Abstract 18323: Positive Frequency-Dependent Effects of Highly Selective Kv1.5 Blockers (XEN-D0103 & MK-0448) in Right Atrial Trabeculae From Patients in Sinus Rhythm
Aim: Despite promising effects of Kv1.5 blockers in experimental models of atrial fibrillation, limited data is available for man. Therefore we investigated two selective Kv1.5 channel blockers, XEN-D0103 and MK-0448, on atrial myocardium from patients in sinus rhythm (SR).
Method: Kv1.5 currents were measured with in CHO cells expressing hKv1.5. Sharp microelectrodes were used to record action potentials (AP) at various stimulation frequencies (37°C) in right atrial trabeculae from consenting patients in SR.
Results: Kv1.5 was activated by voltage-clamp steps from -80 to 0mV (900ms)at 0.2Hz (room temp). XEN-D0103 and MK-0448 inhibited Kv1.5 with IC50 of 25nM and 32nM resp.. Both compounds display >500-fold selectivity over hERG, Kv4.3, Nav1.5, Cav1.2, Kir2.1. The plateau phase of the atrial AP was elevated with XEN-D0103 and MK-0448 in a concentration-dependent manner. At 1Hz this effect was associated with shortening of APD90 and of effective refractory period (ERP) (see Table). At higher stimulation rates the APD90 and ERP shortening effects of XEN-D0103 and MK-0448 (3μM each) diminished and eventually converted to prolongation. With XEN-D0103, significant prolongation of APD90/ERP occurred at 3Hz and higher rates. In control, 10 out of 16 trabeculae followed stimulation at 5Hz, however, in the presence of XEN-D0103 10 out of 10, and with MK-0448 4 out of 6 preparations failed to capture stimulation.
Conclusion: This is the first report of robust frequency dependence of selective Kv1.5 channel blockers in human atrial myocardium suggesting that these drugs are more effective at high than at low activation rates. Therefore, XEN-D0103 and MK-0448 should possess potential for suppressing episodes of rapid atrial excitation.
Table: Frequency-dependent effects of the Kv1.5 blockers XEN-D0103 and MK-0448 in human right atrial trabeculae. Differences between pre-drug controls and values after 1 hour of drug superfusion (means ± SEM).
- © 2013 by American Heart Association, Inc.