Inhibitory effect of digoxin on testosterone secretion through mechanisms involving decreases of cyclic AMP production and cytochrome P450(scc) activity in rat testicular interstitial cells

1 In vivo and in vitro experiments were performed to examine inhibitory eff ects of digoxin on testosterone secretion and to determine possible underly ing mechanisms. 2 A single intravenous injection of digoxin (1 mu g kg(-1)) decreased the b asal and human chorionic gonadotropin (hCG)-stimulated plasma testosterone concentrations in adult male rats. 3 Digoxin (10(-7)-10(-4) M) decreased the basal and hCG-stimulated release of testosterone from rat testicular interstitial cells in vitro. 4 Digoxin (10(-7)-10(-4) M) also diminished the basal and hCG-stimulated pr oduction of cyclic 3':5'-adenosine monophosphate (AMP) and attenuated the s timulatory effects of forskolin and 8-Br-cyclic AMP on testosterone product ion by rat testicular interstitial cells. 5 Digoxin (10(-4) M) inhibited cytochrome P450 side chain cleavage enzyme ( cytochrome P450(scc)) activity (conversion of 25-hydroxy cholesterol to pre gnenolone) in the testicular interstitial cells but did not influence the a ctivity of other steroidogenic enzymes. 6 These results suggest that digoxin inhibits the production of testosteron e in rat testicular interstitial cells, at least in part, via attenuation o f the activities of adenylyl cyclase and cytochrome P450(scc).