Differential effects of uridine adenosine tetraphosphate on purinoceptors in the rat isolated perfused kidney

Charité- Universitätsmedizin Berlin, Medical. Klinik mit Schwerpunkt Nephrologie, Hindenburgdamm 30, 12203 Berlin, Germany.
British Journal of Pharmacology (Impact Factor: 4.84). 10/2010; 161(3):530-40. DOI: 10.1111/j.1476-5381.2010.00914.x
Source: PubMed

ABSTRACT Purinergic signalling plays an important role in vascular tone regulation in humans. We have identified uridine adenosine tetraphosphate (Up(4)A) as a novel and highly potent endothelial-derived contracting factor. Up(4)A induces strong vasoconstrictive effects in the renal vascular system mainly by P2X(1) receptor activation. However, other purinoceptors are also involved and were analysed here.
The rat isolated perfused kidney was used to characterize vasoactive actions of Up(4)A.
After desensitization of the P2X(1) receptor by α,β-methylene ATP (α,β-meATP), Up(4)A showed dose-dependent P2Y(2)-mediated vasoconstriction. Continuous perfusion with Up(4)A evoked a biphasic vasoconstrictor effect: there was a strong and rapidly desensitizing vasoconstriction, inhibited by P2X(1) receptor desensitization. In addition, there is a long-lasting P2Y(2)-mediated vasoconstriction. This vasoconstriction could be blocked by suramin, but not by PPADS or reactive blue 2. In preparations of the rat isolated perfused kidney model with an elevated vascular tone, bolus application of Up(4)A showed a dose-dependent vasoconstriction that was followed by a dose-dependent vasodilation. The vasoconstriction was in part sensitive to P2X(1) receptor desensitization by α,β-meATP, and the remaining P2Y(2)-mediated vasoconstriction was only inhibited by suramin. The Up(4)A-induced vasodilation depended on activation of nitric oxide synthases, and was mediated by P2Y(1) and P2Y(2) receptor activation.
Up(4)A activated P2X(1) and P2Y(2) receptors to act as a vasoconstrictor, whereas endothelium-dependent vasodilation was induced by P2Y(1/2) receptor activation. Up(4)A might be of relevance in the physiology and pathophysiology of vascular tone regulation.

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Available from: Markus Toelle, Aug 06, 2014
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    • "Jankowski et al. [14] observed that in rat isolated perfused kidney, Up4A stimulated vasoconstriction mainly via P2X1 receptors and probably also via P2Y2 and P2Y4 receptors. Very recently, findings from this same group indicate that in the rat perfused kidney, in addition to smooth muscle P2X1 receptor-mediated vasoconstriction, Up4A showed concentration-dependent P2Y2 receptor-mediated, long-lasting vasoconstriction [37]. Moreover, they demonstrated that Up4A-induced vasoconstriction was followed by vasodilation mediated by P2Y1 and P2Y2 receptor activation on endothelial cells leading to the release of NO [37]. "
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    ABSTRACT: The endothelium plays a pivotal role in vascular homeostasis, and endothelial dysfunction is a major feature of cardiovascular diseases, such as arterial hypertension, atherosclerosis, and diabetes. Recently, uridine adenosine tetraphosphate (Up(4)A) has been identified as a novel and potent endothelium-derived contracting factor (EDCF). Up(4)A structurally contains both purine and pyrimidine moieties, which activate purinergic receptors. There is an accumulating body of evidence to show that Up(4)A modulates vascular function by actions on endothelial and smooth muscle cells. In this paper, we discuss the effects of Up(4)A on vascular function and a potential role for Up(4)A in cardiovascular diseases.
    Advances in Pharmacological Sciences 11/2011; 2011(21, supplement 1):435132. DOI:10.1155/2011/435132
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    ABSTRACT: In this Commentary, the roles of uridine adenosine tetraphosphate as an endothelium-derived contracting or relaxing factor described in the paper by Tölle et al. are considered and put into the wider context of the mechanisms of control of vascular tone by purinergic signalling via receptors located on both smooth muscle and endothelial cells.
    British Journal of Pharmacology 10/2010; 161(3):527-9. DOI:10.1111/j.1476-5381.2010.00937.x · 4.84 Impact Factor
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    ABSTRACT: It is very well established that purinergic signaling plays a relevant role in vascular physiology and pathophysiology. Recently, a new purinoceptor agonist uridine adenosine tetraphosphate (Up(4)A) has been identified as a highly potent endothelial-derived contracting factor (EDCF). The purpose of the study was to investigate Up(4)A's influence on pro-inflammatory mechanisms. An early component of the inflammatory response in atherogenesis is the oxidative stress-induced formation of monocyte chemoattractant protein-1 (MCP-1). Here, we investigated the influence of Up(4)A on MCP-1 formation and characterized the underlying signaling transduction mechanisms in rat vascular smooth muscle cells (VSMCs). Up(4)A induced MCP-1 expression and secretion in VSMCs via the activation of P2Y(2) in a concentration-dependent manner. MCP-1 formation depends on generation of reactive oxygen species (ROS). To determine whether the predominant source of ROS in the vasculature, the NAD(P)H oxidase (Nox), is involved, we used different approaches. The ROS scavenger, tiron, the Nox inhibitor, apocynin and diphenyl-iodonium, as well as Nox1 knockdown, diminished the Up(4)A-induced MCP-1 formation. Rac1 activation and p47(phox) translocation from cytosol to the plasma membrane-both required for assembling and activation of Nox, were stimulated by Up(4)A. ERK1/2 and p38 activation is essential for the intracellular signal transduction. In summary, Up(4)A induced Nox1-dependent ROS generation, which further stimulated MCP-1 formation via MAPK phosphorylation in VSMCs. This process requires the activation of the G-protein coupled receptor P2Y(2). Therefore, Up(4)A is not only a potent EDCF but also a potent inductor of pro-inflammatory response in the vascular wall.
    Journal of Molecular Medicine 04/2011; 89(8):799-810. DOI:10.1007/s00109-011-0750-6 · 5.11 Impact Factor
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