Selective up-regulation of phosphodiesterase-4 cyclic adenosine 3 ',5 '-monophosphate (cAMP)-specific phosphodiesterase variants by elevated cAMP content in human myometrial cells in culture

In human myometrium, the modulation of intracellular cAMP content resulting from agonist-mediated stimulation of the receptor-adenylyl cyclase complex is largely influenced by the rate of cAMP hydrolysis by phosphodiesterase (PDE) isoenzymes. We have previously shown that the PDE4 family contributes to the predominant cAMP-hydrolyzing activity in human myometrium and that elevation of the PDE4B2 messenger RNA steady state level occurs in pregnant myometrial tissue. In the present study, we used a model of human myometrial cells in culture to determine whether an elevated cAMP concentration could influence PDE exp ression. As in myometrial tissue, high levels of PDE4 activity were detecte d in these smooth muscle cells. Long term treatment with 8-bromo-cAMP or fo rskolin resulted in a selective induction of PDE4B and of PDE4D short form messenger RNA variants. Concurrently, an increased immunoreactive signal fo r the PDE4B- and PDE4D-related isoenzymes was detected. This induction was consistent with an observed significant up-regulation of PDE4 activity. Accordingly, our results demonstrate that in human cultured myometrial cell s, cAMP-elevating agents manipulate PDE4 activity through selective inducti on of synthesis of PDE4B and PDE4D short forms. Such a mechanism might have physiological importance during pregnancy by dampening hormonal stimulatio n and could thereby be involved in tolerance to the tocolytic effect of bet a-adrenoceptor agonists.