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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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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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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DOI: https://doi.org/10.1007/s00380-021-01830-1