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 inotro pism by cAMP-dependent phosphorylation of cardiac calcium channels. Further more, hypertrophy of different tissues including the heart have been relate d to the stimulation of these adrenoceptors via mechanisms coupled to activ ation of transcription and protein synthesis. Early effects of isoprotereno l 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 mu M) indu ced 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 mu M) and inhibit ed by a protein kinase A inhibitor, (R)p-cAMPS (10 mu M). The inhibitor of transcription, actinomycin D (4 mu M), and the protein synthesis inhibitor, cycloheximide (35.5 mu M), significantly decreased the positive inotropism induced by isoproterenol. Forskolin (0.1 to 3 mu M), an activator of adeny lyl cyclase, induced a concentration-dependent positive inotropism which wa s also inhibited by (R)p-cAMPS, actinomycin D and cycloheximide. In the lef t atrium of rat, isoproterenol induced a positive inotropism which seems, a t 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 see ms to be mediated by a cAMP-dependent mechanism. As it was inhibited by a p rotein kinase A inhibitor ((R)p-cAMPS) and similarly to isoproterenol, the positive inotropism induced by forskolin, which increases cytosolic cAMP, w as also inhibited by actinomycin D and cycloheximide.