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(Circulation Research. 2008;103:1100.)
© 2008 American Heart Association, Inc.

Integrative Physiology

Adenosine 5'-Tetraphosphate Is a Highly Potent Purinergic Endothelium-Derived Vasoconstrictor

Markus Tölle, Vera Jankowski, Mirjam Schuchardt, Annette Wiedon, Tao Huang, Franziska Hub, Joanna Kowalska, Jacek Jemielity, Andrzej Guranowski, Christoph Loddenkemper, Walter Zidek, Joachim Jankowski, Markus van der Giet

From the Medizinische Klinik IV–Nephrology (M.T., V.J., M.S., A.W., T.H., F.H., W.Z., J. Jankowski, M.v.d.G.) and Insitut für Pathologie (C.L.), Charite–Campus Benjamin Franklin, Berlin, Germany; Department of Biophysics (J.K., J. Jemielity), Institute of Experimental Physics, Warsaw University, Poland; and Department of Biochemistry and Biotechnology (A.G.), University of Life in Sciences Pozna, Poland.

Correspondence to Prof Dr Markus van der Giet, Charité–Campus Benjamin Franklin, Med. Klinik IV–Nephrology, Hindenburgdamm 30, 12203 Berlin, Germany. E-mail markus.vandergiet{at}charite.de

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.

Key Words: purinoceptors • P2X • adenosine 5'-tetraphosphate • endothelium-derived contracting factor

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