December 1, 1992Biochemical Journal57 citationsOpen Access
Increases in endothelial cyclic AMP levels amplify agonist-induced formation of endothelium-derived relaxing factor (EDRF)
Key Result
Stimulators of adenylate cyclase (forskolin, adenosine, and isoprenaline) amplified bradykinin- and ATP-induced biosynthesis and release of EDRF in pig aortic endothelial cells.
Structured PICO
P
Population
Pig aortic endothelial cells
I
Intervention
Stimulators of adenylate cyclase (forskolin, adenosine, isoprenaline) and dibutyryl cyclic AMP
C
Comparator
Basal conditions (absence of stimulators)
O
Outcome
Agonist-induced formation and release of endothelium-derived relaxing factor (EDRF/NO) and intracellular free Ca2+ concentrationsurrogate
Increases in endothelial cyclic AMP levels amplify agonist-induced EDRF formation by modulating calcium signaling, suggesting a joint regulation mechanism by tissue factors.
Abstract
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.