Abstract
Oseltamivir has been shown to prolong the atrial conduction time and effective refractory period, and to suppress the onset of burst pacing-induced atrial fibrillation in vitro. To better predict its potential clinical benefit as an anti-atrial fibrillatory drug, we performed translational studies by assessing in vivo anti-atrial fibrillatory effect along with in vivo and in vitro electropharmacological analyses. Oseltamivir in intravenous doses of 3 (n = 6) and 30 mg/kg (n = 7) was administered in conscious state to the persistent atrial fibrillation model dogs to confirm its anti-atrial fibrillatory action. The model was prepared by tachypacing to the atria of chronic atrioventricular block dogs for > 6 weeks. Next, oseltamivir in doses of 0.3, 3 and 30 mg/kg was intravenously administered to the halothane-anesthetized intact dogs to analyze its in vivo electrophysiological actions (n = 4). Finally, its in vitro effects of 10–1,000 μM on IK,ACh, IKur, IKr, INa and ICaL were analyzed by using cell lines stably expressing Kir3.1/3.4, KV1.5, hERG, NaV1.5 or CaV1.2, respectively (n = 3 for IK,ACh and IKr or n = 6 for IKr, INa and ICaL). Oseltamivir in doses of 3 and 30 mg/kg terminated the atrial fibrillation in 1 out of 6 and in 6 out of 7 atrial fibrillation model dogs, respectively without inducing any lethal ventricular arrhythmia. Its 3 and 30 mg/kg delayed inter-atrial conduction in a frequency-dependent manner, whereas they prolonged atrial effective refractory period in a reverse frequency-dependent manner in the intact dogs. The current assay indicated that IC50 values for IK,ACh and IKr were 160 and 231 μM, respectively, but 1,000 µM inhibited INa, ICaL and IKur by 22, 19 and 13%, respectively. The extent of INa blockade was enhanced at faster beating rate and more depolarized resting membrane potential. Oseltamivir effectively terminated the persistent atrial fibrillation, which may be largely due to the prolongation of the atrial effective refractory period and inter-atrial conduction time induced by IK,ACh and IKr inhibitions along with INa suppression. Thus, oseltamivir can exert a powerful anti-atrial fibrillatory action through its ideal multi-channel blocking property; and oseltamivir would become a promising seed compound for developing efficacious and safe anti-atrial fibrillatory drugs.
Highlights
Since existing anti-atrial fibrillation (AF) drugs have been known to block both atrial and ventricular ionic channels, adverse effects were largely induced by their ionic channel blockade in the ventricle, which may often blunt their therapeutic benefits for the atrial arrhythmias (Geng et al, 2020)
Animals showing the heart rate of > 200 bpm or < 50 bpm, mean blood pressure of > 150 mmHg or < 50 mmHg, and/or electrocardiogram of other than normal sinus rhythm after the initial induction of anesthesia were excluded from the studies
There was no animal excluded from cardioversion experiments (Exp. 1) or electrophysiological studies (Exp. 2) after its randomization
Summary
Since existing anti-atrial fibrillation (AF) drugs have been known to block both atrial and ventricular ionic channels, adverse effects were largely induced by their ionic channel blockade in the ventricle, which may often blunt their therapeutic benefits for the atrial arrhythmias (Geng et al, 2020). In a previous study using the Langendorff-perfused rabbit hearts, 100 μM of oseltamivir suppressed the onset of AF induced by burst pacing with ACh and isoproterenol pretreatment (Frommeyer et al, 2017). Those known basic findings (Kitahara et al, 2013; Takahara et al, 2013; Nakamura et al, 2016; Frommeyer et al, 2017) would not be enough to make the clinical development of oseltamivir as an anti-AF drug valid
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