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In vivo characterization of anti-atrial fibrillatory potential and pharmacological safety profile of INa,L plus IKr inhibitor ranolazine using the halothane-anesthetized dogs

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Abstract

To characterize in vivo anti-atrial fibrillatory potential and pharmacological safety profile of ranolazine having INa,L plus IKr inhibitory actions in comparison with those of clinically available anti-atrial fibrillatory drugs; namely, dronedarone, amiodarone, bepridil and dl-sotalol in our previous studies, ranolazine dihydrochloride in sub-therapeutic (0.3 mg/kg) and supra-therapeutic (3 mg/kg) doses was intravenously infused over 10 min to the halothane-anesthetized dogs (n = 5). The low dose increased the heart rate, cardiac output and atrioventricular conduction velocity possibly via vasodilator action-induced, reflex-mediated increase of adrenergic tone. Meanwhile, the high dose decreased the heart rate, ventricular contraction, cardiac output and mean blood pressure, indicating that drug-induced direct actions may exceed the reflex-mediated compensation. In addition, it prolonged the atrial and ventricular effective refractory periods, of which potency and selectivity for the former were less great compared with those of the clinically-available drugs. Moreover, it did not alter the ventricular early repolarization period in vivo, but prolonged the late repolarization with minimal risk for re-entrant arrhythmias. These in vivo findings of ranolazine suggest that INa,L suppression may attenuate IKr inhibition-associated prolongation of early repolarization in the presence of reflex-mediated increase of adrenergic tone. Thus, ranolazine alone may be less promising as an anti-atrial fibrillatory drug, but its potential risk for inducing torsade de pointes will be small. These information can be used as a guide to predict the utility and adverse effects of anti-atrial fibrillatory drugs having multi-channel modulatory action.

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References

  1. Katzung BG (2018) Vasodilators & the treatment of angina pectoris. In: Katzung BG (ed) Basic and clinical pharmacology, 14th edn. McGraw-Hill Education, New York, pp 194–211

    Google Scholar 

  2. Geng M, Lin A, Nguyen TP (2020) Revisiting antiarrhythmic drug therapy for atrial fibrillation: reviewing lessons learned and redefining therapeutic paradigms. Front Pharmacol 11:581837

    Article  CAS  Google Scholar 

  3. Harvey RD, Grant AO (2018) Agents used in cardiac arrhythmias. In: Katzung BG (ed) Basic and clinical pharmacology, 14th edn. McGraw-Hill Education, New York, pp 228–253

    Google Scholar 

  4. Lei M, Wu L, Terrar DA, Huang CL (2018) Modernized classification of cardiac antiarrhythmic drugs. Circulation 138:1879–1896

    Article  CAS  Google Scholar 

  5. Antzelevitch C, Belardinelli L, Zygmunt AC, Burashnikov A, Di Diego JM, Fish JM, Corderio JM, Thomas G (2004) Electrophysiological effects of ranolazine, a novel antianginal agent with antiarrhythmic properties. Circulation 110:904–910

    Article  CAS  Google Scholar 

  6. Undrovinas AI, Belardinelli L, Undrovinas NA, Sabbah HN (2006) Ranolazine improves abnormal repolarization and contraction in left ventricular myocytes of dogs with heart failure by inhibiting late sodium current. J Cardiovasc Electrophysiol 17(Suppl 1):S169–S177

    Article  Google Scholar 

  7. Sicouri S, Glass A, Belardinelli L, Antzelevitch C (2008) Antiarrhythmic effects of ranolazine in canine pulmonary vein sleeve preparations. Heart Rhythm 5:1019–1026

    Article  Google Scholar 

  8. Kumar K, Nearing BD, Carvas M, Nascimento BCG, Acar M, Belardinelli L, Verrier RL (2009) Ranolazine exerts potent effects on atrial electrical properties and abbreviates atrial fibrillation duration in the intact porcine heart. J Cardiovasc Electrophysiol 20:796–802

    Article  Google Scholar 

  9. Scirica BM, Morrow DA, Hod H, Murphy SA, Belardinelli L, Hedgepeth CH, Molhoek P, Verheugt FWA, Gersh BJ, McCabe CH, Braunwald E (2007) Effect of ranolazine, an antianginal agent with novel electrophysiological properties, on the incidence of arrhythmias in patients with non ST-segment elevation acute coronary syndrome: results from the metabolic efficiency with ranolazine for less ischemia in non ST-elevation acute coronary syndrome thrombolysis in myocardial infarction 36 (MERLIN-TIMI 36) randomized controlled trial. Circulation 116:1647–1652

    Article  CAS  Google Scholar 

  10. Koskinas KC, Fragakis N, Katritsis D, Skeberis V, Vassilikos V (2014) Ranolazine enhances the efficacy of amiodarone for conversion of recent-onset atrial fibrillation. Europace 16:973–979

    Article  Google Scholar 

  11. Simopoulos V, Hevas A, Hatziefthimiou A, Dipla K, Skoularigis I, Tsilimingas N, Aidonidis I (2018) Amiodarone plus ranolazine for conversion of post-cardiac surgery atrial fibrillation: enhanced effectiveness in reduced versus preserved ejection fraction patients. Cardiovasc Drugs Ther 32:559–565

    Article  CAS  Google Scholar 

  12. White CM, Nguyen E (2017) Novel use of ranolazine as an antiarrhythmic agent in atrial fibrillation. Ann Pharmacother 51:245–252

    Article  CAS  Google Scholar 

  13. De Vecchis R, Ariano C, Giasi A, Cioppa C (2018) Antiarrhythmic effects of ranolazine used both alone for prevention of atrial fibrillation and as an add-on to intravenous amiodarone for its pharmacological cardioversion: a meta-analysis. Minerva Cardioangiol 66:349–359

    Article  Google Scholar 

  14. Reiffel JA, Camm AJ, Belardinelli L, Zeng D, Karwatowska-Prokopczuk E, Olmsted A, Zareba W, Rosero S, Kowey P, HARMONY Investigators (2015) The HARMONY trial: combined ranolazine and dronedarone in the management of paroxysmal atrial fibrillation: mechanistic and therapeutic synergism. Circ Arrhythm Electrophysiol 8:1048–1056

    Article  CAS  Google Scholar 

  15. Sugiyama A (2008) Sensitive and reliable proarrhythmia in vivo animal models for predicting drug-induced torsades de pointes in patients with remodelled hearts. Br J Pharmacol 154:1528–1537

    Article  CAS  Google Scholar 

  16. Motokawa Y, Nakamura Y, Hagiwara-Nagasawa M, Goto A, Chiba K, Lubna NJ, Izumi-Nakaseko H, Ando K, Naito AT, Yamazaki H, Sugiyama A (2018) In vivo analysis of the anti-atrial fibrillatory, proarrhythmic and cardiodepressive profile of dronedarone as a guide for safety pharmacological evaluation of antiarrhythmic drugs. Cardiovasc Toxicol 18:242–251

    Article  CAS  Google Scholar 

  17. Matsukura S, Nakamura Y, Cao X, Wada T, Izumi-Nakaseko H, Ando K, Naito AT, Sugiyama A (2017) Anti-atrial fibrillatory versus proarrhythmic potentials of amiodarone: a new protocol for safety evaluation in vivo. Cardiovasc Toxicol 17:157–162

    Article  CAS  Google Scholar 

  18. Ishizaka T, Takahara A, Iwasaki H, Mitsumori Y, Kise H, Nakamura Y, Sugiyama A (2008) Comparison of electropharmacological effects of bepridil and sotalol in halothane-anesthetized dogs. Circ J 72:1003–1011

    Article  CAS  Google Scholar 

  19. Johannesen L, Vicente J, Mason JW, Sanabria C, Waite-Labott K, Hong M, Guo P, Lin J, Sorensen JS, Galeotti L, Florian J, Ugander M, Stockbridge N, Strauss DG (2014) Differentiating drug-induced multichannel block on the electrocardiogram: randomized study of dofetilide, quinidine, ranolazine, and verapamil. Clin Pharmacol Ther 96:549–558

    Article  CAS  Google Scholar 

  20. Hagiwara-Nagasawa M, Kambayashi R, Goto A, Nunoi Y, Izumi-Nakaseko M, Takei Y, Matsumoto A, Sugiyama A (2020) Cardiohemodynamic and arrhythmogenic effects of the anti-atrial fibrillatory compound vanoxerine in halothane-anesthetized dogs. Cardiovasc Toxicol 21:206–215

    Article  Google Scholar 

  21. Sugiyama A, Hashimoto K (2002) Effects of a typical IKr channel blocker sematilide on the relationship between ventricular repolarization, refractoriness and onset of torsades de pointes. Jpn J Pharmacol 88:414–421

    Article  CAS  Google Scholar 

  22. Nagueh SF, Sun H, Kopelen HA, Middleton KJ, Khoury DS (2001) Hemodynamic determinants of the mitral annulus diastolic velocities by tissue Doppler. J Am Coll Cardiol 37:278–285

    Article  CAS  Google Scholar 

  23. Van de Water A, Verheyen J, Xhonneux R, Reneman RS (1989) An improved method to correct the QT interval of the electrocardiogram for changes in heart rate. J Pharmacol Methods 22:207–217

    Article  Google Scholar 

  24. Ando K, Nakamura Y, Hagiwara-Nagasawa M, Harada H, Miyamoto H, Inamura N, Takagi K, Goto A, Chiba K, Lubna NJ, Izumi-Nakaseko H, Naito AT, Sugiyama A (2018) Comparison of electropharmacological effects between terfenadine and its active derivative fexofenadine using a cross-over study in halothane-anesthetized dogs to analyze variability of pharmacodynamic and pharmacokinetic profiles of terfenadine and torsadogenic risk of fexofenadine. J Toxicol Sci 43:183–192

    Article  CAS  Google Scholar 

  25. Chiba K, Sugiyama A, Satoh Y, Shiina H, Hashimoto K (2000) Proarrhythmic effects of fluoroquinolone antibacterial agents: in vivo effects as physiologic substrate for torsades. Toxicol Appl Pharmacol 169:8–16

    Article  CAS  Google Scholar 

  26. Yoshida H, Sugiyama A, Satoh Y, Ishida Y, Kugiyama K, Hashimoto K (2002) Effects of disopyramide and mexiletine on the terminal repolarization process of the in situ heart assessed using the halothane-anesthetized in vivo canine model. Circ J 66:857–862

    Article  CAS  Google Scholar 

  27. Virsolvy A, Farah C, Pertuit N, Kong L, Lacampagne A, Reboul C, Aimond F, Richard S (2015) Antagonism of Nav channels and α1-adrenergic receptors contributes to vascular smooth muscle effects of ranolazine. Sci Rep 5:17969

    Article  CAS  Google Scholar 

  28. Liu Z, Williams RB, Rosen BD (2013) The potential contribution of ranolazine to Torsade de pointes. J Cardio Dis Res 4:187–190

    Article  Google Scholar 

Download references

Acknowledgements

This study was supported in part by research grants from the Japan Society for the Promotion of Science (JSPS KAKENHI) Grant Number 20K16136 (to R.K.) and 19K16505 (to M.H-N.). The authors thank Mrs. Yuri Ichikawa for her technical assistance.

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Correspondence to Atsushi Sugiyama.

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Nunoi, Y., Kambayashi, R., Goto, A. et al. In vivo characterization of anti-atrial fibrillatory potential and pharmacological safety profile of INa,L plus IKr inhibitor ranolazine using the halothane-anesthetized dogs. Heart Vessels 36, 1088–1097 (2021). https://doi.org/10.1007/s00380-021-01830-1

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