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Effects of the novel amiodarone-like compound SAR114646A on cardiac ion channels and ventricular arrhythmias in rats

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Abstract

Amiodarone is the "gold standard" for current antiarrhythmic therapy because it combines efficacy with good hemodynamic and electrophysiological tolerance. Amiodarone is effective against both atrial and ventricular arrhythmias by intravenous (i.v.) or oral route. However, the i.v. formulation has limitations. Therefore, we identified SAR114646A, an amiodarone-like antiarrhythmic agent with good aqueous solubility suitable for i.v. application. Patch–clamp experiments were performed with isolated cardiomyocytes from guinea pigs and rats. In guinea pig ventricular cardiomyocytes, the fast Na+ channel and the L-type Ca2+ channels were blocked by SAR114646A with half-maximal concentrations (IC50) of 2.0 and 1.1 μM, respectively. The tail current of the fast activating rectifying potassium channel IKr was blocked with an IC50 value of 0.6 μM, whereas the IC50 values for inhibition of the IKs and IK1 channels was >10 μM. ATP-sensitive K+ channels were evoked by application of the channel opener rilmakalim (3 μM). SAR114646A blocked this current with an IC50 value of 2.8 μM. In guinea pig atrial cardiomyocytes, carbachol (1 μM) was used to activate the IKACh and SAR114646A inhibited this current with IC50 of 36.5 nM. The transient outward current Ito and the sustained current Isus were investigated in rat ventricular myocytes. SAR114646A blocked these currents with IC50 of 1.8 and 1.2 μM, respectively. When expressed in Chinese hamster ovary cells, the currents hKv1.5 and hHCN4 were inhibited with IC50 values of 1.1 and 0.4 μM, respectively. Micropuncture experiments in isolated rabbit left atria revealed that SAR114646A prolonged the 50% repolarization significantly at 3 and 10 μM. In guinea pig papillary muscle, the APD at 90% of repolarization was slightly prolonged at 3 and 10 μM. SAR114646A demonstrates antiarrhythmic activity in anaesthetised rats, subjected to 5 min ischemia followed by 10 min reperfusion, where 1 mg/kg of SAR114646A applied as i.v. bolus 5 min prior to ischemia, decreased mortality to 0% compared to 80% under control conditions. In conclusion, SAR114646A is a multichannel blocker with improved water solubility, compared to amiodarone. In contrast to amiodarone, SAR114646A also blocks the K+ channels Ito and Isus. A potent antiarrhythmic effect as observed in rats can also be expected in other animal models.

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Acknowledgments

We acknowledge the skillful assistance of Ms. Karin Kopp and Mr. Roland Klein in performing part of the experiments. We want to thank PD Dr. Klaus Steinmeyer for valuable discussion.

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All authors are employees of Sanofi-Aventis.

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Authors and Affiliations

  1. Sanofi-Aventis Deutschland GmbH, Industriepark Hoechst, H 821, 65926, Frankfurt am Main, Germany

    Heinz Goegelein & Hartmut Ruetten

  2. Sanofi-Aventis R&D, 371, Rue du Pr Blayac, 34184, Montpellier cedex 4, France

    Patrick Gautier & Alain Roccon

  3. Sanofi-Aventis R&D, 1, Avenue Pierre Brossolette, 93185, Chilly-Mazarin cedex, France

    Stephen O’Connor

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  1. Heinz Goegelein
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  2. Patrick Gautier
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  5. Hartmut Ruetten
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Correspondence to Heinz Goegelein.

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Goegelein, H., Gautier, P., Roccon, A. et al. Effects of the novel amiodarone-like compound SAR114646A on cardiac ion channels and ventricular arrhythmias in rats. Naunyn-Schmiedeberg's Arch Pharmacol 384, 231–244 (2011). https://doi.org/10.1007/s00210-011-0664-4

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