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 1 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.