Blocking Characteristics of hERG, hNav1.5, and hKvLQT1/hminK after Administration of the Novel Anti‐Arrhythmic Compound AZD7009

Persson, Frida; Carlsson, Leif; Duker, Göran; Jacobson, Ingemar

doi:10.1046/j.1540-8167.2005.40427.x

Cited by 45 publications

(20 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[12][13][14] AZD7009 was in clinical development for conversion of atrial fibrillation to sinus rhythm and showed low proarrhythmic potential and very promising antiarrhythmic efficacy in patients with atrial fibrillation episodes lasting up to 3 months but was recently discontinued clinical development for noncardiovascular reasons. 15,16 Actually, in a subgroup of patients with atrial fibrillation lasting for one month the conversion rate was 82%, similar to the conversion rate seen in the placebo-treated patients subjected DC cardioversion (83% conversion rate).…”

Section: Discussionmentioning

confidence: 99%

Assessment of the Ion Channel-blocking Profile of the Novel Combined Ion Channel Blocker AZD1305 and Its Proarrhythmic Potential Versus Dofetilide in the Methoxamine-sensitized Rabbit In Vivo

Carlsson

Andersson

Linhardt

et al. 2009

Journal of Cardiovascular Pharmacology

Self Cite

View full text Add to dashboard Cite

AZD1305 is a novel antiarrhythmic agent under clinical evaluation for management of atrial fibrillation. This study assessed its ion channel-blocking potency by the whole cell patch-clamp technique in vitro and its proarrhythmic liability in anesthetized methoxamine-sensitized rabbits in comparison with dofetilide. AZD1305 predominantly blocked the hERG, the L-type calcium and the hNav1.5 currents in a concentration-dependent manner. In vivo AZD1305 increased the QT interval (from 145 +/- 8 to 196 +/- 18 ms, P < 0.01) without inducing ventricular extrasystoles or torsades de pointes (TdP). In contrast, dofetilide prolonged the QT interval from 161 +/- 3 to 256 +/- 15 ms (P < 0.001) and caused TdP in 12/17 rabbits (P < 0.01 vs. AZD1305). During AZD1305 and dofetilide infusion, the QTend-peak interval maximally increased by 14 +/- 4 and 30 +/- 6 ms (P < 0.05 vs. AZD1305) and the beat-by-beat QT interval variability (quantified as the short-term variability, STV) changed from 2 +/- 0.8 to 2 +/- 0.3 ms (NS) and from 2 +/- 0.2 to 12 +/- 1.1 ms (P < 0.001), respectively. Following dofetilide-induced TdP, 6 rabbits each were injected with saline or AZD1305. In contrast to saline, AZD1305 abbreviated the QT interval (from 275 +/- 25 to 216 +/- 9 ms, P < 0.05), reduced the STV to 1 +/- 0.1 ms (P < 0.001) and suppressed TdP in all 6 rabbits (P < 0.01 vs. saline). In conclusion, AZD1305 can be characterised as a combined ion channel blocker that delays repolarization without increasing beat-by-beat variability of repolarization (BVR) or inducing TdP whereas selective IKr blockade by dofetilide prolongs the QT interval and eventually increases BVR resulting in TdP.

show abstract

Section: Discussionmentioning

confidence: 99%

Assessment of the Ion Channel-blocking Profile of the Novel Combined Ion Channel Blocker AZD1305 and Its Proarrhythmic Potential Versus Dofetilide in the Methoxamine-sensitized Rabbit In Vivo

Carlsson

Andersson

Linhardt

et al. 2009

Journal of Cardiovascular Pharmacology

Self Cite

View full text Add to dashboard Cite

show abstract

“…Experiments were repeated three times. When used, tetrodotoxin (500 mol/l, Sigma) (27,30) (20 mol/l), ANG II (100 nmol/l) alone, or combined with apocynin (100 mol/l), polyethylene glycol-conjugated catalase (PEG-CAT; 50 U/ml), 4,5-dihydroxy-1,3-benzene disulfonic acid (tiron;10 mmol/l) or 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl (Tempol; 3 mmol/l) for 48 h. Total RNA from untreated and treated cardiomyocytes was isolated using the RNeasy Mini Kit (Qiagen, Valencia, CA) with the addition of RNase-free DNase I. Reverse transcription was carried out at 42°C for 30 min with iScript reverse transcriptase (Bio-Rad, Hercules, CA), 1 g total RNA, and 4 l of 5ϫ iScript reaction mix following the manufacturer's instructions.…”

Section: Methodsmentioning

confidence: 99%

NF-κB-dependent transcriptional regulation of the cardiac scn5a sodium channel by angiotensin II

Shang¹,

Sanyal²,

Pfahnl³

et al. 2008

American Journal of Physiology-Cell Physiology

108

View full text Add to dashboard Cite

(ANG II) increases oxidative stress and is associated with increased risk of sudden cardiac death. The cardiac Na ϩ channel promoter contains elements that confer redox sensitivity. We tested the hypothesis that ANG IImediated oxidative stress may modulate Na ϩ channel current through altering channel transcription. In H9c2 myocytes treated for 48 h with ANG II (100 nmol/l) or H2O2 (10 mol/l) showed delayed macroscopic inactivation, increased late current, and 59.6% and 53.8% reductions in Na ϩ current, respectively (P Յ 0.01). By quantitative real-time RT-PCR, the cardiac Na ϩ channel (scn5a) mRNA abundance declined by 47.3% (P Ͻ 0.01) in H9c2 myocytes treated for 48 h with 100 nmol/l ANG II. A similar change occurred with 20 mol/l H2O2 (46.9%, P Ͻ 0.01) after 48 h. Comparable effects were seen in acutely isolated ventricular myocytes. The effects of ANG II could be inhibited by prior treatment of H9c2 cells with scavengers of reactive oxygen species or an inhibitor of the NADPH oxidase. Mutation of the scn5a promoter NF-B binding site prevented decreased activity in response to ANG II and H2O2. Gel shift and chromosomal immunoprecipitation assays confirmed that nuclear factor (NF)-B bound to the scn5a promoter in response to ANG II and H2O2. Overexpression of the p50 subunit of NF-B in H9c2 cells reduced scn5a mRNA (77.3%, P Ͻ 0.01). In conclusion, ANG II can decrease scn5a transcription and current. This effect appears to be through production of H2O2 resulting in NF-B binding to the Na ϩ channel promoter. arrhythmia, gene expression; sodium channel; redox signaling; renin angiotensin system ACTIVATION of the renin-angiotensin system (RAS) has been implicated in arrhythmia associated with heart failure because inhibitors of this pathway reduce the incidence of sudden death (18,39,42,43). One major effecter of RAS activation is angiotensin II (ANG II), produced by enzymatic activity of angiotensin-converting enzyme (ACE) on angiotensin I. ANG II is known to increase oxidative stress through NADPH oxidase activation (7,20,31). Increased oxygen free radical production is associated with congestive heart failure (13, 21) and arrhythmias (6, 32). Nevertheless, the molecular basis whereby ANG II may cause arrhythmias and any role for ANG II-induced oxidative stress are not clear.Ion channel transcriptional regulation is implicated in increasing ventricular and atrial arrhythmic risk (1,9,25,29,44).Often referred to as electrical remodeling, the changes in myocyte electrical properties in states of increased arrhythmic risk are related to underlying changes in expression of several ion channel genes, including reductions in connexins and Na ϩ channels, and may be responsible for the arrhythmic effects of ANG II. Downregulations of Na ϩ channels and connexin 43 are seen in heart failure, a condition associated with increased RAS activation (4, 15, 37, 46). Moreover, forms of electrical remodeling can be inhibited by agents altering RAS signaling and by antioxidants (8,24,38), suggesting that ANG IImediated ion channe...

show abstract

“…Interestingly, the minor structural differences in AZD1305 versus AZD7009 introduce potent I CaL activity to the I Kr -and I Na -blocking characteristics described for both agents. 7,8,17 Hence, with its combined ion channel-blocking profile, AZD1305 has been proposed as an antiarrhythmic agent against AF with a lower proarrhythmic potential than other antiarrhythmic drugs. AZD1305 has been demonstrated to cause atrial-predominant effects in the …”

Section: Discussionmentioning

confidence: 99%

Reduced Ventricular Proarrhythmic Potential of the Novel Combined Ion-Channel Blocker AZD1305 Versus Dofetilide in Dogs With Remodeled Hearts

Johnson

Jong

Crijns

et al. 2012

Circ: Arrhythmia and Electrophysiology

View full text Add to dashboard Cite

Background-AZD1305 is an investigational antiarrhythmic agent for management of atrial fibrillation. It blocks various cardiac ion currents at different potencies and has atrial-predominant electrophysiological effects. We investigated the electrophysiological and proarrhythmic effects of AZD1305 versus dofetilide in dogs with chronic complete atrioventricular block and myocardial hypertrophic remodeling. Methods and Results-AZD1305 was administered to anesthetized mongrel dogs before and Ͼ2 weeks after the induction of atrioventricular block and ventricular and atrial electrophysiological parameters were assessed. In all dogs, the selective I Kr blocker dofetilide was used to examine susceptibility to acquired torsades de pointes in chronic atrioventricular block and for comparison.

show abstract

Blocking Characteristics of hERG, hNav1.5, and hKvLQT1/hminK after Administration of the Novel Anti‐Arrhythmic Compound AZD7009

Abstract: AZD7009 inhibits both the hERG and the hNav1.5 current, and it is most likely this combined current block that underlies the prolongation of the refractoriness and the low proarrhythmic activity demonstrated in animals in vivo.

Cited by 45 publications

References 33 publications

Assessment of the Ion Channel-blocking Profile of the Novel Combined Ion Channel Blocker AZD1305 and Its Proarrhythmic Potential Versus Dofetilide in the Methoxamine-sensitized Rabbit In Vivo

Assessment of the Ion Channel-blocking Profile of the Novel Combined Ion Channel Blocker AZD1305 and Its Proarrhythmic Potential Versus Dofetilide in the Methoxamine-sensitized Rabbit In Vivo

NF-κB-dependent transcriptional regulation of the cardiac scn5a sodium channel by angiotensin II

Reduced Ventricular Proarrhythmic Potential of the Novel Combined Ion-Channel Blocker AZD1305 Versus Dofetilide in Dogs With Remodeled Hearts

Contact Info

Product

Resources

About