Introduction: 

Chronic hypoxia (CH) may affect cardiac myocyte function through its direct action, concerning both right (RV) and left (LV) ventricles, and by causing selective RV hypertrophy through pressure overload (pulmonary hypertension). Enhancement of the late Na⁺ current (I_NaL), transiently induced by acute hypoxia, and present in cardiac hypertrophy/failure, may contribute to repolarization abnormalities and remodeling. Whether chronic hypoxia (CH) may cause stable I_NaL enhancement and whether this may contribute to myocardial remodeling is unknown.

Aim: 

1) to study the effects of CH on cardiac electrical activity and I_NaL; 2) to discriminate between its direct (occurring in both ventricles) and overload-dependent (occurring in RV only) effects.

Methods: 

Cardiomyocytes were isolated separately from RV and LV of rats exposed to CH (1 month to 11% O₂) and from aged-matched normoxic rats (NORM). Action potential (AP) and I_Na were recorded in whole cell configuration at physiological and room temperature respectively. I_NaT and I_NaL were identified as the peak and the persistent TTX-sensitive current respectively. I_NaL was recorded during 1) depolarizing steps (at 70 mM Na⁺ and expressed as % of I_NaT) and 2) repolarization in AP-clamp conditions. I_NaL I/V relations were obtained by recording TTX-sensitive current during slow ramp depolarization (at 140 mM Na⁺). All measurements were performed in normoxic conditions.

Results: 

In NORM: RV myocytes showed smaller C_m, larger dV/dt_max and I_NaT, shorter AP duration (APD) and smaller I_NaL/I_NaT ratio than LV myocytes; I_NaL I/V relations differed between RV and LV myocytes, because I_NaL at membrane potentials (V_m) >= 0mV was smaller in the RV. CH caused a marked RV hypertrophy, prolonged APD, increased C_m, and the I_NaL/I_NaT ratio, reduced dV/dt_max and I_NaT in RV myocytes only. The I_NaL blocker ranolazine (10 mM) shortened APD more in CH than in NORM RV myocytes. However, as a consequence of slower repolarization rate, peak I_NaL activated during the plateau phase of RV action potentials (AP-clamp) was actually reduced by CH. CH increased I_NaL at V_m>= 0mV in RV myocytes only, thereby making I_NaL I/V relations similar between RV and LV. None of CH-induced changes were observed in LV myocytes.

Conclusion: 

1) CH caused hypertrophy, repolarization abnormalities and I_NaL enhancement in the RV only; 2) I_NaL enhancement may contribute to RV APD prolongation; 3) increased afterload may be required for CH-induced changes.