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 (IK(1)) is a primary determinant of the ventricular resting membrane potential, and an important contributor to myocardial excitability.


RESULTS
Using the whole-cell patch-clamp technique, we evaluated the effects of dihydrotestosterone (DHT) on IK(1) 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 IK(1) 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 IK(1) 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 IK(1) rectification. We found that inclusion of the intracellular polyamines spermidine and putrescine in the pipette solution caused a decrease in inward IK(1), accompanied by an increase in peak outward current and a reduction in the RR.


CONCLUSIONS
In summary, DHT modulates IK(1) 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 IK(1).
College of Pharmacy and the Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH 43210, USA. carnes.4@osu.edu
Cynthia A
CA
Carnes
Spencer J
SJ
Dech
D000818:Animals; D013196:Dihydrotestosterone / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects*; D008297:Male; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D009919:Orchiectomy; D018408:Patch-Clamp Techniques; D024661:Potassium Channels, Inwardly Rectifying / Q000187:drug effects* / Q000378:metabolism; D011700:Putrescine / Q000494:pharmacology; D011817:Rabbits; D012727:Sex Characteristics; D013095:Spermidine / Q000494:pharmacology
D024661:Potassium Channels, Inwardly Rectifying; D013196:Dihydrotestosterone; D013095:Spermidine; D011700:Putrescine