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Article: Potentiation by 2,2′-pyridylisatogen tosylate of ATP-responses at a recombinant P2Y1 purinoceptor

TitlePotentiation by 2,2′-pyridylisatogen tosylate of ATP-responses at a recombinant P2Y1 purinoceptor
Authors
Issue Date1996
PublisherJohn Wiley & Sons Ltd. The Journal's web site is located at http://www.wiley.com/bw/journal.asp?ref=0007-1188&site=1
Citation
British Journal Of Pharmacology, 1996, v. 117 n. 6, p. 1111-1118 How to Cite?
Abstract1 2,2′-Pyridylisatogen tosylate (PIT) has been reported to be an irreversible antagonist of responses to adenosine 5′-triphosphate (ATP) at metabotropic purinoceptors (of the P2Y family) in some smooth muscles. When a recombinant P2Y1 purinoceptor (derived from chick brain) is expressed in Xenopus oocytes, ATP and 2-methylthioATP (2-MeSATP) evoke calcium-activated chloride currents (ICl,Ca) in a concentration-dependent manner. The effects of PIT on these agonist responses were examined at this cloned P2Y purinoceptor. 2 PIT (0.1-100 μM) failed to stimulate P2Y1 purinoceptors directly but, over a narrow concentration range (0.1-3 μM), caused a time-dependent potentiation (2-5 fold) of responses to ATP. The potentiation of ATP-responses by PIT was not caused by inhibition of oocyte ecto-ATPase. At high concentrations (3-100 μM), PIT irreversibly inhibited responses to ATP with a IC50 value of 13±9 μM (pKB = 4.88±0.22; n = 3). PIT failed to potentiate inward currents evoked by 2-MeSATP and only inhibited the responses to this agonist in an irreversible manner. 3 Known P2 purinoceptor antagonists were tested for their ability to potentiate ATP-responses at the chick P2Y1 purinoceptor. Suramin (IC50 = 230±80 nM; n = 5) and Reactive blue-2 (IC50 = 580±130 nM; n = 6) reversibly inhibited but did not potentiate ATP-responses. Coomassie brilliant blue-G (0.1-3 μM) potentiated ATP-responses in three experiments, while higher concentrations (3-100 μM) irreversibly inhibited ATP-responses. The results indicated that potentiation and receptor antagonism were dissociable and not a feature common to all known P2 purinoceptor antagonists. 4 In radioligand binding assays, PIT showed a low affinity (pKi < 5) for a range of membrane receptors, including: α1, α2-adrenoceptors, 5-HT1A, 5-HT1B, 5-HT2, 5-HT3, D1, D2, muscarinic, central benzodiazepine, H1, μ-opioid, dihydropyridine and batrachotoxin receptors. PIT showed some affinity (pKi = 5.3) for an adenosine (A1) receptor. 5 In guinea-pig isolated taenia caeci, PIT (12.5-50 μM) irreversibly antagonized relaxations to ATP (3-1000 μM); PIT also directly relaxed the smooth muscle and histamine was used to restore tone. Relaxations to nicotine (10-100 μM), evoked by stimulating intrinsic NANC nerves of taenia caeci preparations in the presence of hyoscine (0.3 μM) and guanethidine (17 μM), were not affected by PIT (50 μM, for 25-60 min). 6 These experiments indicate that PIT causes an irreversible antagonism of ATP receptors but, for recombinant chick P2Y1 purinoceptors, this effect is preceded by potentiation of ATP agonism. The initial potentiation by PIT (and by Coomassie brilliant blue-G) of ATP-responses raises the possibility of designing a new class of modulatory drugs to enhance purinergic transmission at metabotropic purinoceptors.
Persistent Identifierhttp://hdl.handle.net/10722/171185
ISSN
2015 Impact Factor: 5.259
2015 SCImago Journal Rankings: 2.368
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorKing, BFen_US
dc.contributor.authorDacquet, Cen_US
dc.contributor.authorZiganshin, AUen_US
dc.contributor.authorWeetman, DFen_US
dc.contributor.authorBurnstock, Gen_US
dc.contributor.authorVanhoutte, PMen_US
dc.contributor.authorSpedding, Men_US
dc.date.accessioned2012-10-30T06:12:34Z-
dc.date.available2012-10-30T06:12:34Z-
dc.date.issued1996en_US
dc.identifier.citationBritish Journal Of Pharmacology, 1996, v. 117 n. 6, p. 1111-1118en_US
dc.identifier.issn0007-1188en_US
dc.identifier.urihttp://hdl.handle.net/10722/171185-
dc.description.abstract1 2,2′-Pyridylisatogen tosylate (PIT) has been reported to be an irreversible antagonist of responses to adenosine 5′-triphosphate (ATP) at metabotropic purinoceptors (of the P2Y family) in some smooth muscles. When a recombinant P2Y1 purinoceptor (derived from chick brain) is expressed in Xenopus oocytes, ATP and 2-methylthioATP (2-MeSATP) evoke calcium-activated chloride currents (ICl,Ca) in a concentration-dependent manner. The effects of PIT on these agonist responses were examined at this cloned P2Y purinoceptor. 2 PIT (0.1-100 μM) failed to stimulate P2Y1 purinoceptors directly but, over a narrow concentration range (0.1-3 μM), caused a time-dependent potentiation (2-5 fold) of responses to ATP. The potentiation of ATP-responses by PIT was not caused by inhibition of oocyte ecto-ATPase. At high concentrations (3-100 μM), PIT irreversibly inhibited responses to ATP with a IC50 value of 13±9 μM (pKB = 4.88±0.22; n = 3). PIT failed to potentiate inward currents evoked by 2-MeSATP and only inhibited the responses to this agonist in an irreversible manner. 3 Known P2 purinoceptor antagonists were tested for their ability to potentiate ATP-responses at the chick P2Y1 purinoceptor. Suramin (IC50 = 230±80 nM; n = 5) and Reactive blue-2 (IC50 = 580±130 nM; n = 6) reversibly inhibited but did not potentiate ATP-responses. Coomassie brilliant blue-G (0.1-3 μM) potentiated ATP-responses in three experiments, while higher concentrations (3-100 μM) irreversibly inhibited ATP-responses. The results indicated that potentiation and receptor antagonism were dissociable and not a feature common to all known P2 purinoceptor antagonists. 4 In radioligand binding assays, PIT showed a low affinity (pKi < 5) for a range of membrane receptors, including: α1, α2-adrenoceptors, 5-HT1A, 5-HT1B, 5-HT2, 5-HT3, D1, D2, muscarinic, central benzodiazepine, H1, μ-opioid, dihydropyridine and batrachotoxin receptors. PIT showed some affinity (pKi = 5.3) for an adenosine (A1) receptor. 5 In guinea-pig isolated taenia caeci, PIT (12.5-50 μM) irreversibly antagonized relaxations to ATP (3-1000 μM); PIT also directly relaxed the smooth muscle and histamine was used to restore tone. Relaxations to nicotine (10-100 μM), evoked by stimulating intrinsic NANC nerves of taenia caeci preparations in the presence of hyoscine (0.3 μM) and guanethidine (17 μM), were not affected by PIT (50 μM, for 25-60 min). 6 These experiments indicate that PIT causes an irreversible antagonism of ATP receptors but, for recombinant chick P2Y1 purinoceptors, this effect is preceded by potentiation of ATP agonism. The initial potentiation by PIT (and by Coomassie brilliant blue-G) of ATP-responses raises the possibility of designing a new class of modulatory drugs to enhance purinergic transmission at metabotropic purinoceptors.en_US
dc.languageengen_US
dc.publisherJohn Wiley & Sons Ltd. The Journal's web site is located at http://www.wiley.com/bw/journal.asp?ref=0007-1188&site=1en_US
dc.relation.ispartofBritish Journal of Pharmacologyen_US
dc.subject.meshAdenosine Triphosphatases - Metabolismen_US
dc.subject.meshAdenosine Triphosphate - Pharmacologyen_US
dc.subject.meshAnimalsen_US
dc.subject.meshChickensen_US
dc.subject.meshDose-Response Relationship, Drugen_US
dc.subject.meshDrug Synergismen_US
dc.subject.meshIsatin - Analogs & Derivatives - Metabolism - Pharmacologyen_US
dc.subject.meshOocytes - Metabolismen_US
dc.subject.meshPatch-Clamp Techniquesen_US
dc.subject.meshReceptors, Purinergic P2 - Drug Effects - Genetics - Metabolismen_US
dc.subject.meshRecombinant Proteins - Metabolismen_US
dc.subject.meshXenopusen_US
dc.titlePotentiation by 2,2′-pyridylisatogen tosylate of ATP-responses at a recombinant P2Y1 purinoceptoren_US
dc.typeArticleen_US
dc.identifier.emailVanhoutte, PM:vanhoutt@hku.hken_US
dc.identifier.authorityVanhoutte, PM=rp00238en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1111/j.1476-5381.1996.tb16704.x-
dc.identifier.pmid8882604-
dc.identifier.scopuseid_2-s2.0-0030003638en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-0030003638&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume117en_US
dc.identifier.issue6en_US
dc.identifier.spage1111en_US
dc.identifier.epage1118en_US
dc.identifier.isiWOS:A1996UB81600018-
dc.publisher.placeUnited Kingdomen_US
dc.identifier.scopusauthoridKing, BF=7402688418en_US
dc.identifier.scopusauthoridDacquet, C=6602490738en_US
dc.identifier.scopusauthoridZiganshin, AU=35493836100en_US
dc.identifier.scopusauthoridWeetman, DF=36639480000en_US
dc.identifier.scopusauthoridBurnstock, G=36037094600en_US
dc.identifier.scopusauthoridVanhoutte, PM=7202304247en_US
dc.identifier.scopusauthoridSpedding, M=7005213217en_US

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