A possible mechanism for alteration of human erectile function by digoxin: Inhibition of corpus cavernosum sodium/potassium adenosine triphosphatase activity

Purpose: Digoxin use has long been recognized to affect adversely male sexual function but the underlying mechanism is poorly understood, Digoxin is a known inhibitor of sodium/potassium adenosine triphosphatase (sodium pump), a plasma membrane enzyme that has a role in the regulation of smooth muscle tone. We investigated the effects of digoxin on human corpus cavernosum smooth muscle contractility and overall erectile function. Materials and Methods: In human corporeal smooth muscle strips the in vitro effects of digoxin were assessed on sodium pump activity as measured by digoxin inhibitable uptake of (86)rubidium, basal tone and endothelium dependent, neurogenic and nitric oxide donor induced relaxation. An in vivo prospective double-blind, placebo controlled, crossover, 4-period investigation was performed in 6 healthy male volunteers. The effects of digoxin on serum hormones, erectile function questionnaire, visual sexual stimulation and nocturnal penile tumescence were recorded, Results: In vitro digoxin caused concentration dependent inhibition of (86)rubidium uptake (half maximum effect at 0.01 mu M.) and contraction of corporeal smooth muscle (half maximum effect at 0.8 mu M.). Therapeutic concentrations of digoxin (2 nM.) also inhibited relaxation induced by acetylcholine and electrical field stimulation, which release nitric oxide from corpus cavernosum endothelial cells and nonadrenergic noncholinergic nerves, respectively. In vivo digoxin diminished penile rigidity during visual sexual stimulation and nocturnal penile tumescence testing compared to placebo without influencing libido or serum testosterone, estrogen or luteinizing hormone levels. Conclusions: Digoxin associated alteration of human erectile function may be explained, in part, by inhibition of corporeal smooth muscle sodium pump activity, which promotes contraction and impedes nitric oxide induced relaxation. Such findings suggest therapeutic use of digoxin for treatment of recurrent priapism states.