Suramin antagonizes responses to P<sub>2</sub>‐purinoceptor agonists and purinergic nerve stimulation in the guinea‐pig urinary bladder and taenia coli

Hoyle, Charles H.V.; Knight, Gillian E.; Burnstock, Geoffrey

doi:10.1111/j.1476-5381.1990.tb12979.x

Cited by 310 publications

(203 citation statements)

References 29 publications

(31 reference statements)

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“…The broad-spectrum purinergic receptor blocker suramin (P7643, 50 μM; Sigma-Aldrich) or nucleotide-degrading enzyme apyrase (A7646, 6.8 U/mL; Sigma-Aldrich), was used to explore the role of P2Rs in intercellular signaling (62,63). Membrane currents were measured in response to stimulation of distal regions of an unapposed cell process in the presence and absence of suramin (incubation for 2-3 min).…”

Section: Methodsmentioning

confidence: 99%

Matrix-dependent adhesion mediates network responses to physiological stimulation of the osteocyte cell process

Schaffler

Weinbaum

et al. 2013

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

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Osteocytes are bone cells that form cellular networks that sense mechanical loads distributed throughout the bone tissue. Interstitial fluid flow in the lacunar canalicular system produces focal strains at localized attachment sites around the osteocyte cell process. These regions of periodic attachment between the osteocyte cell membrane and its canalicular wall are sites where pN-level fluid-flow induced forces are generated in vivo. In this study, we show that focally applied forces of this magnitude using a newly developed Stokesian fluid stimulus probe initiate rapid and transient intercellular electrical signals in vitro. Our experiments demonstrate both direct gap junction coupling and extracellular purinergic P2 receptor signaling between MLO-Y4 cells in a connected bone cell network. Intercellular signaling was initiated by pN-level forces applied at integrin attachment sites along both appositional and distal unapposed cell processes, but not initiated at their cell bodies with equivalent forces. Electrical coupling was evident in 58% of all cell pairs tested with appositional connections; coupling strength increased with the increasing number of junctional connections. Apyrase, a nucleotidedegrading enzyme, suppressed and abolished force-induced effector responses, indicating a contribution from ATP released by the stimulated cell. This work extends the understanding of how osteocytes modulate their microenvironment in response to mechanical signals and highlights mechanisms of intercellular relay of mechanoresponsive signals in the bone network.cell signaling | electrophysiology | mechanotransduction | junctional conductance I ncreasing evidence indicates that bone homeostasis and osteogenic remodeling require mechanical loading of whole bone tissue (1-4). Interstitial fluid in bone passes through hierarchical levels of porosity when bone tissue is deformed by external loads. The interstitial fluid is the medium that translates endogenous whole tissue mechanical loads to cellular level forces in bone. Measuring the magnitude of endogenous forces acting on osteocytes in vivo has been a major challenge experimentally, but is of significance for investigating force-induced cell signals in vitro. Mathematical models of in vivo forces acting within the bone porosity of the lacunar-canalicular system (LCS) containing osteocytes have theoretically predicted forces between 1 and 10 pN acting on attachment sites along the osteocyte cell process membrane (5-7). These predictions guided the development of a Stokesian fluid stimulus probe (SFSP) used to focally stimulate osteocytes in vitro at in vivo-level forces (8). In this study, we examined the intercellular electrical signals induced by pN-level forces in interconnected MLO-Y4 bone cell networks, and measured the intercellular signaling through gap junction channels and through changes in nonjunctional conductance. Signaling through nonjunctional membranes likely involves ATP release and binding to purinergic receptors (P2Rs), as demonstrated by the partia...

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Section: Methodsmentioning

confidence: 99%

Matrix-dependent adhesion mediates network responses to physiological stimulation of the osteocyte cell process

Schaffler

Weinbaum

et al. 2013

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

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“…These are thought to be due to ATP, which is co-released with NA, acting through P2x-purinoceptors because they are abolished following desensitization of P2x-purinoceptors with the stable adenosine 5'-triphosphate (ATP) analogue cxj-methylene ATP (Ramme et al, 1987;Hirst & Jobling, 1989;Evans & Cunnane, 1992). Recently the trypanocide, suramin, has been demonstrated to be an antagonist at the P2-purinoceptor in the rodent vas deferens (Dunn & Blakeley, 1988; Kugelgen & Starke, 1989) and the guinea-pig taenia caeci (Den Hertog et al, 1989;Hoyle et al, 1990). ' Author for correspondence.…”

Section: Introductionmentioning

confidence: 99%

Vasoconstriction of guinea‐pig submucosal arterioles following sympathetic nerve stimulation is mediated by the release of ATP

Evans

Surprenant

1992

British J Pharmacology

151

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The nature of the transmitter mediating vasoconstriction of guinea-pig submucosal arterioles following sympathetic nerve stimulation was studied.2 Prazosin (0.1 pM) abolished the response to exogenously applied phenylephrine (I pM) but had no effect on constrictions of submucosal arterioles evoked by nerve stimulation (100 pulses at 10 Hz). 3 Vasoconstrictions and excitatory junction potentials elicited by nerve stimulation were potentiated by idazoxan (0.1 pM).4 Following reserpine treatment, catecholamine fluorescence was absent in submucosal arterioles but nerve-evoked vasoconstrictions were unaltered. 5 Vasoconstrictions and excitatory junction potentials recorded in response to sympathetic nerve stimulation, as well as constrictions evoked by exogenously applied ATP (3 tiM), were abolished by the P,-purinoceptor antagonist, suramin (100 liM). Suramin had no effect on the vasoconstriction in response to noradrenaline (3 jM), or the nicotinic excitatory postsynaptic potentials (e.p.s.ps) and noradrenergic inhibitory postsynaptic potentials (i.p.s.ps) recorded from submucosal neurones. 6 We conclude that postjunctional responses of submucosal arterioles following sympathetic nerve stimulation are mediated solely through the activation of P2x-purinoceptors by ATP or a related purine nucelotide. The function of neurally released noradrenaline is to act through prejunctional M2-adrenoceptors to depress transmitter release.

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“…Effects of suramin on contractile responses to LCN stimulation Suramin (50, 1001AM), a reversible antagonist of P2x-purinoceptors in mouse and guinea-pig vas deferens (Dunn & Blakeley, 1988;Leff et al, 1990;von Kugelgen et al, 1990), guinea-pig urinary bladder (Hoyle et al, 1990) 6b), and shifted the concentration-response curves to the right. At higher concentrations of a,-methylene ATP (10, 100JIM), suramin potentiated contractile responses.…”

Section: Effects Of P2-purinoceptor Antagonistsmentioning

confidence: 99%

“…The involvement of a,-and x2-adrenoceptors and P-adrenoceptors in the nervemediated contractions was studied by the use of selective antagonists. The involvement of purinoceptors in the nervemediated contractions was studied by desensitization of P2-purinoceptors with the P2X-receptor agonist, a,-methylene ATP (Burnstock & Kennedy, 1985;Kennedy, 1990) and by antagonists of the P2-purinoceptor, suramin (Dunn & Blakeley, 1988;Den Hertog et al, 1989;Hoyle et al, 1990) and arylazido amino propionyl adenosine triphosphate (ANAPP3) (Hogaboom et al, 1980;Fedan et al, 1982). Also, the inhibitory effects of antagonists on nerve-mediated contractile responses were compared to their actions on contractile responses to agonists.…”

Section: Introductionmentioning

confidence: 99%

Stimulation of lumbar sympathetic nerves evokes contractions of cat colon circular muscle mediated by ATP and noradrenaline

Venkova

Krier

1993

British J Pharmacology

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1 The action of the lumbar sympathetic nerves to cat colon was studied in vitro using isolated muscle strips with attached lumbar colonic nerves (LCN) orientated in the axis of circular muscle layer. Electrical stimulation of LCN caused frequency-dependent increases in resting tension and in amplitude of spontaneous contractions. Contractile responses were abolished by tetrodotoxin (31M) and by guanethidine (30 JAM), indicating that they were neurogenic, involving the release of neurotransmitter from sympathetic fibres.2 Propranolol (I-9 J1M), a B-adrenoceptor antagonist, caused a concentration-dependent potentiation of LCN-evoked contractile responses. Propranolol (3 JAM) potentiated contractile responses to exogenously applied noradrenaline but not to phenylephrine.3 Phentolamine (1-9 JAM), an a-adrenoceptor antagonist, and prazosin (1-9 pM), an xl-adrenoceptor antagonist, caused a concentration-dependent reduction of amplitude but did not abolish LCN-evoked contractile responses. Prazosin (3 AM) or phentolamine (3 jaM) antagonized contractile responses to noradrenaline and phenylephrine.4 Desensitization of purinoceptors with the P2x-receptor agonist, a,j3-methylene ATP, caused a decrease in amplitude of LCN-evoked contractile responses and abolished contractile responses to ATP. In muscle strips where xl-adrenoceptors were blocked with prazosin (3 JAM) and P2-purinoceptors were desensitized with a,-methylene ATP, the amplitude of contractile responses was reduced by 82-100%.5 The P2X-purinoceptor antagonists, arylazido amino propyl adenosine triphosphate (ANAPP3) and suramin, affected LCN-evoked contractile responses. ANAPP3 (50-100 AIM) caused a concentrationdependent reduction in the amplitude of contractile response. Suramin (100 JiM) caused a small reduction in amplitude of contractile responses but potentiated their amplitude at a concentration of 500 JAM.6 ANAPP3 (100 AM) irreversibly inhibited contractions to X,P-methylene ATP or ATP. Suramin (100-500 JiM) inhibited contractions to ax,P-methylene ATP (0.5-1IJM) or low concentrations of ATP (10-50 AM) but potentiated contractions at higher concentrations. ANAPP3 (100 JiM) and suramin (100, 500 JAM) had no affect on contractile responses to noradrenaline. 7 Clonidine (0.05-1 JAM), a selective 'X2-adrenoceptor agonist, caused a concentration-dependent reduction in amplitude of LCN-evoked contractile responses, at 10 Hz, while yohimbine (0.1-1 JAM), a selective a2-adrenoceptor antagonist, increased them. At 1 JAM, both compounds affected LCN-evoked contractions at all frequencies. This suggests that prejunctional M2-receptors are involved in autoinhibition at sympathetic terminals. 8 In summary, LCN-evoked contractile responses involve the corelease of noradrenaline and ATP or a related purine nucleotide from sympathetic fibres. It is likely that the neurogenic responses are mediated through excitatory postjunctional ax-adrenoceptors, excitatory suramin-sensitive and suramin-insensitive P2X-purinoceptors and inhibitory ,-adrenoceptors. Also, autoinhibitor...

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Suramin antagonizes responses to P₂‐purinoceptor agonists and purinergic nerve stimulation in the guinea‐pig urinary bladder and taenia coli

Cited by 310 publications

References 29 publications

Matrix-dependent adhesion mediates network responses to physiological stimulation of the osteocyte cell process

Matrix-dependent adhesion mediates network responses to physiological stimulation of the osteocyte cell process

Vasoconstriction of guinea‐pig submucosal arterioles following sympathetic nerve stimulation is mediated by the release of ATP

Stimulation of lumbar sympathetic nerves evokes contractions of cat colon circular muscle mediated by ATP and noradrenaline

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Suramin antagonizes responses to P2‐purinoceptor agonists and purinergic nerve stimulation in the guinea‐pig urinary bladder and taenia coli

Cited by 310 publications

References 29 publications

Matrix-dependent adhesion mediates network responses to physiological stimulation of the osteocyte cell process

Matrix-dependent adhesion mediates network responses to physiological stimulation of the osteocyte cell process

Vasoconstriction of guinea‐pig submucosal arterioles following sympathetic nerve stimulation is mediated by the release of ATP

Stimulation of lumbar sympathetic nerves evokes contractions of cat colon circular muscle mediated by ATP and noradrenaline

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Suramin antagonizes responses to P₂‐purinoceptor agonists and purinergic nerve stimulation in the guinea‐pig urinary bladder and taenia coli