Background and purpose
This study was designed to establish the pathology‐specific inhibitory effects of the
I
Kur
/
I
to
/
I
K,ACh
blocker AVE0118 on atrium‐selective channels and its corresponding ...effects on action potential shape and effective refractory period in patients with chronic AF (cAF).
Experimental approach
Outward K
+
‐currents of right atrial myocytes and action potentials of atrial trabeculae were measured with whole‐cell voltage clamp and microelectrode techniques, respectively. Outward currents were dissected by curve fitting.
Key results
Four components of outward K
+
‐currents and AF‐specific alterations in their properties were identified.
I
to
was smaller in cAF than in SR, and AVE0118 (10 μ
M
) apparently accelerated its inactivation in both groups without reducing its amplitude. Amplitudes of rapidly and slowly inactivating components of
I
Kur
were lower in cAF than in SR. The former was abolished by AVE0118 in both groups, the latter was partially blocked in SR, but not in cAF, even though its inactivation was apparently accelerated in cAF. The large non‐inactivating current component was similar in magnitude in both groups, but decreased by AVE0118 only in SR. AVE0118 strongly suppressed AF‐related constitutively active
I
K,ACh
and prolonged atrial action potential and effective refractory period exclusively in cAF.
Conclusions and implications
In atrial myocytes of cAF patients, we detected reduced function of distinct
I
Kur
components that possessed decreased component‐specific sensitivity to AVE0118 most likely as a consequence of AF‐induced electrical remodelling. Inhibition of profibrillatory constitutively active
I
K,ACh
may lead to pathology‐specific efficacy of AVE0118 that is likely to contribute to its ability to convert AF into SR.
British Journal of Pharmacology
(2008)
154
, 1619–1630; doi:
10.1038/bjp.2008.209
; published online 9 June 2008
The sustained component of the K
+
outward current in human atrial myocytes is believed to be due to the slowly inactivating ultra-rapid potassium current
I
Kur
and not to the fast inactivating ...transient outward current
I
to
. Here we provide evidence for contribution of
I
to
to this late current due to the effects of dipeptidyl peptidase-like protein (DPP) 10 (DPP10a) interacting with Kv4.3 channels. We studied the late current component of
I
to
in human atrial myocytes and CHO cells co-expressing Kv4.3 or Kv4.3/KChIP2 (control) and DPP proteins using voltage-clamp technique and a pharmacological approach. A voltage dependent and slowly inactivating late current (43 % of peak amplitude) could be observed in atrial myocytes. We found a similar current in CHO cells expressing Kv4.3/KChIP2 + DPP10a, but not in cells co-expressing Kv4.3 + DPP or Kv4.3/KChIP2 + DPP6-S. Assuming that DPP10a influences atrial
I
to
, we detected DPP10 expression of three alternatively spliced mRNAs, DPP10 protein and colocalization of Kv4.3 and DPP10 proteins in human atrial myocytes. DPP10a did not affect properties of expressed Kv1.5 excluding a contribution to the sustained
I
Kur
in atrial cells. To test for the contribution of Kv4-based
I
to
on sustained K
+
outward currents in human atrial myocytes, we used 4-AP to block
I
Kur
, in combination with
Heteropoda
toxin 2 to block Kv4 channels. We could clearly separate an
I
to
fraction of about 19 % contributing to the late current in atrial myocytes. Thus, the interaction of DPP10a, expressed in human atrium, with Kv4.3 channels generates a sustained current component of
I
to
, which may affect late repolarization phase of atrial action potentials.
We have investigated electronic excitation transfer in individual molecular dimers by time and spectrally resolved confocal fluorescence microscopy. The single molecule measurements allow for ...directly probing the distribution of the electronic coupling strengths due to static disorder in the polymer host. We find dimers where the excitation is delocalized (superradiant emission) while for others emission originates from a localized state. Transitions between delocalized and localized states as observed for a given dimer are attributed to structural fluctuations of the guest-host system.
Activation of both beta(1)- and beta(2)-adrenoceptors increases the contractility of human atrial myocardium through cyclic AMP-dependent pathways. Cyclic AMP is hydrolised by phosphodiesterases, but ...little is known about which isoenzymes catalyse inotropically relevant cyclic AMP accumulated upon stimulation of beta-adrenoceptor subtypes. We have compared the positive inotropic effects of (-)-noradrenaline and (-)-adrenaline, mediated through beta(1)- and beta(2)-adrenoceptors, respectively, in the absence and presence of the PDE3 inhibitor cilostamide (300 nM) or PDE4 inhibitor rolipram (1 muM) on human atrial trabeculae from non-failing hearts. Cilostamide, but not rolipram, potentiated the effects of both (-)-noradrenaline and (-)-adrenaline. Cilostamide increased the -logEC(50)M of (-)-adrenaline more than of (-)-noradrenaline (P < 0.05), regardless of whether or not the patients had been chronically treated with beta-blockers. The results are consistent with a greater PDE3-catalysed hydrolysis of inotropically relevant cyclic AMP produced through beta(2)-adrenoceptors than beta(1)-adrenoceptors in human atrium.
We study the production of Σ±π∓pK+ particle quartets in p + p reactions at 3.5 GeV kinetic beam energy. The data were taken with the HADES experiment at GSI. This report evaluates the contribution of ...resonances like Λ(1405), Σ(1385)0, Λ(1520), Δ(1232), N⁎ and K⁎0 to the Σ±π∓pK+ final state. The resulting simulation model is compared to the experimental data in several angular distributions and it shows itself as suitable to evaluate the acceptance corrections properly.
Atrial fibrillation (AF) is accompanied by a high risk of thromboembolic complications necessitating anticoagulation therapy. Arrhythmias have a high tendency to become persistent. Catheter ablation ...techniques are highly effective in the treatment of AF; however, these procedures are far too costly and time-consuming for the routine treatment of large numbers of AF patients. Moreover, many patients prefer drug treatment although conventional antiarrhythmic drugs are moderately effective and are burdened with severe cardiac and noncardiac side effects. New antifibrillatory drugs developed for the treatment of AF include multichannel blockers with a high degree of atrial selectivity. The rationale of this approach is to induce antiarrhythmic actions only in the atria without conferring proarrhythmic effects in the ventricles.
Atrial selective drug action is expected with ion channel blockers targeting ion channels that are expressed predominantly in the atria, i.e., Kv1.5 (I
Kur
), or Kir 3.1 and Kir 3.4 (I
K,ACh
). Na
+
channel blockers that dissociate rapidly may exert atrial selectivity because of subtle differences in atrial and ventricular action potentials. Finally, atrial-selective targets may evolve due to disease-specific processes (e.g., rate-dependent Na
+
channel blockers, selective drugs against constitutively active I
K,ACh
channels).
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