TY - JOUR
T1 - Antiarrhythmic effect of either negative modulation or blockade of small conductance Ca2+ activated K+ channels on ventricular fibrillation in guinea pig Langendorff perfused heart
AU - Diness, Jonas Goldin
AU - Kirchhoff, Jeppe Egedal
AU - Sheykhzade, Majid
AU - Jespersen, Thomas
AU - Grunnet, Morten
PY - 2015/9/21
Y1 - 2015/9/21
N2 - During recent years, small conductance Ca2+-activated K+ (SK) channels have been reported to play a role in cardiac electrophysiology. SK channels seem to be expressed in atria and ventricles, but from a functional perspective, atrial activity is predominant. A general notion seems to be that cardiac SK channels are predominantly coming into play during arrhythmogenic events where intracellular concentration of Ca2+ is increased. During ventricular fibrillation (VF), a surge of [Ca2+]i has the potential to bind to and open SK channels. To obtain mechanistic insight into possible roles of SK channels during VF, we conducted experiments with an SK channel pore blocker (ICA) and a negatively allosteric modulator (NS8395) in a Langendorff-perfused heart model. Both compounds increased the action potential duration, effective refractory period, and Wenckebach cycle length to comparable extents. Despite these similarities, the SK channel modulator was found to revert and prevent VF more efficiently than the SK channel pore blocker. In conclusion, either negative allosteric modulation of the SK channel with NS8593 is more favorable than pure channel block with ICA or the 2 compounds have different selectivity profiles that makes NS8593 more antiarrhythmic than ICA in a setting of VF.
AB - During recent years, small conductance Ca2+-activated K+ (SK) channels have been reported to play a role in cardiac electrophysiology. SK channels seem to be expressed in atria and ventricles, but from a functional perspective, atrial activity is predominant. A general notion seems to be that cardiac SK channels are predominantly coming into play during arrhythmogenic events where intracellular concentration of Ca2+ is increased. During ventricular fibrillation (VF), a surge of [Ca2+]i has the potential to bind to and open SK channels. To obtain mechanistic insight into possible roles of SK channels during VF, we conducted experiments with an SK channel pore blocker (ICA) and a negatively allosteric modulator (NS8395) in a Langendorff-perfused heart model. Both compounds increased the action potential duration, effective refractory period, and Wenckebach cycle length to comparable extents. Despite these similarities, the SK channel modulator was found to revert and prevent VF more efficiently than the SK channel pore blocker. In conclusion, either negative allosteric modulation of the SK channel with NS8593 is more favorable than pure channel block with ICA or the 2 compounds have different selectivity profiles that makes NS8593 more antiarrhythmic than ICA in a setting of VF.
UR - https://www.ncbi.nlm.nih.gov/pubmed/25978690
U2 - 10.1097/FJC.0000000000000278
DO - 10.1097/FJC.0000000000000278
M3 - Journal article
C2 - 25978690
SN - 0160-2446
VL - 66
SP - 294
EP - 299
JO - Journal of Cardiovascular Pharmacology
JF - Journal of Cardiovascular Pharmacology
IS - 3
ER -