title: Adenosine 5'-tetraphosphate is a highly potent purinergic endothelium-derived vasoconstrictor.
abstract: Besides serving as a mechanical barrier, the endothelium has important regulatory functions. The discovery of nitric oxide revolutionized our understanding of vasoregulation. In contrast, the identity of endothelium-derived vasoconstrictive factors still remains uncertain. The supernatant from mechanically stimulated human microvascular endothelial cells elicited a potent vasoconstrictive response in the isolated perfused rat kidney. Whereas a nonselective purinoceptor blocker blocked this vasoactivity most potently, the inhibition of the endothelin receptor by BQ123 weakly affected that vasoconstrictive response. As a compound responsible for that vasoconstrictive effect, we have isolated from HMECs and identified the mononucleotide adenosine 5'-tetraphosphate (AP4). This nucleotide proved to be the most potent vasoactive purinergic mediator identified to date, exerting the vasoconstriction predominantly through activation of the P2X1 receptor. The intraarterial application of AP4 in a Wistar-Kyoto rat induced a strong increase of the mean arterial pressure. The plasma concentration of AP4 is in the nanomolar range, which, in vivo, induces a significant change in the mean arterial pressure. To our knowledge, AP4, which exerts vasoactive effects, is the most potent endogenous mononucleotide identified to date in mammals. The effects of AP4, the plasma concentration of AP4, and its release suggest that this compound functions as an important vasoregulator.
authors.affiliation: Medizinische Klinik IV-Nephrology, Charite-Campus Benjamin Franklin, Berlin, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Tölle
authors.forename: Vera
authors.initials: V
authors.lastname: Jankowski
authors.forename: Mirjam
authors.initials: M
authors.lastname: Schuchardt
authors.forename: Annette
authors.initials: A
authors.lastname: Wiedon
authors.forename: Tao
authors.initials: T
authors.lastname: Huang
authors.forename: Franziska
authors.initials: F
authors.lastname: Hub
authors.forename: Joanna
authors.initials: J
authors.lastname: Kowalska
authors.forename: Jacek
authors.initials: J
authors.lastname: Jemielity
authors.forename: Andrzej
authors.initials: A
authors.lastname: Guranowski
authors.forename: Christoph
authors.initials: C
authors.lastname: Loddenkemper
authors.forename: Walter
authors.initials: W
authors.lastname: Zidek
authors.forename: Joachim
authors.initials: J
authors.lastname: Jankowski
authors.forename: Markus
authors.initials: M
authors.lastname: van der Giet
mesh_terms: D000227:Adenine Nucleotides / Q000097:blood / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D007668:Kidney / Q000098:blood supply / Q000378:metabolism; D010456:Peptides, Cyclic / Q000494:pharmacology; D058910:Purinergic P2 Receptor Agonists; D051381:Rats; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D058469:Receptors, Purinergic P2X; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000097:blood / Q000494:pharmacology*
chemical_list: D000227:Adenine Nucleotides; D000959:Antihypertensive Agents; D010456:Peptides, Cyclic; D058910:Purinergic P2 Receptor Agonists; D018048:Receptors, Purinergic P2; D058469:Receptors, Purinergic P2X; D014662:Vasoconstrictor Agents; C017991:adenosine 5'-tetraphosphate; C072247:cyclo(Trp-Asp-Pro-Val-Leu)