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

Tölle, Markus; Schuchardt, Mirjam; Wiedon, Annette; Huang, Tao; Klöckel, Lars; Jankowski, Joachim; Jankowski, Vera; Zidek, Walter; Giet, Markus van der

doi:10.1111/j.1476-5381.2010.00914.x

Cited by 32 publications

(43 citation statements)

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“…Up4A also contracts rat and human airways (6) and rat gastric smooth muscles (7). Pharmacological studies suggest that Up4A causes vasoconstriction via activation of P2X1, P2Y2, and P2Y4 receptors (1) and endothelium-dependent vasodilatation via activation of P2Y1 and P2Y2 receptors (8). In porcine coronary artery Up4A causes vasodilatation via adenosine (P1) receptors (9).…”

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confidence: 99%

Uridine adenosine tetraphosphate is a novel neurogenic P2Y1 receptor activator in the gut

Durnin

Hwang

Kurahashi

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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confidence: 99%

Uridine adenosine tetraphosphate is a novel neurogenic P2Y1 receptor activator in the gut

Durnin

Hwang

Kurahashi

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…1C) (43)(44)(45)(46). Indeed, Up 4 A-induced NO-dependent relaxation has been observed in rat aorta (41) and in rat perfused kidney (58). To mask any putative NO component in Up 4 A-induced contraction in the RA and PA, we used a representative NOS inhibitor.…”

Section: Resultsmentioning

confidence: 99%

“…Although Up 4 A has been characterized as a potent constrictor in rat aorta (41), rat pulmonary arteries (23), rat perfused kidney (35,58), mouse aorta (24), and mouse renal afferent arterioles (34), there are no studies on its vascular effects in vessels from animals with vascular disease. The present study is the first to show enhancement of Up 4 A-induced contraction in RA in a salt-dependent model of hypertension, the DOCA-salt rats.…”

Section: Discussionmentioning

confidence: 99%

“…More recently, findings from this same group indicate that in the rat isolated perfused kidney, in addition to smooth muscle P2X 1 receptor-mediated vasoconstriction, Up 4 A showed dose-dependent P2Y 2 receptor-mediated, long-lasting vasoconstriction (58). Furthermore, they demonstrated that vasoconstriction by Up 4 A was followed by vasodilation mediated by P2Y 1 and P2Y 2 receptor activation on endothelial cells leading to the release of nitric oxide (NO) (58). So far, these studies have been carried out only in normal animals, and there is no study to indicate the vascular effects of Up 4 A under pathophysiological conditions, such as arterial hypertension.…”

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confidence: 93%

“…Moreover, Jankowski et al (35) found that in isolated perfused kidney, Up 4 A stimulated vasoconstriction mainly through P2X 1 receptors and probably also through P2Y 2 and P2Y 4 receptors. More recently, findings from this same group indicate that in the rat isolated perfused kidney, in addition to smooth muscle P2X 1 receptor-mediated vasoconstriction, Up 4 A showed dose-dependent P2Y 2 receptor-mediated, long-lasting vasoconstriction (58). Furthermore, they demonstrated that vasoconstriction by Up 4 A was followed by vasodilation mediated by P2Y 1 and P2Y 2 receptor activation on endothelial cells leading to the release of nitric oxide (NO) (58).…”

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Uridine adenosine tetraphosphate-induced contraction is increased in renal but not pulmonary arteries from DOCA-salt hypertensive rats

Matsumoto

Tostes

Webb

2011

American Journal of Physiology-Heart and Circulatory Physiology

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Matsumoto T, Tostes RC, Webb RC. Uridine adenosine tetraphosphate-induced contraction is increased in renal but not pulmonary arteries from DOCA-salt hypertensive rats. Am J Physiol Heart Circ Physiol 301: H409 -H417, 2011. First published May 6, 2011 doi:10.1152/ajpheart.00084.2011.-Uridine adenosine tetraphosphate (Up 4A) was reported as a novel endothelium-derived contracting factor. Up 4A contains both purine and pyrimidine moieties, which activate purinergic (P2)X and P2Y receptors. However, alterations in the vasoconstrictor responses to Up 4A in hypertensive states remain unclear. The present study examined the effects of Up 4A on contraction of isolated renal arteries (RA) and pulmonary arteries (PA) from DOCA-salt rats using isometric tension recording. RA from DOCAsalt rats exhibited increased contraction to Up 4A versus arteries from control uninephrectomized rats in the absence and presence of N Gnitro-L-arginine (nitric oxide synthase inhibitor). On the other hand, the Up 4A-induced contraction in PA was similar between the two groups. Up 4A-induced contraction was inhibited by suramin (nonselective P2 antagonist) but not by diinosine pentaphosphate pentasodium salt hydrate (Ip 5I; P2X1 antagonist) in RA from both groups. Furthermore, 2-thiouridine 5=-triphosphate tetrasodium salt (2-Thio-UTP; P2Y 2 agonist)-, uridine-5=-(␥-thio)-triphosphate trisodium salt (UTP␥S; P2Y 2/P2Y4 agonist)-, and 5-iodouridine-5=-O-diphosphate trisodium salt (MRS 2693; P2Y 6 agonist)-induced contractions were all increased in RA from DOCA-salt rats. Protein expression of P2Y 2-, P2Y4-, and P2Y6 receptors in RA was similar between the two groups. In DOCA-salt RA, the enhanced Up 4A-induced contraction was reduced by PD98059, an ERK pathway inhibitor, and Up 4A-stimulated ERK activation was increased. These data are the first to indicate that Up 4A-induced contraction is enhanced in RA from DOCA-salt rats. Enhanced P2Y receptor signaling and activation of the ERK pathway together represent a likely mechanism mediating the enhanced Up 4A-induced contraction. Up4A might be of relevance in the pathophysiology of vascular tone regulation and renal dysfunction in arterial hypertension. extracellular nucleotide; ERK; purinoceptor EXTRACELLULAR NUCLEOTIDES contribute to the local regulation of vascular tone and play important roles in pathophysiological processes, including hypertension, diabetes, atherosclerosis, and remodeling (7,9,16). In blood vessels, nucleotides, such as ATP and UTP, can be released from platelets or from adventitial nerves and endothelial cells to induce either vasoconstriction or vasodilation through cell surface purinergic (P2) receptors (1,8,15).P2 receptors for nucleotides belong to two major families: ionotropic P2X receptors and metabotropic P2Y receptors (1,8,15). Several reports demonstrated that these purinoceptors are expressed in renal and pulmonary vascular beds (12,25,31,38,52,53), contributing to the physiology of these specialized organ systems (4,22,30). However, the involvement of these pu...

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The endothelium-derived contracting factor uridine adenosine tetraphosphate induces P2Y2-mediated pro-inflammatory signaling by monocyte chemoattractant protein-1 formation

Schuchardt

Prüfer

et al. 2011

J Mol Med

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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.

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

Cited by 32 publications

References 29 publications

Uridine adenosine tetraphosphate is a novel neurogenic P2Y1 receptor activator in the gut

Uridine adenosine tetraphosphate is a novel neurogenic P2Y1 receptor activator in the gut

Uridine adenosine tetraphosphate-induced contraction is increased in renal but not pulmonary arteries from DOCA-salt hypertensive rats

The endothelium-derived contracting factor uridine adenosine tetraphosphate induces P2Y2-mediated pro-inflammatory signaling by monocyte chemoattractant protein-1 formation

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