Nature Medicine11, 223 - 227 (2005)
Published online: 23 January 2005; | doi:10.1038/nm1188
Uridine adenosine tetraphosphate: a novel endothelium- derived vasoconstrictive factor
Vera Jankowski1, 4, Markus Tölle1, 4, Raymond Vanholder2, Gilbert Schönfelder3, Markus van der Giet1, Lars Henning1, Hartmut Schlüter1, Martin Paul3, Walter Zidek1
& Joachim Jankowski1
1
Charité-Universitaetsmedizin Berlin, Campus Benjamin Franklin, Medizinische Klinik IV, Hindenburgdamm 30, D-12200 Berlin, Germany.
2
University Hospital, Department of Internal Medicine, Nephrology Section, De Pintelaan 185, B-9000 Gent, Belgium.
3
Charité-Universitaetsmedizin Berlin, Campus Benjamin Franklin, Institute for Clinical Pharmacology and Toxicology, Garystr. 5, D-14195 Berlin, Germany.
Beyond serving as a mechanical barrier, the endothelium has important regulatory functions. The discovery of nitric oxide1 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 (Up4A) was isolated from the supernatant of stimulated human endothelium and identified by mass spectrometry. Up4A is likely to exert vasoconstriction predominantly through P2X1 receptors, and probably also through P2Y2 and P2Y4 receptors. Plasma concentrations of Up4A 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 Up4A from endothelium, suggesting that Up4A contributes to vascular autoregulation. To our knowledge, Up4A is the first dinucleotide isolated from living organisms that contains both purine and pyrimidine moieties. We conclude that Up4A is a novel potent nonpeptidic EDCF. Its vasoactive effects, plasma concentrations and its release upon endothelial stimulation strongly suggest that Up4A has a functional vasoregulatory role.
MORE ARTICLES LIKE THIS
These links to content published by NPG are automatically generated.
