Block of HERG current expressed in HEK293 cells by the Na+-channel blocker cibenzoline.

A Na(+)-channel blocker, cibenzoline, blocks the delayed rectifier potassium current ( I(k)), but its detailed action on the rapidly activating component ( I(kr)) of I(k) encoded by the human ether-a-go-go-related gene ( HERG) has not been clarified. We examined the effects of cibenzoline on stably expressed HERG current in HEK293 cells recorded by the patch-clamp technique of whole-cell configuration. Cibenzoline blocked HERG current expressed in HEK293 cells with IC(50) = 3.7 +/- 0.963 micro M and Hill coefficient = 0.74 +/- 0.12. Voltage-depended activation was shifted in a negative direction by cibenzoline. No block or minor block was induced at test depolarization of -40 to -30 mV, and the block increased with depolarization reaching a plateau at 0 mV without a further increase at positive voltages. Voltage-dependent activation of HERG currents became faster at negative test voltages but there were no changes at positive voltages after cibenzoline. No frequency-dependent block of HERG tail current by cibenzoline after equilibration was noted between 1.33 and 0.2 Hz. Steady-state inactivation of the HERG current was shifted in a negative direction by approximately 8 mV but the time constants of fast inactivation were little affected by cibenzoline. Cibenzoline blocks the I(kr)-like current reconstituted by HERG clone transfection with an IC(50) value comparable to therapeutic concentrations. Cibenzoline has a preferential affinity, at least, to the open state of the HERG channel with a rapid access to the binding site.

Ion channel remodeling in cardiac hypertrophy is prevented by blood pressure reduction without affecting heart weight increase in rats with abdominal aortic banding.

This study investigates changes in the messenger RNA (mRNA) expression levels of HCN2 and HCN4 encoding rat If channels; ClC-3, a candidate gene for swelling-activated Cl- channel, and pICln, a regulatory subunit of Cl- channels in rat hypertrophied heart induced by banding the abdominal aorta. The mRNA expression levels were quantified with competitive reverse transcription polymerase chain reaction methods. Plasma renin activity, blood pressure, and heart weight increased. HCN2, HCN4, and ClC-3 mRNA levels decreased in the early phase after banding, whereas they increased in the late phase; pICln mRNA levels did not change at any stage. Administration of candesartan, an angiotensin II receptor blocker, prevented cardiac hypertrophy, but amlodipine, a Ca2+ channel blocker, did not prevent it, whereas both drugs lowered blood pressure. Changes in mRNA levels of HCN2, HCN4, and ClC-3 were alleviated by both candesartan and amlodipine, and these levels of the treated groups were not different from those in the sham control group. This study is the first to demonstrate changes in mRNA levels of HCN2, HCN4, and ClC-3 in cardiac hypertrophy induced by abdominal aortic banding. The data further suggest that the changes in channel mRNA levels were prevented by blood pressure reduction without affecting heart weight increase in this model.