P1,P4‐diadenosine 5′ tetraphosphate induces nitric oxide release from bovine aortic endothelial cells

Hilderman, Richard H.; Christensen, Eric F

doi:10.1016/s0014-5793(98)00454-2

Cited by 29 publications

(33 citation statements)

References 37 publications

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“…As previously shown, cAMP-mediated reduction in TM cell volume (Srinivas et al, 2004) could increase outflow facility. Finally, since activation of the NO/cGMP pathway has also been involved in aqueous outflow facilitation (Kee et al, 1994), we cannot rule out the possibility that Ap n As may induce NO release in TM cells as reported in other cell types (Hilderman and Christensen, 1998). The finding that selective (2-MeSADP) and nonselective (Ap 3 A and Ap 4 A) P2Y 1 agonists increase outflow facility together with the lack of effect observed by the P2Y 2 /P2Y 4 agonist (Up 4 U) leads us to propose P2Y 1 as a specific receptor linked to an increase in TM permeability.…”

Section: Dinucleotide Effects In Aqueous Humormentioning

confidence: 87%

Effects of Dinucleoside Polyphosphates on Trabecular Meshwork Cells and Aqueous Humor Outflow Facility

Soto¹,

Pintor²,

Peral³

et al. 2005

J Pharmacol Exp Ther

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The most important risk factor for the development of glaucoma is elevated intraocular pressure (IOP). Hypotensive drugs decrease IOP, preventing optic nerve damage and further vision loss. The balance between aqueous humor (AH) production and drainage determines IOP, and problems in AH outflow pathways are associated with open-angle glaucoma development. Previous studies have shown the presence of diadenosine tetraphosphate (Ap 4 A) and pentaphosphate (Ap 5 A) in the AH. Topic application of Ap 4 A to the cornea decreased IOP, whereas Ap 5 A increased it. Because dinucleoside polyphosphates stimulate P2Y purinergic receptors, we studied their presence in trabecular meshwork (TM) cells. Additionally, the effects of diadenosine polyphosphates (Ap n As; n ϭ 3-5) and Up 4 U (P 1 ,P 4 -(diuridine 5Ј)-tetraphosphate; INS365) in outflow facility were tested. P2Y 1 , P2Y 2 , and P2Y 4 receptors were detected in TM cells by Western blot and immunocytochemistry. In TM cells, Ap 3 A, Ap 4 A, and Ap 5 A induced discrete intracellular calcium concentration ([Ca 2ϩ ] i ) mobilizations compared with higher and more sustained [Ca 2ϩ ] i mobilizations after Up 4 U application. In bovine ocular anterior segments perfused at constant pressure, 1 M Ap 3 A or Ap 4 A increased outflow facility, whereas Up 4 U or Ap 5 A did not modify it. 2-MeSADP, a selective P2Y 1 agonist, induced outflow facility increases similar to those obtained after Ap 3 A and Ap 4 A, and these were prevented by addition of the selective P2Y 1 receptor antagonist MRS-2179 (2Ј-deoxy-N 6 -methyladenosine-3Ј,5Ј-diphosphate). Our results demonstrate that the hypotensive effect of Ap 4 A and other dinucleotides is mediated, at least in part, by increasing trabecular outflow facility through activation of P2Y 1 receptors. The latter would seem to be an interesting target in the development of antiglaucomatous drugs to selectively increase AH outflow.In the eye, elevated intraocular pressure (IOP) due to impaired aqueous humor (AH) drainage is a major risk factor in the development of glaucoma. Glaucoma is the most important cause of irreversible nontraumatic blindness in the world and affects more than 66 million people. The main determinant of IOP is the volume of AH contained in the anterior and posterior chambers. AH is produced in the ciliary epithelium and eliminated through the outflow pathways in the anterior chamber angle. In several species, but especially in the primate eye, most AH flows through the trabecular meshwork (TM), a sponge-like filtering tissue, where it reaches Schlemm's canal and the collector channels before finally entering the venous system. The structure of the TM and its ability to modify its resistance to AH outflow play a key role in maintaining the IOP in the anterior chamber within its physiological range. TM cells express several receptors to substances released either in the AH from different ocular tissues (Mitchell et al., 1998;Coca-Prados et al., 1999) or from ocular innervation (Selbach et al., 2000) in physiologic...

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Section: Dinucleotide Effects In Aqueous Humormentioning

confidence: 87%

Effects of Dinucleoside Polyphosphates on Trabecular Meshwork Cells and Aqueous Humor Outflow Facility

Soto¹,

Pintor²,

Peral³

et al. 2005

J Pharmacol Exp Ther

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“…This is however consistent with our findings on the human cell line ECV304 [15]where Ap 4 A, Ap 5 A and Ap 6 A were inactive at the P2Y receptors but where Ap 3 A was recognized with an equal affinity to ADP at the P2Y 1 receptor. However, cultured endothelial cells from both bovine and rat aorta are sensitive to Ap 4 A, generating increases in [Ca 2+ ] c and nitric oxide [30, 31]. In rat hepatocytes [Ca 2+ ] c transients mediated by Ap 4 A and Ap 3 A have been linked to natively expressed P2Y 1 and P2Y 2 receptors [32, 33].…”

Section: Discussionmentioning

confidence: 99%

Diadenosine Polyphosphates Are Largely Ineffective as Agonists at Natively Expressed P2Y1 and P2Y2 Receptors on Cultured Human Saphenous Vein Endothelial Cells

et al. 2000

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The diadenosine polyphosphates are a group of long-lasting compounds, released into the bloodstream by platelet degranulation. They mediate endothelium-dependent vasodilatation in several animal vascular systems via P2Y receptors coupled to increases in cytoplasmic calcium ([Ca²⁺]_c). However, there is little evidence of diadenosine-mediated vasodilatation in the human vasculature, and a direct interaction with natively expressed P2Y receptors on human endothelium has not been demonstrated. We have therefore studied the effects of diadenosines on primary cultures of human saphenous vein endothelial cells (HSVECs) and related this to the expression of P2Y receptors. HSVECs were loaded with the calcium-sensitive dye fura-2, and nucleotide-stimulated [Ca²⁺]_c responses were recorded. HSVECs responded to 10 µM UTP, ATP and 2-methylthio-ATP but not to UDP. Consistent with the recorded [Ca²⁺]_c responses, RT-PCR analysis of HSVEC RNA amplified specific products for the P2Y₁ and P2Y₂ receptors but not the P2Y₄ and P2Y₆ receptors. HSVECs responded to Ap₃A with a rise in [Ca²⁺]_c, but none of the other diadenosines tested elicited a response. Therefore natively expressed human P2Y₁ and P2Y₂ receptors are insensitive to diadenosine polyphosphates with the exception of Ap₃A. We would therefore predict that the diadenosine polyphosphates have only a limited vasodilatory role in human saphenous veins.

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“…These studies suggest that two adenosines are required for binding to this receptor. Since ATP is rapidly hydrolysed by BAECs [Hilderman and Christensen, 1998], synthetic ATP analogues were used to determine whether ATP interacted with the Ap 4 A receptor. These synthetic ATP agonists and antagonists do not interact with the Ap 4 A receptor [Campbell et al, 1999].…”

Section: A Specific Diadenosine Polyphosphate Receptormentioning

confidence: 99%

“…This increase in cytosolic [Ca 2+ ] i appears to trigger the synthesis of nitric oxide (NO) and prostacyclin (PGI 2 ) [Hilderman and Christensen, 1998;Haghiac et al, 2000]. On the other hand, Ap 3 A, Ap 5 A, and Ap 6 A did not induce the synthesis of NO or PGI 2 above basal level [Hilderman and Christensen, 1998;Haghiac et al, 2000]. The ability of Ap 4 A and Ap 2 A to induce the synthesis of both NO and PGI 2 is consistent with their ability to interact with the Ap 4 A receptor.…”

Section: A Specific Diadenosine Polyphosphate Receptormentioning

confidence: 99%

Diadenosine polyphosphates as extracellular signal molecules

Hoyle

Hilderman

Pintor

et al. 2001

Drug Development Research

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Dinucleoside polyphosphates are an interesting group of signalling molecules that control numerous physiological functions. Diadenosine compounds, with a backbone of anything from two to seven phosphates, are known to occur naturally. Some of them have been isolated from cerebral nerve terminals and, acting via nucleoside (P1), nucleotide (P2), or dinucleotide receptors, can affect central nervous system function. Many of them have been isolated from human blood platelet secretory granules and are potentially involved in haemostatic mechanisms and peripheral control of vascular tone. Many visceral organs respond to the application of adenine dinucleotides and, although they act on receptors in the periphery that can be mainly defined as either P1 or P2, evidence is now accumulating for discrete dinucleotide receptors. In the periphery, adenine dinucleotides can be potent agonists, with diverse functions, causing contraction or relaxation of smooth muscle. Many P2X receptor proteins and P2Y receptors have been cloned and adenine dinucleotides have a variable pharmacological profile at these receptors and may be useful tools for characterising subtypes of P2X and P2Y receptors. This review provides a broad description of the many extracellular roles of diadenosine polyphosphates as emerging, yet increasingly important, natural ligands for a plethora of structurally diverse mononucleotide and dinucleotide receptors. Drug Dev. Res. 52:260-273, 2001.

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P¹,P⁴‐diadenosine 5′ tetraphosphate induces nitric oxide release from bovine aortic endothelial cells

Cited by 29 publications

References 37 publications

Effects of Dinucleoside Polyphosphates on Trabecular Meshwork Cells and Aqueous Humor Outflow Facility

Effects of Dinucleoside Polyphosphates on Trabecular Meshwork Cells and Aqueous Humor Outflow Facility

Diadenosine Polyphosphates Are Largely Ineffective as Agonists at Natively Expressed P2Y<sub>1</sub> and P2Y<sub>2</sub> Receptors on Cultured Human Saphenous Vein Endothelial Cells

Diadenosine polyphosphates as extracellular signal molecules

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