Adenosine 5'-tetraphosphate is a highly potent purinergic endothelium-derived vasoconstrictor.
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.
Tölle
Markus
M
Medizinische Klinik IV-Nephrology, Charite-Campus Benjamin Franklin, Berlin, Germany.
Jankowski
Vera
V
Schuchardt
Mirjam
M
Wiedon
Annette
A
Huang
Tao
T
Hub
Franziska
F
Kowalska
Joanna
J
Jemielity
Jacek
J
Guranowski
Andrzej
A
Loddenkemper
Christoph
C
Zidek
Walter
W
Jankowski
Joachim
J
van der Giet
Markus
M
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*
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)