Sex and regional differences in rabbit right ventricular L-type calcium current levels and mathematical modelling of...

What is the central question of this study? Regional variations of ventricular L-type calcium current (I_Ca-L ) amplitude may underlie the increased arrhythmia risk in adult females. Current amplitude variations have been described for the left ventricle but not for the right ventricle. What is the main finding and its importance? Adult female rabbit right ventricular base myocytes exhibit elevated I_Ca-L compared with female apex or male myocytes. Oestrogen upregulated I_Ca-L in cultured female myocytes. Mathematical simulations modelling long QT syndrome type 2 demonstrated that elevated I_Ca-L prolonged action potentials and induced early after-depolarizations. Thus, ventricular arrhythmias in adult females may be associated with an oestrogen-induced upregulation of I_Ca-L . Previous studies have shown that adult rabbit left ventricular myocytes exhibit sex and regional differences in L-type calcium current (I_Ca-L ) levels that contribute to increased female susceptibility to arrhythmogenic early after-depolarizations (EADs). We used patch-clamp recordings from isolated adult male and female rabbit right ventricular myocytes to determine apex-base differences in I_Ca-L density and used mathematical modelling to examine the contribution of I_Ca-L to EAD formation. Current density measured at 0 mV in female base myocytes was 67% higher than in male base myocytes and 55% higher than in female apex myocytes. No differences were observed between male and female apex myocytes, between male apex and base myocytes, or in the voltage dependences of I_Ca-L activation or inactivation. The role of oestrogen was investigated using cultured adult female right ventricular base myocytes. After 2 days, 17β-estradiol (1 nm) produced a 65% increase in I_Ca-L density compared with untreated control myocytes, suggesting an oestrogen-induced upregulation of I_Ca-L . Action potential simulations using a modified Luo-Rudy cardiomyocyte model showed that increased I_Ca-L density, at the level observed in female base myocytes, resulted in longer duration action potentials, and when combined with a 50% reduction of the rapidly inactivating delayed rectifier potassium current conductance to model long QT syndrome type 2, the action potential was accompanied by one or more EADs. Thus, we found higher levels of I_Ca-L in adult female right ventricle base myocytes and the upregulation of this current by oestrogen. Simulations of long QT syndrome type 2 showed that elevated I_Ca-L contributed to genesis of EADs.