Uridine adenosine tetraphosphate: a novel endothelium- derived vasoconstrictive factor.
Beyond 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 (EDCFs) remains unclear. The supernatant obtained from mechanically stimulated human endothelial cells obtained from dermal vessels elicited a vasoconstrictive response in an isolated perfused rat kidney. A purinoceptor blocker had a greater effect than an endothelin receptor blocker in decreasing endothelially derived vasoconstriction in the isolated perfused rat kidney. The nucleotide uridine adenosine tetraphosphate (Up(4)A) was isolated from the supernatant of stimulated human endothelium and identified by mass spectrometry. Up(4)A is likely to exert vasoconstriction predominantly through P2X1 receptors, and probably also through P2Y2 and P2Y4 receptors. Plasma concentrations of Up(4)A that cause vasoconstriction are found in healthy subjects. Stimulation with adenosine 5'-triphosphate (ATP), uridine 5'-triphosphate (UTP), acetylcholine, endothelin, A23187 and mechanical stress releases Up(4)A from endothelium, suggesting that Up(4)A contributes to vascular autoregulation. To our knowledge, Up(4)A is the first dinucleotide isolated from living organisms that contains both purine and pyrimidine moieties. We conclude that Up(4)A is a novel potent nonpeptidic EDCF. Its vasoactive effects, plasma concentrations and its release upon endothelial stimulation strongly suggest that Up(4)A has a functional vasoregulatory role.
Jankowski
Vera
V
Charité-Universitaetsmedizin Berlin, Campus Benjamin Franklin, Medizinische Klinik IV, Hindenburgdamm 30, D-12200 Berlin, Germany.
Tölle
Markus
M
Vanholder
Raymond
R
Schönfelder
Gilbert
G
van der Giet
Markus
M
Henning
Lars
L
Schlüter
Hartmut
H
Paul
Martin
M
Zidek
Walter
W
Jankowski
Joachim
J
D000227:Adenine Nucleotides / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D013058:Mass Spectrometry; D008970:Molecular Weight; D051381:Rats; D014500:Uracil Nucleotides / Q000737:chemistry / Q000378:metabolism*; D014662:Vasoconstrictor Agents / Q000737:chemistry / Q000378:metabolism*
D000227:Adenine Nucleotides; D014500:Uracil Nucleotides; D014662:Vasoconstrictor Agents