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.

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 Inducibility, but not stability, of atrial fibrillation is increased by NOX2 overexpression in mice

2021 ◽  
Author(s):  
Alexandra S Mighiu ◽  
Alice Recalde ◽  
Klemen Ziberna ◽  
Ricardo Carnicer ◽  
Jakub Tomek ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Superoxide Production ◽  
Right Atrial ◽  
Burst Stimulation ◽  
Lv Mass ◽  
Surface Ecg ◽  
Tissue Homogenates ◽  
Genotype Difference ◽  
Left And Right

Abstract Aims Gp91-containing NADPH oxidases (NOX2) are a significant source of myocardial superoxide production. An increase in NOX2 activity accompanies atrial fibrillation (AF) induction and electrical remodelling in animal models and predicts incident AF in humans; however, a direct causal role for NOX2 in AF has not been demonstrated. Accordingly, we investigated whether myocardial NOX2 overexpression in mice (NOX2-Tg) is sufficient to generate a favourable substrate for AF and further assessed the effects of atorvastatin, an inhibitor of NOX2, on atrial superoxide production and AF susceptibility. Methods and results NOX2-Tg mice showed a 2- to 2.5-fold higher atrial protein content of NOX2 compared with wild-type (WT) controls, which was associated with a significant (twofold) increase in NADPH-stimulated superoxide production (2-hydroxyethidium by HPLC) in left and right atrial tissue homogenates (P = 0.004 and P = 0.019, respectively). AF susceptibility assessed in vivo by transoesophageal atrial burst stimulation was modestly increased in NOX2-Tg compared with WT (probability of AF induction: 88% vs. 69%, respectively; P = 0.037), in the absence of significant alterations in AF duration, surface ECG parameters, and LV mass or function. Mechanistic studies did not support a role for NOX2 in promoting electrical or structural remodelling, as high-resolution optical mapping of atrial tissues showed no differences in action potential duration and conduction velocity between genotypes. In addition, we did not observe any genotype difference in markers of fibrosis and inflammation, including atrial collagen content and Col1a1, Il-1β, Il-6, and Mcp-1 mRNA. Similarly, NOX2 overexpression did not have consistent effects on RyR2 Ca2+ leak nor did it affect PKA or CaMKII-mediated RyR2 phosphorylation. Finally, treatment with atorvastatin significantly inhibited atrial superoxide production in NOX2-Tg but had no effect on AF induction in either genotype. Conclusion Together, these data indicate that while atrial NOX2 overexpression may contribute to atrial arrhythmogenesis, NOX2-derived superoxide production does not affect the electrical and structural properties of the atrial myocardium.

Abstract P780: Myosin Light Chain Dephosphorylation by Ppp1r12c Promotes Atrial Hypocontractility in Atrial Fibrillation

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Francisco J Gonzalez-Gonzalez ◽  
Perike Srikanth ◽  
Andrielle E Capote ◽  
Alsina Katherina M ◽  
Benjamin Levin ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Light Chain ◽  
Myosin Light Chain ◽  
Molecular Mechanisms ◽  
Contractile Function ◽  
Right Atrial ◽  
Western Blots

Atrial fibrillation (AF) is the most common sustained arrhythmia, with an estimated prevalence in the U.S.of 6.1 million. AF increases the risk of a thromboembolic stroke in five-fold. Although atrial hypocontractility contributes to stroke risk in AF, the molecular mechanisms reducing myofilament contractile function in AF remains unknown. We have recently identified protein phosphatase 1 subunit 12c (PPP1R12C) as a key molecule targeting myosin light-chain phosphorylation in AF. Objective: We hypothesize that the overexpression of PPP1R12C causes hypophosphorylation of atrial myosin light-chain 2 (MLC2a), thereby decreasing atrial contractility in AF. Methods and Results: Left and right atrial appendage tissues were isolated from AF patients versus sinus rhythm (SR). To evaluate the role of the PP1c-PPP1R12C interaction in MLC2a de-phosphorylation, we utilized Western blots, co-immunoprecipitation, and phosphorylation assays. In patients with AF, PPP1R12C expression was increased 3.5-fold versus SR controls with an 88% reduction in MLC2a phosphorylation. PPP1R12C-PP1c binding and PPP1R12C-MLC2a binding were significantly increased in AF. In vitro studies of either pharmacologic (BDP5290) or genetic (T560A), PPP1R12C activation demonstrated increased PPP1R12C binding with both PP1c and MLC2a, and dephosphorylation of MLC2a. Additionally, to evaluate the role of PPP1R12C expression in cardiac function, mice with lentiviral cardiac-specific overexpression of PPP1R12C (Lenti-12C) were evaluated for atrial contractility using echocardiography, versus wild-type and Lenti-controls. Lenti-12C mice demonstrated a 150% increase in left atrium size versus controls, with reduced atrial strain and atrial ejection fraction. Also, programmed electrical stimulation was performed to evaluate AF inducibility in vivo. Pacing-induced AF in Lenti-12C mice was significantly higher than controls. Conclusion: The overexpression of PPP1R12C increases PP1c targeting to MLC2a and provokes dephosphorylation, associated with a reduction in atrial contractility and an increase in AF inducibility. All these discoveries suggest that PP1 regulation of sarcomere function at MLC2a is a main regulator of atrial contractility in AF.

Abstract P458: Myosin Light Chain Dephosphorylation By Ppp1r12c Promotes Atrial Hypocontractility In Atrial Fibrillation

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Francisco J Gonzalez-Gonzalez ◽  
Srikanth Perike ◽  
Frederick Damen ◽  
Andrielle Capote ◽  
Katherina M Alsina ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Light Chain ◽  
Myosin Light Chain ◽  
Molecular Mechanisms ◽  
Contractile Function ◽  
Right Atrial ◽  
Western Blots

Introduction: Atrial fibrillation (AF), is the most common sustained arrhythmia, with an estimated prevalence in the U.S. of 2.7 million to 6.1 million and is predictive to increase to 12.1 million in 2030. AF increases the chances of a thromboembolic stroke in five-fold. Although atrial hypocontractility contributes to stroke risk in AF, the molecular mechanisms reducing myofilament contractile function in AF remains unknown. Objective: The overexpression of PPP1R12C, causes hypophosphorylation of atrial myosin light chain 2 (MLC2a), decreasing atrial contractility. Methods and Results: Left and right atrial appendage tissues were isolated from AF patients versus sinus rhythm (SR). To evaluated the role of PP1c-PPP1R12C interaction in MLC2a de-phosphorylation we used Western blots, coimmunoprecipitation, and phosphorylation assays. In patients with AF, PPP1R12C expression was increased 3.5-fold versus SR controls with an 88% reduction in MLC2a phosphorylation. PPP1R12C-PP1c binding and PPP1R12C-MLC2a binding were significantly increased in AF. In vitro studies of either pharmacologic (BDP5290) or genetic (T560A) PPP1R12C activation demonstrated increased PPP1R12C binding with both PP1c and MLC2a, and dephosphorylation of MLC2a. Additionally, to evaluate the role of PPP1R12C expression in cardiac function, mice with lentiviral cardiac-specific overexpression of PPP1R12C (Lenti-12C) were evaluated for atrial contractility using echocardiography, versus wild-type and Lenti-controls. Lenti-12C mice demonstrated a 150% increase in left atrium size versus controls, with reduced atrial strain and atrial ejection fraction. Also, programmed electrical stimulation was performed to evaluate AF inducibility in vivo. Pacing-induced AF in Lenti-12C mice was significantly higher than controls. Conclusion: The Overexpression of PPP1R12C increases PP1c targeting to MLC2a and provokes dephosphorylation, that cause a reduction in atrial contractility and increases AF inducibility. All these discoveries advocate that PP1 regulation of sarcomere function at MLC2a is a main regulator of atrial contractility in AF.

Effects of probucol, a typical hERG expression inhibitor, on in vivo QT interval prolongation in conscious dogs

2013 ◽  
Vol 720 (1-3) ◽  
pp. 29-37 ◽  
Author(s):  
Hisashi Nogawa ◽  
Tomoyuki Kawai ◽  
Miho Yajima ◽  
Masahiro Miura ◽  
Tetsurou Ogawa ◽  
...  
Keyword(s):  
Qt Interval ◽  
Conscious Dogs ◽  
Interval Prolongation ◽  
Qt Interval Prolongation
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