Increases in endothelial cyclic AMP levels amplify agonist-induced formation of endothelium-derived relaxing factor (EDRF).
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
W F
WF
Institut für Pharmakologie und Toxikologie, Universität Graz, Austria.
Groschner
K
K
Schmidt
K
K
Kukovetz
W R
WR
D000241:Adenosine / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D001920:Bradykinin / Q000494:pharmacology; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism*; D004988:Ethers, Cyclic / Q000494:pharmacology; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D009599:Nitroprusside / Q000494:pharmacology; D019319:Okadaic Acid; D011494:Protein Kinases / Q000494:pharmacology; D013552:Swine
D004988:Ethers, Cyclic; D007546:Isoquinolines; D009599:Nitroprusside; D005576:Colforsin; D019319:Okadaic Acid; D009569:Nitric Oxide; D000001:Calcimycin; C053177:N-(2-(methylamino)ethyl)-5-isoquinolinesulfonamide; D000255:Adenosine Triphosphate; D000242:Cyclic AMP; D011494:Protein Kinases; D000241:Adenosine; D007545:Isoproterenol; D001920:Bradykinin; D002118:Calcium