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 interactions, and the existence of membrane receptors in several tissues, support the hypothesis of nongenomic action of steroids. The androgens, 5alpha- and 5beta-dihydrotestosterone (0.1 to 100 microM), induce a rapid positive inotropism in the isolated left atrium of male Wistar rats whose time course of response might suggest that it is a non-genomic effect. However, the fact that the facilitation of contractility was inhibited by actinomycin D (5 microg/ml) and cycloheximide (10 microg/ml) indicates that a transcriptional component might play a role. The existence of a rapid functional genomic role would be somewhat surprising. However, rapid transcriptional mechanisms were also observed in certain cAMP-dependent responses. In the left atrium of rat, Rp-cAMPS (10 microM), a cAMP-dependent protein kinase inhibitor, antagonized 5alpha- but not 5beta-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 inhibited by actinomycin D and cycloheximide, suggest that a cAMP-dependent transcriptional component may be partly involved in the positive inotropism induced by 5alpha-dihydrotestosterone. In addition, 5alpha-dihydrotestosterone might increase the basal adenylyl cyclase activity by acting on unoccupied beta-adrenoceptor-G-protein-adenylyl cyclase complexes, since the elicited inotropism was inhibited by a beta-blocker, atenolol (1 microM), a G-protein inhibitor, pertussis toxin (2 microg/ml, 3 h), and an adenylyl cyclase inhibitor, dideoxy-adenosine (10 microM).
Rubín
J M
JM
Servicio de Cardiología, Hospital Central Asturias, Oviedo, Spain.
Hidalgo
A
A
Bordallo
C
C
Cantabrana
B
B
Sánchez
M
M
D037361:Adenylate Cyclase Toxin; D000818:Animals; D001262:Atenolol / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D003513:Cycloheximide / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D016048:Dideoxyadenosine / Q000494:pharmacology; D013196:Dihydrotestosterone / Q000494:pharmacology*; D004558:Electric Stimulation; D015870:Gene Expression / Q000187:drug effects; D006325:Heart Atria / Q000187:drug effects* / Q000378:metabolism*; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D037342:Pertussis Toxin; D051381:Rats; D017208:Rats, Wistar; D012110:Reserpine / Q000494:pharmacology; D013268:Stimulation, Chemical; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D037361:Adenylate Cyclase Toxin; D010566:Virulence Factors, Bordetella; D013196:Dihydrotestosterone; D003609:Dactinomycin; D016048:Dideoxyadenosine; D001262:Atenolol; D012110:Reserpine; D003513:Cycloheximide; D000242:Cyclic AMP; D037342:Pertussis Toxin; D007545:Isoproterenol