Regulation of the cAMP-elevating effects of isoproterenol and forskolin in cardiac myocytes by treatments that cause increases in cAMP. We have found that elevations in cyclic AMP (cAMP) have long-term effects on both the beta-adrenergic receptor and adenylyl cyclase in cultured chick ventricular myocytes. Pretreatment with isoproterenol for 15 min markedly reduced the cAMP-elevating effect of a subsequent treatment with isoproterenol 18 h later. Responses to isoproterenol were similarly reduced after overnight treatments with forskolin or phosphodiesterase inhibitors. Furthermore, these same treatments also markedly blunted the cAMP-elevating effect of forskolin, a direct activator of adenylyl cyclase. The blunting of the isoproterenol effect was greater than that of the forskolin effect, at least partially because the pretreatments caused a decrease in the number of beta-adrenergic receptors as well as a net decrease in adenylyl cyclase activity. Experiments with a recombinant adenovirus to express luciferase under the control of cAMP responsive elements (CREs) showed that the same treatments elevated cAMP sufficiently to drive the transcription of a gene with CREs in its promoter. The blunting of both the isoproterenol and forskolin responses was blocked by the inhibition of protein synthesis or by infecting cells with a recombinant adenovirus that expresses rabbit muscle cAMP-dependent protein kinase inhibitor (PKI). It is hypothesized that one or more adenylyl cyclase isozymes responsible for the generation of cAMP in the myocytes, along with other proteins previously reported to regulate beta-adrenergic receptors and perhaps adenylyl cyclase, are negatively regulated by cAMP. most likely at the level of gene expression, and that this regulation may have therapeutic consequences in the treatment of cardiac diseases. (C) 2003 Elsevier Science (USA). All rights reserved.