Positive inotropism induced by androgens in isolated left atrium of rat: Evidence for a cAMP-dependent transcriptional mechanism

Steroid hormones exert their biological actions via intracellular receptors modulation of transcription. In addition, a number of molecular interactio ns, and the existence of membrane receptors in several tissues, support the hypothesis of nongenomic action of steroids. The androgens, 5 alpha- and 5 beta-dihydrotestosterone (0.1 to 100 mu M), induce a rapid positive inotro pism in the isolated left atrium of male Wistar rats whose time course of r esponse might suggest that it is a non-genomic effect. However, the fact th at the facilitation of contractility was inhibited by actinomycin D (5 mu g /ml) and cycloheximide (10 mu g/ml) indicates that a transcriptional compon ent might play a role. The existence of a rapid functional genomic role wou ld be somewhat surprising. However, rapid transcriptional mechanisms were a lso observed in certain cAMP-dependent responses. In the left atrium of rat , Rp-cAMBS (10 mu M), a cAMP-dependent protein kinase inhibitor, antagonize d 5 alpha- but not 5 beta-dihydrotestosterone-induced positive inotropism. The inhibition by Rp-cAMPS of isoproterenol- and forskolin-induced positive inotropism, and the fact that these cAMP-dependent effects were also inhib ited by actinomycin D and cycloheximide, suggest that a cAMP-dependent tran scriptional component may be partly involved in the positive inotropism ind uced by 5 alpha-dihydrotestosterone. In addition, 5 alpha-dihydrotestostero ne might increase the basal adenylyl cyclase activity by acting on unoccupi ed beta-adrenoceptor-G-protein-adenylyl cyclase complexes, since the elicit ed inotropism was inhibited by a beta-blocker, atenolol (1 mu M), a G-prote in inhibitor, pertussis toxin (2 mu g/ml, 3 h), and an adenylyl cyclase inh ibitor, dideoxy-adenosine (10 mu M).