scholarly journals Translational Studies on Anti-Atrial Fibrillatory Action of Oseltamivir by its in vivo and in vitro Electropharmacological Analyses

2021 ◽  
Vol 12 ◽  
Author(s):  
Ryuichi Kambayashi ◽  
Hiroko Izumi-Nakaseko ◽  
Ai Goto ◽  
Kazuya Tsurudome ◽  
Hironori Ohshiro ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Refractory Period ◽  
Persistent Atrial Fibrillation ◽  
Effective Refractory Period ◽  
Conduction Time ◽  
Dependent Manner ◽  
Atrial Conduction Time ◽  
Atrial Effective Refractory Period

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.

scholarly journals Angiotensin-(1–7) attenuates atrial tachycardia-induced sympathetic nerve remodeling

2017 ◽  
Vol 18 (3) ◽  
pp. 147032031772928 ◽  
Author(s):  
Wenfeng Shangguan ◽  
Wen Shi ◽  
Guangping Li ◽  
Yuanyuan Wang ◽  
Jian Li ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Nerve Growth Factor ◽  
Growth Factor ◽  
Tyrosine Hydroxylase ◽  
Sympathetic Nerve ◽  
Refractory Period ◽  
Atrial Tachycardia ◽  
Effective Refractory Period ◽  
Sympathetic Nerve Stimulation ◽  
Atrial Effective Refractory Period

Introduction: The effect of Angiotensin-(1–7) (Ang-(1–7)) on atrial autonomic remodeling is still unknown. We hypothesized that Ang-(1–7) could inhibit sympathetic nerve remodeling in a canine model of chronic atrial tachycardia. Materials and methods: Eighteen dogs were randomly assigned to sham group, pacing group and Ang-(1–7) group. Rapid atrial pacing was maintained for 14 days in the pacing and Ang-(1–7) groups. Ang-(1–7) was administered intravenously in the Ang-(1–7) group. The atrial effective refractory period and atrial fibrillation inducibility level were measured at baseline and under sympathetic nerve stimulation after 14 days of measurement. The atrial sympathetic nerves labeled with tyrosine hydroxylase were detected using immunohistochemistry and Western blotting, and tyrosine hydroxylase and nerve growth factor mRNA levels were measured by reverse transcription polymerase chain reaction. Results: Pacing shortened the atrial effective refractory period and increased the atrial fibrillation inducibility level at baseline and under sympathetic nerve stimulation. Ang-(1–7) treatment attenuated the shortening of the atrial effective refractory period and the increase in the atrial fibrillation inducibility level. Immunohistochemistry and Western blotting showed sympathetic nerve hyperinnervation in the pacing group, while Ang-(1–7) attenuated sympathetic nerve proliferation. Ang-(1–7) alleviated the pacing-induced increases in tyrosine hydroxylase and nerve growth factor mRNA expression levels. Conclusion: Ang-(1–7) can attenuate pacing-induced atrial sympathetic hyperinnervation.

scholarly journals Canagliflozin Suppresses Atrial Remodeling in a Canine Atrial Fibrillation Model

2021 ◽  
Author(s):  
Ryo Nishinarita ◽  
Shinichi Niwano ◽  
Hiroe Niwano ◽  
Hironori Nakamura ◽  
Daiki Saito ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Conduction Velocity ◽  
Refractory Period ◽  
Interstitial Fibrosis ◽  
Sglt2 Inhibitor ◽  
Effective Refractory Period ◽  
Control Group ◽  
Atrial Remodeling ◽  
Atrial Pacing ◽  
Atrial Effective Refractory Period

Background Recent clinical trials have demonstrated the possible pleiotropic effects of SGLT2 (sodium–glucose cotransporter 2) inhibitors in clinical cardiovascular diseases. Atrial electrical and structural remodeling is important as an atrial fibrillation (AF) substrate. Methods and Results The present study assessed the effect of canagliflozin (CAN), an SGLT2 inhibitor, on atrial remodeling in a canine AF model. The study included 12 beagle dogs, with 10 receiving continuous rapid atrial pacing and 2 acting as the nonpacing group. The 10 dogs that received continuous rapid atrial pacing for 3 weeks were subdivided as follows: pacing control group (n=5) and pacing+CAN (3 mg/kg per day) group (n=5). The atrial effective refractory period, conduction velocity, and AF inducibility were evaluated weekly through atrial epicardial wires. After the protocol, atrial tissues were sampled for histological examination. The degree of reactive oxygen species expression was evaluated by dihydroethidium staining. The atrial effective refractory period reduction was smaller ( P =0.06) and the degree of conduction velocity decrease was smaller in the pacing+CAN group compared with the pacing control group ( P =0.009). The AF inducibility gradually increased in the pacing control group, but such an increase was suppressed in the pacing+CAN group ( P =0.011). The pacing control group exhibited interstitial fibrosis and enhanced oxidative stress, which were suppressed in the pacing+CAN group. Conclusions CAN and possibly other SGLT2 inhibitors might be useful for preventing AF and suppressing the promotion of atrial remodeling as an AF substrate.

Recovery of the right atrial effective refractory period after cardioversion of chronic atrial fibrillation

1999 ◽  
Vol 84 (10) ◽  
pp. 1261-1264 ◽  
Author(s):  
Yasutaka Tanabe ◽  
Masaomi Chinushi ◽  
Kohji Taneda ◽  
Satoshi Fujita ◽  
Hidehiro Kasai ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Refractory Period ◽  
Chronic Atrial Fibrillation ◽  
Effective Refractory Period ◽  
Right Atrial ◽  
The Right ◽  
Atrial Effective Refractory Period

scholarly journals Comparison of the effects of IK,ACh, IKr, and INa block in conscious dogs with atrial fibrillation and on action potentials in remodeled atrial trabeculae

2018 ◽  
Vol 96 (1) ◽  
pp. 18-25 ◽  
Author(s):  
Viktor Juhász ◽  
Tibor Hornyik ◽  
Attila Benák ◽  
Norbert Nagy ◽  
Zoltán Husti ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Action Potentials ◽  
Qt Interval ◽  
Structural Heart Disease ◽  
Conscious Dogs ◽  
Right Atrial ◽  
Conduction Time ◽  
Antiarrhythmic Agents ◽  
Atrial Conduction Time

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and a major cause of morbidity and mortality. Traditional antiarrhythmic agents used for restoration of sinus rhythm have limited efficacy in long-term AF and they may possess ventricular proarrhythmic adverse effects, especially in patients with structural heart disease. The acetylcholine receptor-activated potassium channel (IK,ACh) represents an atrial selective target for future AF management. We investigated the effects of the IK,ACh blocker tertiapin-Q (TQ), a derivative of the honeybee toxin tertiapin, on chronic atrial tachypacing-induced AF in conscious dogs, without the influence of anesthetics that modulate a number of cardiac ion channels. Action potentials (APs) were recorded from right atrial trabeculae isolated from dogs with AF. TQ significantly and dose-dependently reduced AF incidence and AF episode duration, prolonged atrial effective refractory period, and prolonged AP duration. The reference drugs propafenone and dofetilide, both used in the clinical management of AF, exerted similar effects against AF in vivo. Dofetilide prolonged atrial AP duration, whereas propafenone increased atrial conduction time. TQ and propafenone did not affect the QT interval, whereas dofetilide prolonged the QT interval. Our results show that inhibition of IK,ACh may represent a novel, atrial-specific target for the management of AF in chronic AF.

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