The stable pyrimidines UDPβS and UTPγS discriminate between the P2 receptors that mediate vascular contraction and relaxation of the rat mesenteric artery

Malmsjö, Malin; Adner, Mikael; Harden, T. Kendall; Pendergast, William; Edvinsson, Lars; Erlinge, David

doi:10.1038/sj.bjp.0703536

Cited by 66 publications

(79 citation statements)

References 32 publications

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“…Contractions Fig. 4 Original tracings showing the effects on the spontaneous mechanical activity of the longitudinal muscle of a mouse ileum induced by the P2Y 2 , P2Y 2 / 4 , and P2Y 6 receptor agonists, 2-thio-UTP, UTPγS, and PSB 0474 (10 μM each), respectively generated by UTP and UDP in ileum muscle are identical, indicating that the tissue responds similarly to UTP and UDP, as reported in rat mesenteric and basilar arteries [26,27] or in rat urinary bladder [28].…”

Section: Discussionmentioning

confidence: 83%

Pharmacological characterization of uracil nucleotide-preferring P2Y receptors modulating intestinal motility: a study on mouse ileum

Zizzo

Mastropaolo

Grählert

et al. 2011

Purinergic Signalling

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We investigated the possible modulation of the intestinal contractility by uracil nucleotides (UTP and UDP), using as model the murine small intestine. Contractile activity of a mouse ileum longitudinal muscle was examined in vitro as changes in isometric tension. Transcripts encoding for uracil-sensitive receptors was investigated by RT-PCR. UDP induced muscular contractions, sensitive to PPADS, suramin, or MRS 2578, P2Y 6 receptor antagonist, and mimicked by PSB 0474, P2Y 6 -receptor agonist. UTP induced biphasic effects characterized by an early inhibition of the spontaneous contractile activity followed by muscular contraction. UTP excitatory effects were antagonized by PPADS, suramin, but not by MRS 2578, whilst the inhibitory effects were antagonized by PPADS but not by suramin or MRS 2578. UTPγS, P2Y 2 / 4 receptor agonist but not 2-thio-UTP, P2Y 2 receptor agonist, mimicked UTP effects. The inhibitory effects induced by UTP was abolished by ATP desensitization and increased by extracellular acidification. UDP or UTP responses were insensitive to TTX, atropine, or L-NAME antagonized by U-73122, inhibitor of phospholipase C (PLC) and preserved in the presence of nifedipine or low Ca 2+ solution.

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Section: Discussionmentioning

confidence: 83%

Pharmacological characterization of uracil nucleotide-preferring P2Y receptors modulating intestinal motility: a study on mouse ileum

Zizzo

Mastropaolo

Grählert

et al. 2011

Purinergic Signalling

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“…The vasorelaxant effect to ATPgS was entirely dependent on a functional endothelium and it is therefore likely to act via endothelial cell receptor activation, presumably involving intracellular calcium elevation. Reports of the presence of both P2Y 2 and P2Y 4 receptors on endothelial cells (Malmsjo¨et al, 1998;2000a) may offer an explanation for the biphasic relaxant response. Thus, P2Y 2 receptors could be involved at lower concentrations but P2Y 4 at higher concentrations.…”

Section: H Mistry Et Al Endothelium-dependent Relaxation and Hyperpomentioning

confidence: 99%

Endothelium‐dependent relaxation and endothelial hyperpolarization by P2Y receptor agonists in rat‐isolated mesenteric artery

Mistry¹,

Gitlin²,

Mitchell³

2003

British J Pharmacology

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1 Vasorelaxation and hyperpolarization of endothelial cells by adenosine 5 0 -[b-thio]diphosphate (ADPbS) and adenosine 5 0 -[g-thio]triphosphate (ATPgS) were studied in rat-isolated mesenteric artery. Effects from stimulation of P2X receptors were avoided by desensitization with a,b-methylene adenosine triphosphate. 2 ADPbS caused concentration-and endothelium-dependent relaxations of methoxamineprecontracted small (third generation) and main mesenteric artery. These were inhibited by N o -nitro-L-arginine methyl ester (L-NAME) or a combination of apamin plus charybdotoxin (inhibitors of Ca 2+ -activated K + channels); L-NAME, apamin and charybdotoxin applied together abolished the response. 3 ATPgS induced limited relaxation (35% of methoxamine-induced tone at 10 mM) of small mesenteric artery, which was sensitive to L-NAME or endothelium denudation. However, it almost completely relaxed the main mesenteric artery over an extended concentration range (46 orders of magnitude) in an endothelium-dependent manner. This relaxation was inhibited by either L-NAME or a combination of apamin with charybdotoxin, and abolished by a combination of all the three inhibitors. 4 The P2Y 1 receptor antagonist MRS 2179 (2 0 -deoxy-N 6 -methyladenosine 3 0 ,5 0 -bisphosphate; 0.3 -3 mM) caused parallel rightward shifts of the concentration/relaxation curve to ADPbS (pA 2 ¼ 7.1). However, MRS 2179 did not inhibit, but potentiated, relaxant responses to ATPgS. MRS 2179 did not affect the contractile responses ATPgS in small mesenteric artery; ATPgS did not contract the main mesenteric artery. 5 ADPbS hyperpolarized the endothelium of the main mesenteric artery in a concentrationdependent manner. This was unaffected by L-NAME but antagonized by MRS 2179. ATPgS also hyperpolarized the mesenteric artery endothelium in a concentration-dependent manner but, when ATPgS was applied at 10 mM, its effect was potentiated by MRS 2179 (3 mM). 6 It is concluded that both relaxation and hyperpolarization to ADPbS are mediated by P2Y 1 receptors and that the endothelial hyperpolarization is related to the L-NAME-resistant relaxation. Relaxation to the P2Y 2 agonist ATPgS shows regional variation along the mesenteric vasculature. The mechanisms for potentiation of relaxation and hyperpolarization by ATPgS are unknown, but may indicate interactions between P2Y receptor subtypes.

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“…For example, UTP-γ-S and UDP-β-S are selective agonists for P2Y 2 /P2Y 4 and P2Y 6 receptors, respectively (Malmsjö et al 2000). These thiophosphate derivatives may be prepared using enzymatic methods (Lazarowski et al 1996).…”

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confidence: 99%

Agonists and Antagonists for P2 Receptors

Jacobson

Costanzi

Joshi

et al. 2006

Novartis Foundation Symposia

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Recent work has identified nucleotide agonists selective for P2Y 1 , P2Y 2 and P2Y 6 receptors and nucleotide antagonists selective for P2Y 1 , P2Y 12 and P2X 1 receptors. Selective non-nucleotide antagonists have been reported for P2Y 1 , P2Y 2 , P2Y 6 , P2Y 12 , P2Y 13 , P2X 2/3 /P2X 3 and P2X 7 receptors. For example, the dinucleotide INS 37217 (Up 4 dC) potently activates the P2Y 2 receptor, and the non-nucleotide antagonist A-317491 is selective for P2X 2/3 /P2X 3 receptors. Nucleotide analogues in which the ribose moiety is substituted by a variety of novel ring systems, including conformation-ally locked moieties, have been synthesized as ligands for P2Y receptors. The focus on conformational factors of the ribose-like moiety allows the inclusion of general modifications that lead to enhanced potency and selectivity. At P2Y 1,2,4,11 receptors, there is a preference for the North conformation as indicated with (N)-methanocarba analogues. The P2Y 1 antagonist MRS2500 inhibited ADP-induced human platelet aggregation with an IC 50 of 0.95 nM. MRS2365, an (N)-methanocarba analogue of 2-MeSADP, displayed potency (EC 50 ) of 0.4 nM at the P2Y 1 receptor, with >10 000-fold selectivity in comparison to P2Y 12 and P2Y 13 receptors. At P2Y 6 receptors there is a dramatic preference for the South conformation. Three-dimensional structures of P2Y receptors have been deduced from structure activity relationships (SAR), mutagenesis and modelling studies. Detailed three-dimensional structures of P2X receptors have not yet been proposed. Extracellular purine and pyrimidine nucleotides act as neurotransmitters/modulators . These ubiquitous signalling molecules modulate the function of diverse mammalian cell types and tissues under both normal and pathophysiological conditions. Receptors for extracellular nucleotides have been characterized through medicinal chemical, molecular biological, and pharmacological approaches. The eight subtypes of P2Y receptors, denoted P2Y 1 , P2Y 2 , P2Y 4 , P2Y 6 , P2Y 11 , P2Y 12 , P2Y 13 and P2Y 14 , are all seven transmembrane-spanning (7TM) receptors, which couple to G proteins. The seven P2X receptor subunits (P2X 1 -P2X 7 ) form multimeric ligand-gated ion channels. The distribution of P2Y receptors is broad, and the relevant therapeutic interests include antithrombotic therapy, modulation of the immune system and cardiovascular system, and treatment of cystic fibrosis and other pulmonary diseases (Yerxa et al 2002). Several of the

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The stable pyrimidines UDPβS and UTPγS discriminate between the P2 receptors that mediate vascular contraction and relaxation of the rat mesenteric artery

Cited by 66 publications

References 32 publications

Pharmacological characterization of uracil nucleotide-preferring P2Y receptors modulating intestinal motility: a study on mouse ileum

Pharmacological characterization of uracil nucleotide-preferring P2Y receptors modulating intestinal motility: a study on mouse ileum

Endothelium‐dependent relaxation and endothelial hyperpolarization by P2Y receptor agonists in rat‐isolated mesenteric artery

Agonists and Antagonists for P2 Receptors

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