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An antisense oligonucleotide against H1 inhibits the classical sodium current but not I_Ca(TTX) in rat ventricular cells

Qun Sha*, Shawn W. Robinson*, Stacey L. McCulle*, Stephen R. Shorofsky*, Paul A. Welling†, L. Goldman† and C. William Balke*†

I_Ca(TTX) is a sodium current component, functionally distinct from the main body of sodium current, seen in cardiac and other cells. To determine if I_Ca(TTX) channels are a separate isoform from the classical cardiac sodium channels, we exposed rat ventricular cells in primary culture to an antisense oligonucleotide (AON) directed against rH1 (rNa_v1.5): 5'-CTCCTCATACCCTCT-3'. The homologous human sequence has been identified (and confirmed by us on HEK 293 cells) as effective against hH1 expressed heterologously. Scrambled sequence (5'-CCCCCCTTATCTACT-3') controls were also included. The AON (10 µM; day 2 of exposure) reduced the classical sodium current by 69.6 % compared to untreated and 60.8 % compared to scrambled sequence (10 µM; day 2 of exposure) controls (mean ± S.E.M. maximum peak inward current density of -8.23 ± 0.60 pA pF^-1, 18 cells, for untreated; -6.37 ± 0.79 pA pF^-1, 16 cells, for scrambled sequence; and -2.50 ± 0.31 pA pF^-1, 18 cells, for AON-treated cells). The two control groups are not significantly different from each other, but are both significantly different from the AON-treated group (P < 0.001). The inhibition was specific for sodium channels, with no significant AON effect on the L-type calcium current. This confirms that H1 generates the classical cardiac sodium current. This same AON at the same concentration and time of exposure had no significant effect on I_Ca(TTX) (mean of -4.72 ± 0.55, 15 cells; -5.47 ± 0.53, 13 cells; and -5.04 ± 0.63 pA pF^-1, 15 cells, for untreated controls, scrambled controls and AON treated, respectively). Hence, I_Ca(TTX), which is functionally distinct from the classical cardiac sodium current, is encoded by a distinct gene.

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