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When dinucleoside polyphosphates (dinucleotides) were first identified in organisms, most of the attention was focussed on their intracellular actions. However, since the discovery of the diadenosine polyphosphates Ap3A [17], Ap4A [18], Ap5A and Ap6A [19] in the granules of platelets, investigations have been directed to determine the roles of dinucleotides in modulating cardiovascular parameters. The number of known dinucleotides in the human organism is currently 18, i.e. Ap2A [20, 21], Ap3A [17], Ap4A [18], Ap5A, Ap6A [19], Ap7A [22], Ap2G [21], Ap3G, Ap4G, Ap5G, Ap6G [23], Gp2G [21], Gp3G, Gp4G, Gp5G, Gp6G [23] and Ap4U [24]. All these members of dinucleotides were demonstrated to be released from secretory granules from human adrenal glands [25], platelets [17-19], endothelial cells [24] and heart tissue [20] upon stimulation, yielding physiological relevant concentrations in human plasma [25] thus underlining their role as extracellular signalling molecules of the cardiovascular system. In vascular beds the action of the dinucleotides is dependent on the expression profile of the purinergic receptors on the surface of endothelial cells and vascular smooth muscle cells [26-28]. Dinucleotides with at least one adenosine and with phosphate group numbers of 4, 5 or 6 activate P2X receptor subtypes while dinucleotides with phosphate group numbers smaller than 5 activate P2Y receptors. As a result in the renal vasculature Ap4A, Ap5A, Ap6A and Ap4U act as vasoconstrictors whereas Ap2A and Ap3A induce vasodilations. In the extracellular space a number of different hydrolases [29] convert dinuclotides into mononucleotides thereby not inactivating but changing the action towards the purinergic system. In summary the extracellular signalling system of dinucleotides presents itself as an extremely complex communication system being dependent on the composition and the individual concentrations of the dinucleotides which are released, on the expression profile of purinergic receptors and on the expression profile of dinucleotide-hydrolysing enzymes thus resulting in a huge diversity of signalling patterns.
References:
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19. Schlüter H, Offers E, Bruggemann G, van der Giet M, Tepel M, Nordhoff E, Karas M, Spieker C, Witzel H, Zidek W: Diadenosine phosphates and the physiological control of blood pressure. Nature 1994, 367(6459):186-188.
20. Luo J, Jankowski J, Knobloch M, Van der Giet M, Gardanis K, Russ T, Vahlensieck U, Neumann J, Schmitz W, Tepel M, Deng MC, Zidek W, Schlüter H: Identification and characterization of diadenosine 5',5"'-P1,P2 -diphosphate and diadenosine 5',5"'-P1,P3-triphosphate in human myocardial tissue. Faseb J 1999, 13(6):695-705.
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22. Jankowski J, Tepel M, van der Giet M, Tente IM, Henning L, Junker R, Zidek W, Schlüter H: Identification and characterization of P(1), P(7)-Di(adenosine-5')-heptaphosphate from human platelets. J Biol Chem 1999, 274(34):23926-23931.
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26. Ralevic V, Jankowski J, Schlüter H: Structure-activity relationships of diadenosine polyphosphates (Ap(n)As), adenosine polyphospho guanosines (Ap(n)Gs) and guanosine polyphospho guanosines (Gp(n)Gs) at P2 receptors in the rat mesenteric arterial bed. Br J Pharmacol 2001, 134(5):1073-1083.
27. van der Giet M, Khattab M, Borgel J, Schlüter H, Zidek W: Differential effects of diadenosine phosphates on purinoceptors in the rat isolated perfused kidney. Br J Pharmacol 1997, 120(8):1453-1460.
28. van der Giet M, Schmid A, Jankowski J, Schlüter H, Zidek W, Tepel M: CoenzymeA glutathione disulfide is a potent modulator of angiotensin II-induced vasoconstriction. Am J Hypertens 2001, 14(2):164-168.
29. Zimmermann H: Extracellular metabolism of ATP and other nucleotides. Naunyn Schmiedebergs Arch Pharmacol 2000, 362(4-5):299-309.
