Stimulators of adenylate cyclase (forskolin, adenosine, and isoprenaline) amplified bradykinin- and ATP-induced biosynthesis and release of EDRF in pig aortic endothelial cells.
Increases in endothelial cyclic AMP levels amplify agonist-induced EDRF formation by modulating calcium signaling, suggesting a joint regulation mechanism by tissue factors.
The interaction between intracellular cyclic AMP and agonist-induced endothelium-derived relaxing factor (EDRF) (NO) formation was investigated in pig aortic endothelial cells. Three potent stimulators of adenylate cyclase, namely forskolin, adenosine and isoprenaline, amplified bradykinin- and ATP-induced biosynthesis and release of EDRF. None of the substances by itself affected basal EDRF formation. The effects of forskolin, adenosine and isoprenaline corresponded to an enhanced agonist-induced rise in intracellular free Ca2+ concentration (Ca2+i), were mimicked by the membrane-permeable cyclic AMP analogue dibutyryl cyclic AMP and were antagonized by the protein kinase inhibitor N-2-(methylamino)ethyl-5-isoquinolinesulphonamide dihydrochloride (H-8). Our data suggest that cyclic AMP-dependent phosphorylation modulates Ca(2+)-signalling and thus the function of endothelial cells. This mechanism may be of particular physiological importance, since it allows a joint regulation of endothelial functions by tissues factors such as bradykinin, which directly affects Ca2+i and agonists which affect intracellular cyclic AMP levels.
Graier et al. (1992) studied this question. Stimulators of adenylate cyclase (forskolin, adenosine, isoprenaline) vs. Basal state was evaluated on Agonist-induced biosynthesis and release of EDRF and intracellular free Ca2+ concentration. Stimulators of adenylate cyclase (forskolin, adenosine, and isoprenaline) amplified bradykinin- and ATP-induced biosynthesis and release of EDRF in pig aortic endothelial cells.