Left ventricular hypertrophy is associated with an increased risk of ventricular arrhythmias. However, the underlying molecular basis is poorly understood. It has been reported that small-conductance Ca(2+)-activated K(+) (SK) channels are involved in the pathogenesis of ventricular arrhythmias in
heart failure. The present study aimed to test the hypothesis that SK channel activity is increased via the
Ca(2+)/calmodulin-dependent protein kinase II (
CaMKII)-dependent pathway in hypertensive
cardiac hypertrophy. Normotensive Wistar-Kyoto (WKY) rats and spontaneous hypertensive rats (SHRs) were used. Whole cell membrane currents were recorded in isolated ventricular myocytes by the patch-clamp method, and
apamin-sensitive K(+) current (IKAS), which is inhibited by
apamin (100 nM), an SK channel blocker, was evaluated. IKAS at 40 mV was present in SHRs, whereas it was hardly detectable in WKY rats (0.579 ± 0.046 vs. 0.022 ± 0.062 pA/pF, both n = 6, P < 0.05). IKAS was almost completely abolished by 1 μM
KN-93, a
CaMKII inhibitor, in SHRs. Optical recordings of left ventricular anterior wall action potentials revealed that
apamin prolonged the late phase of repolarization only in SHRs. Western blot analysis of SK channel
protein isoforms demonstrated that SK2 was significantly increased in SHRs compared with WKY rats (SK2/GAPDH: 0.66 ± 0.07 vs. 0.40 ± 0.02, both n = 6, P < 0.05), whereas SK1 and SK3 did not differ between groups. In addition, autophosphorylated
CaMKII was significantly increased in SHRs (phosphorylated
CaMKII/GAPDH: 0.80 ± 0.06 vs. 0.58 ± 0.06, both n = 6, P < 0.05) despite a comparable total amount of
CaMKII between groups. In conclusion, SK channels are upregulated via the enhanced activation of
CaMKII in
cardiac hypertrophy in SHRs.