NS 5806

Differential effects of the transient outward K(+) current activator NS5806 in the canine left ventricle.[Pubmed:19632239]

J Mol Cell Cardiol. 2010 Jan;48(1):191-200.

To examine the electrophysiological and molecular properties of the transient outward current (I(to)) in canine left ventricle using a novel I(to) activator, NS5806, I(to) was measured in isolated epicardial (Epi), midmyocardial (Mid) and endocardial (Endo) cells using whole-cell patch-clamp techniques. NS5806 activation of K(v)4.3 current was also studied in CHO-K1 cells and Xenopus laevis oocytes. In CHO-K1 cells co-transfected with K(v)4.3 and KChIP2, NS5806 (10 microM) caused a 35% increase in current amplitude and a marked slowing of current decay with tau increasing from 7.0+/-0.4 to 10.2+/-0.3 ms. In the absence of KChIP2, current decay was unaffected by NS5806. In ventricular myocytes, NS5806 increased I(to) density by 80%, 82%, and 16% in Epi, Mid, and Endo myocytes, respectively (at +40 mV) and shifted steady-state inactivation to negative potentials. NS5806 also significantly slowed decay of I(to), increasing total charge to 227%, 192% and 83% of control in Epi, Mid and Endo cells, respectively (+40 mV, p<0.05). Quantification of K(v)4.3 and KChIP2 mRNA in the 3 ventricular cell types revealed that levels of K(v)4.3 message was uniform but those of KChIP2 were significantly greater in Epi and Mid cells. The KChIP2 gradient was confirmed at the protein level by Western blot. Our results suggest that NS5806 augments I(to) by increasing current density and slowing decay and that both depend on the presence of KChIP2. I(to) and its augmentation by NS5806 are greatest in Epi and Mid cells because KChIP2 levels are highest in these cell types.

Effect of the I(to) activator NS5806 on cloned K(V)4 channels depends on the accessory protein KChIP2.[Pubmed:20649599]

Br J Pharmacol. 2010 Aug;160(8):2028-44.

BACKGROUND AND PURPOSE: The compound NS5806 increases the transient outward current (I(to)) in canine ventricular cardiomyocytes and slows current decay. In human and canine ventricle, I(to) is thought to be mediated by K(V)4.3 and various ancillary proteins, yet, the exact subunit composition of I(to) channels is still debated. Here we characterize the effect of NS5806 on heterologously expressed putative I(to) channel subunits and other potassium channels. EXPERIMENTAL APPROACH: Cloned K(V)4 channels were co-expressed with KChIP2, DPP6, DPP10, KCNE2, KCNE3 and K(V)1.4 in Xenopus laevis oocytes or CHO-K1 cells. KEY RESULTS: NS5806 increased K(V)4.3/KChIP2 peak current amplitudes with an EC(50) of 5.3 +/- 1.5microM and significantly slowed current decay. KCNE2, KCNE3, DPP6 and DPP10 modulated K(V)4.3 currents and the response to NS5806, but current decay was slowed only in complexes containing KChIP2. The effect of NS5806 on K(V)4.2 was similar to that on K(V)4.3, and current decay was only slowed in presence of KChIP2. However, for K(V)4.1, the slowing of current decay by NS5806 was independent of KChIP2. K(V)1.4 was strongly inhibited by 10 microM NS5806 and K(V)1.5 was inhibited to a smaller extent. Effects of NS5806 on kinetics of currents generated by K(V)4.3/KChIP2/DPP6 with K(V)1.4 in oocytes could reproduce those on cardiac I(to) in canine ventricular myocytes. K(V)7.1, K(V)11.1 and K(ir)2 currents were unaffected by NS5806. CONCLUSION AND IMPLICATIONS: NS5806 modulated K(V)4 channel gating depending on the presence of KChIP2, suggesting that NS5806 can potentially be used to address the molecular composition as well as the physiological role of cardiac I(to).

A transient outward potassium current activator recapitulates the electrocardiographic manifestations of Brugada syndrome.[Pubmed:19073629]

Cardiovasc Res. 2009 Mar 1;81(4):686-94.

AIMS: Transient outward potassium current (I(to)) is thought to be central to the pathogenesis of the Brugada syndrome (BrS). However, an I((to)) activator has not been available with which to validate this hypothesis. Here, we provide a direct test of the hypothesis using a novel I(to) activator, NS5806. METHODS AND RESULTS: Isolated canine ventricular myocytes and coronary-perfused wedge preparations were used. Whole-cell patch-clamp studies showed that NS5806 (10 microM) increased peak I(to) at +40 mV by 79 +/- 4% (24.5 +/- 2.2 to 43.6 +/- 3.4 pA/pF, n = 7) and slowed the time constant of inactivation from 12.6 +/- 3.2 to 20.3 +/- 2.9 ms (n = 7). The total charge carried by I(to) increased by 186% (from 363.9 +/- 40.0 to 1042.0 +/- 103.5 pA x ms/pF, n = 7). In ventricular wedge preparations, NS5806 increased phase 1 and notch amplitude of the action potential in the epicardium, but not in the endocardium, and accentuated the ECG J-wave, leading to the development of phase 2 re-entry and polymorphic ventricular tachycardia (n = 9). Although sodium and calcium channel blockers are capable of inducing BrS only in right ventricular (RV) wedge preparations, the I(to) activator was able to induce the phenotype in wedges from both ventricles. NS5806 induced BrS in 4/6 right and 2/10 left ventricular wedge preparations. CONCLUSION: The I(to) activator NS5806 recapitulates the electrographic and arrhythmic manifestation of BrS, providing evidence in support of its pivotal role in the genesis of the disease. Our findings also suggest that a genetic defect leading to a gain of function of I(to) could explain variants of BrS, in which ST-segment elevation or J-waves are evident in both right and left ECG leads.

NS5806, a potent potassium current activator, increases KV4.3/KChIP2 peak current amplitudes with an EC50 of 5.3 μM. NS5806 slows KV4.3 and KV4.2 current dacay in channel complexes containing KChIP2.

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