Role of genomic mechanisms on cAMP-dependent positive inotropism in isolated left atrium of rat.
It is well known that beta-adrenoceptor stimulation induces positive inotropism by cAMP-dependent phosphorylation of cardiac calcium channels. Furthermore, hypertrophy of different tissues including the heart have been related to the stimulation of these adrenoceptors via mechanisms coupled to activation of transcription and protein synthesis. Early effects of isoproterenol mediated via this pathway has also been associated to the stimulation of beta-adrenoceptors. However, the effects on the inotropism through genomic mechanisms have not yet been described. Isoproterenol (3 nM to 3 microM) induced a concentration-dependent positive inotropism, in isolated left atrium of male Wistar rats electrically stimulated (0.5 Hz, 5 ms, 30-50% above the threshold voltage), which was antagonized by atenolol (1 microM) and inhibited by a protein kinase A inhibitor, (R)p-cAMPS (10 microM). The inhibitor of transcription, actinomycin D (4 microM), and the protein synthesis inhibitor, cycloheximide (35.5 microM), significantly decreased the positive inotropism induced by isoproterenol. Forskolin (0.1 to 3 microM), an activator of adenylyl cyclase, induced a concentration-dependent positive inotropism which was also inhibited by (R)p-cAMPS, actinomycin D and cycloheximide. In the left atrium of rat, isoproterenol induced a positive inotropism which seems, at least in part, dependent upon intact transcription and protein synthesis, as suggested by the fact that the response was inhibited by the incubation with actinomycin D and cycloheximide. In addition, this genomic effect seems to be mediated by a cAMP-dependent mechanism. As it was inhibited by a protein kinase A inhibitor ((R)p-cAMPS) and similarly to isoproterenol, the positive inotropism induced by forskolin, which increases cytosolic cAMP, was also inhibited by actinomycin D and cycloheximide.
Rubín
J M
JM
Departamento de Medicina, Facultad de Medicina, Oviedo, Spain.
Hidalgo
A
A
García de Boto
M J
MJ
Sánchez
M
M
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D016275:Atrial Function; D016279:Atrial Function, Left / Q000235:genetics*; D000242:Cyclic AMP / Q000502:physiology; D003513:Cycloheximide / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D004558:Electric Stimulation; D005786:Gene Expression Regulation / Q000502:physiology*; D016678:Genome; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009124:Muscle Proteins / Q000096:biosynthesis* / Q000235:genetics*; D009200:Myocardial Contraction / Q000235:genetics*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D014158:Transcription, Genetic / Q000187:drug effects
D000318:Adrenergic beta-Agonists; D009124:Muscle Proteins; D011500:Protein Synthesis Inhibitors; D011943:Receptors, Adrenergic, beta; D003609:Dactinomycin; D003513:Cycloheximide; D000242:Cyclic AMP; D007545:Isoproterenol