Prolongation of the action potential is a characteristic feature of cardiac hypertrophy. However, the ionic currents underlying the longer action potential are not fully described. We therefore investigated the role of I_Na in prolongation of the action potential in a mild model of hypertrophy in the guinea-pig.

Hypertrophy was produced by pressure overload caused by constriction of the abdominal aorta with a silver clip (i.d. 0.5 mm). Age- and weight-matched cohorts underwent the same procedure (sham) except the aorta was not clipped (Bryant et al. 1997). After 20 weeks, guinea-pigs were anaesthetised with sodium pentabarbitone (200 mg kg^-1, I.P.) and killed by exsanguination. Left ventricular myocytes were isolated by enzymatic digestion and voltage clamped using conventional whole-cell patch clamp. I_Na were recorded using large tipped microelectrodes (0.5 MΩ) and with low external [Na⁺]. External solutions contained (mmol l^-1): NaCl, 5-20; TEACl, 120; MgCl₂.6H₂O, 1; CaCl₂, 2; glucose, 10; Hepes, 10; adjusted to pH 7.3 with TEAOH. Internal solutions contained (mmol l^-1): CsCl, 120; TEACl, 20; MgCl₂.6H₂O, 5; Na₂ATP, 5; CaCl₂, 1; EGTA, 5; Hepes, 10; pH 7.25 with CsOH. Current-voltage (I-V) relationships were constructed in the absence and presence of 25 mmol l^-1 tetrodotoxin (TTX) following step depolarisations (for 50 ms), in 5 mV increments, from a holding potential of -80 mV. Double-pulse protocols were also used to investigate steady-state activation (d) and inactivation (f) variables. Data are shown as means ± S.E.M. and were analysed with Student’s t test for independent observations.

TTX-sensitive I_Na density (normalised for membrane capacitance) was decreased at voltages between -45 to -30 mV (P < 0.05). Maximal I_Na, recorded following depolarisation to -30 mV (peak of the I-V curve), was -9.65 ± 1.3 pA pF^-1 (n = 5) in control myocytes and -6.2 ± 0.5 pA pF^-1 (n = 6) in hypertrophied myocytes (P < 0.05). The d and f variables were not significantly different between control and hypertrophied myocytes. However, the time constant for the rapid component of inactivation of I_Na was significantly prolonged in hypertrophied myocytes at voltages between -40 and -20 mV (P < 0.05).

In conclusion, these data suggest that although peak I_Na density was decreased and steady-state d and f variables were unchanged, slower time-dependent inactivation of I_Na may permit increased Na⁺ influx and contribute, at least in part, to prolongation of the action potential in hypertrophied cardiac myocytes.

This work was supported by the British Heart Foundation.

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