Enhancement of endothelial cAMP accumulation by adenine nucleotides: role of methylxanthine-sensitive sites.
ATP is a well-known inducer of prostacyclin and nitric oxide release from vascular endothelial cells. These responses are mediated by P2 receptors coupled to a phospholipase C. We have investigated the influence of ATP on the control of adenosine 3',5'-cyclic monophosphate (cAMP) in bovine aortic endothelial cells. ATP produced a slight increase in the cAMP content of unstimulated endothelial cells. A more impressive response to ATP (5-fold) was observed in forskolin-stimulated cells. The rank orders of potency of various ATP analogues were strikingly different for the increase in cAMP and the accumulation of inositol phosphates. The action of ATP was unaffected by indomethacin. Protein kinase C downregulation produced only a partial inhibition of the ATP response. The effect of phorbol 12-myristate 13-acetate and bradykinin on the forskolin-induced accumulation of cAMP was much smaller than that of ATP. Neither adenosine deaminase nor AMP deaminase decreased the response to ATP, which thus cannot result from the ATP degradation into adenosine. However, 8-(p-sulfophenyl)theophylline inhibited the responses to both ATP and adenosine. In conclusion, ATP enhances the accumulation of cAMP in endothelial cells. This action appears to be the sum of two components: a minor one resulting from kinase C activation and a major one mediated either by a direct interaction of ATP with A2 receptors, or by putative methylxanthine-sensitive P2 receptors.
Institute of Interdisciplinary Research School of Medicine, Université Libre de Bruxelles, Belgium.
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Côte
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Van Sande
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Boeynaems
D000227:Adenine Nucleotides / Q000494:pharmacology*; D000241:Adenosine / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism*; D009994:Osmolar Concentration; D011453:Prostaglandins / Q000502:physiology; D011493:Protein Kinase C / Q000502:physiology; D013997:Time Factors; D014970:Xanthines / Q000494:pharmacology*
D000227:Adenine Nucleotides; D011453:Prostaglandins; D014970:Xanthines; D005576:Colforsin; C008514:methylxanthine; D000255:Adenosine Triphosphate; D000242:Cyclic AMP; D011493:Protein Kinase C; D000241:Adenosine