SSR149744C did not modify the resting potential, action potential amplitude and duration, but reduced the dV/dt max of the depolarization phase in a frequency-dependent manner. In isolated guinea pig cardiomyocytes and transfected CHO cells, SSR149744C (0.01-30 microM) inhibited several potassium currents: IKr (IC50 approximately 10 microM), IKs (IC50 approximately 30 microM), IK(ACh) (IC50 = 0.09 microM), and IKv1.5 (IC50 = 2.7 microM), the L-type calcium current: ICa(L) (IC50 approximately 5 microM) and also the amplitude of [Ca2+]i transient and cell shortening. Therefore, SSR149744C appears to have a multifactorial mechanism of action, which combines the blockade of several ion channels with the inhibition of responses of alpha 1 and beta 1 adrenergic as well as AT1 receptor stimulation. Like amiodarone, SSR149744C possesses the pharmacological effects of class I, II, III, and IV antiarrhythmic agents, which may confer upon this new drug a strong antiarrhythmic potential without ventricular proarrhythmia and iodine-related amiodarone-like side-effects.
Gautier
Patrick
P
Sanofi-Synthelabo Recherche, Cardiovascular-Thrombosis Department, Montpellier, France. Patrick.gautier@sanofi-synthelabo.com
Guillemare
Eric
E
Djandjighian
Laurent
L
Marion
Aline
A
Planchenault
Jacques
J
Bernhart
Claude
C
Herbert
Jean-Marc
JM
Nisato
Dino
D
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D018674:Adrenergic Antagonists / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D000804:Angiotensin II / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics*; D001572:Benzofurans / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics*; D001794:Blood Pressure / Q000187:drug effects; D016466:CHO Cells; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000502:physiology; D002468:Cell Physiological Phenomena / Q000187:drug effects; D006224:Cricetinae; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D006168:Guinea Pigs; D006329:Heart Conduction System / Q000187:drug effects / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects; D007275:Injections, Intravenous; D007545:Isoproterenol / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D010210:Papillary Muscles / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques / Q000379:methods; D014677:Pharmaceutical Vehicles / Q000008:administration & dosage / Q000493:pharmacokinetics; D010656:Phenylephrine / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics; D015221:Potassium Channels / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection
D018674:Adrenergic Antagonists; D000889:Anti-Arrhythmia Agents; D001572:Benzofurans; D020746:Calcium Channels, L-Type; D014677:Pharmaceutical Vehicles; D015221:Potassium Channels; D000804:Angiotensin II; D010656:Phenylephrine; C499879:celivarone; D007545:Isoproterenol