Sex‐specific activation of SK current by isoproterenol facilitates action potential triangulation and arrhythmogenesis in rabbit ventricles

Abstract

Sex has a large influence on cardiac electrophysiological properties. Whether sex differences exist in apamin-sensitive small conductance Ca -activated K (SK) current (I ) remains unknown. We performed optical mapping, transmembrane potential, patch clamp, western blot and immunostaining in 62 normal rabbit ventricles, including 32 females and 30 males. I blockade by apamin only minimally prolonged action potential (AP) duration (APD) in the basal condition for both sexes, but significantly prolonged APD in the presence of isoproterenol in females. Apamin prolonged APD at the level of 25% repolarization (APD ) more prominently than APD at the level of 80% repolarization (APD ), consequently reversing isoproterenol-induced AP triangulation in females. In comparison, apamin prolonged APD to a significantly lesser extent in males and failed to restore the AP plateau during isoproterenol infusion. I in males did not respond to the L-type calcium current agonist BayK8644, but was amplified by the casein kinase 2 (CK2) inhibitor 4,5,6,7-tetrabromobenzotriazole. In addition, whole-cell outward I densities in ventricular cardiomyocytes were significantly larger in females than in males. SK channel subtype 2 (SK2) protein expression was higher and the CK2/SK2 ratio was lower in females than in males. I activation in females induced negative intracellular Ca -voltage coupling, promoted electromechanically discordant phase 2 repolarization alternans and facilitated ventricular fibrillation (VF). Apamin eliminated the negative Ca -voltage coupling, attenuated alternans and reduced VF inducibility, phase singularities and dominant frequencies in females, but not in males. We conclude that β-adrenergic stimulation activates ventricular I in females to a much greater extent than in males. I activation plays an important role in ventricular arrhythmogenesis in females during sympathetic stimulation.

Impact of arrhythmogenic calmodulin variants on small conductance Ca 2+ ‐activated K + (SK3) channels

“…As SK channels appears to play a role in some pathological conditions in the ventricles (Gui ; Bonilla ; Hundahl ; Chen ; Hamilton ), it could be speculated that the SK channels also have a contributory role in the pathogenesis of CaM‐associated LQTS. Three out of the four LQTS‐associated CaM variants significantly down‐regulated the SK current, with CaM D130G being the variant most profoundly decreasing SK current with no effect on the trafficking of the channel.…”

“…This atrial selectivity makes SK channels an interesting target in the treatment of atrial arrhythmias, as the ventricular side effects have been speculated to be avoided (Xu ; Diness , ; Skibsbye ; Skibsbye ). However, several recent studies have shown that SK channel current also becomes functional in the ventricles during enhanced sympathetic activation through β ‐adrenergic stimulation (Chen ; Hamilton ).…”

Cardiac small-conductance calcium-activated potassium channels in health and disease

“…Expressions of SK2 channel and SK current density are higher in ventricular myocytes of female rabbits compared to male rabbits [ 14 ]. Furthermore, action potential triangulation, a known proarrhythmic predictor, is observed in female rabbit hearts upon isoproterenol stimulation, which could be reversed by apamin, suggesting the possible roles of SK channels in ventricular fibrillation in female animals during sympathetic stimulation.…”

Sex‐specific density of ventricular SK currents: is this a general feature of SK channel function?

“…The study by Chen et al . () provides clear evidence that SK channels are important contributors to the shape of the ventricular AP under conditions simulating increased sympathetic drive, and that SK channel inhibition might be a promising antiarrhythmic strategy for pharmacological treatment of ventricular fibrillation, particularly in females. Although block of SK channels may prolong ventricular AP, preventing reentrant arrhythmias, it may make the ventricular cardiomyocytes more sensitive to Ca 2+ ‐dependent triggered activity (Hsueh et al .…”

“…As reported in this issue of The Journal of Physiology , Chen et al . () studied sex‐specific SK channel activation in the ventricle, particularly in settings mimicking increased sympathetic drive, which accompanies many pathophysiological conditions and the physiological ‘fight‐or‐flight’ response. In ventricular cardiomyocytes from both male and female rabbits, the highly selective SK channel blocker apamin caused only a small prolongation of the AP under basal conditions.…”