Effects of dihydrotestosterone on cardiac inward rectifier K+ current

There are well-described sexually dimorphic differences both in the electrocardiogram and in the propensity to develop drug-induced arrhythmias. The QT interval and the risk of ventricular proarrhythmia are reduced in males compared with females. Inward rectifier potassium current (I (K1) ) is a primary determinant of the ventricular resting membrane potential, and an important contributor to myocardial excitability.Methods and results: Using the whole-cell patch-clamp technique, we evaluated the effects of dihydrotestosterone (DHT) on I (K1) in ventricular myocytes from castrated rabbits that were treated with either replacement DHT or vehicle-control for 3 weeks. Compared with the DHT-treated group, myocytes from the control animals had a significant reduction in inward I (K1) conductance (p < 0.005) and rectification ratio (RR) (p < 0.04) with no significant change in peak outward current. Acute DHT superfusion of the myocytes increased inward I (K1) conductance from baseline (p < 0.05) and increased the RR (p < 0.05). Testosterone has been reported to increase intracellular ornithine decarboxylase activity in ventricular tissue, which would increase intracellular polyamines, known modulators of I (K1) rectification. We found that inclusion of the intracellular polyamines spermidine and putrescine in the pipette solution caused a decrease in inward I (K1) , accompanied by an increase in peak outward current and a reduction in the RR. Conclusion: In summary, DHT modulates I (K1) in a chronic, as well as, an acute fashion. These effects are not because of altered intracellular polyamines. DHT may modulate myocardial excitability through effects on I (K1) .