Characterization of the receptor mediating relaxation to substance P in canine middle cerebral artery: no evidence for involvement of substance P in neurogenically mediated relaxation
1 The aim of this study was to characterize the neurokinin receptor which mediates relaxation of dog isolated middle cerebral artery by the use of selective agonists and antagonists and to establish whether substance P is involved in the neurogenically mediated relaxant response in this vessel. 2 Su...
Gespeichert in:
| Veröffentlicht in: | British journal of pharmacology 1992-04, Vol.105 (4), p.875-880 |
|---|---|
| Hauptverfasser: | , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 880 |
|---|---|
| container_issue | 4 |
| container_start_page | 875 |
| container_title | British journal of pharmacology |
| container_volume | 105 |
| creator | Stubbs, C.M. Waldron, G.J. Connor, H.E. Feniuk, W. |
| description | 1
The aim of this study was to characterize the neurokinin receptor which mediates relaxation of dog isolated middle cerebral artery by the use of selective agonists and antagonists and to establish whether substance P is involved in the neurogenically mediated relaxant response in this vessel.
2
Substance P caused concentration‐related, endothelium‐dependent relaxations of dog isolated middle cerebral artery, contracted with prostaglandin F2α. The selective NK1 receptor agonists, GR73632 and substance P methyl ester (SPOMe), also caused relaxation with similar maximum effects to those of substance P. GR73632 and SPOMe were approximately 20 times and 6 times less potent respectively than substance P. The selective NK2 and NK3 receptor agonists, GR64349 and senktide, were only weakly active in causing relaxation being at least 425 times and 245 times less potent respectively than substance P.
3
The selective NK1 receptor antagonist, GR82334, was a potent, specific, competitive antagonist of the relaxant effects of substance P. In contrast, the selective NK2 receptor antagonist, R396 (10 μm) had no effect on the response to substance P.
4
Electrical field stimulation of dog isolated middle cerebral artery, contracted with prostaglandin F2α, caused neurogenically mediated, non‐adrenergic non‐cholinergic (NANC) relaxations. These NANC relaxations were unaffected by endothelium removal, GR82334 (10 μm) or by capsaicin (10 μm) treatment. However, the nitric oxide synthesis inhibitor, L‐NG‐monomethyl arginine methyl ester (L‐NMMA) (100 μm) markedly attenuated the response to electrical stimulation.
5
These results suggest that substance P causes relaxation of dog isolated middle cerebral artery via activation of NK1 receptors. However, substance P does not appear to be involved in NANC neurotransmission. In contrast, the marked inhibitory effect of L‐NMMA on NANC relaxations implicates nitric oxide in NANC neurotransmission in this vessel. |
| doi_str_mv | 10.1111/j.1476-5381.1992.tb09071.x |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_1908684</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>73146670</sourcerecordid><originalsourceid>FETCH-LOGICAL-c5371-ba0e4aea9e77dd04f6c859e28c09568a5d1f31c6c31c711b108d9b74afe648993</originalsourceid><addsrcrecordid>eNqVUtGO1CAUbYxmHVc_wYQY41srTGmBfXCjE3VNNnEf9JlQejvDhIER2nHGH_P3pGkzrr4YeQDCOfdwLpwse0FwQdJ4vS0IZXVelZwURIhl0TdYYEaK44NscYYeZguMMcsJ4fxx9iTGLcYJZNVFdkFKjktGF9nP1UYFpXsI5ofqjXfId6jfAAqgYd_7gHbQmoS4dTqy6jiReo_i0MReOQ3oDhmHtHLGAdqZtrWANARogrJIhSR9ukLOIziYFkZ-l1SNO3h7gB24frzxLzEHQ_BrcEYra0-zBWjvOXiaPeqUjfBsXi-zrx_ef1nd5LefP35avb3NdVUykjcKA1WgBDDWtph2teaVgCXXWFQ1V1VLupLoWqeJEdIQzFvRMKo6qCkXorzM3ky6-6FJNnTym9qS-2B2KpykV0b-iTizkWt_kERgXnOaBF7NAsF_GyD2cmeiBmuVAz9EyUpC65rhfxJJTXFF8ah4NRF18DEG6M5uCJZjPuRWjiGQYwjkmA8550MeU_Hz-_38Lp0CkfCXM65ievwupE8x8UyrliRZ4Il2PdG-Gwun_zAg393djLvyF4pU3iY</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>16405404</pqid></control><display><type>article</type><title>Characterization of the receptor mediating relaxation to substance P in canine middle cerebral artery: no evidence for involvement of substance P in neurogenically mediated relaxation</title><source>MEDLINE</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>PubMed Central</source><source>Alma/SFX Local Collection</source><creator>Stubbs, C.M. ; Waldron, G.J. ; Connor, H.E. ; Feniuk, W.</creator><creatorcontrib>Stubbs, C.M. ; Waldron, G.J. ; Connor, H.E. ; Feniuk, W.</creatorcontrib><description>1
The aim of this study was to characterize the neurokinin receptor which mediates relaxation of dog isolated middle cerebral artery by the use of selective agonists and antagonists and to establish whether substance P is involved in the neurogenically mediated relaxant response in this vessel.
2
Substance P caused concentration‐related, endothelium‐dependent relaxations of dog isolated middle cerebral artery, contracted with prostaglandin F2α. The selective NK1 receptor agonists, GR73632 and substance P methyl ester (SPOMe), also caused relaxation with similar maximum effects to those of substance P. GR73632 and SPOMe were approximately 20 times and 6 times less potent respectively than substance P. The selective NK2 and NK3 receptor agonists, GR64349 and senktide, were only weakly active in causing relaxation being at least 425 times and 245 times less potent respectively than substance P.
3
The selective NK1 receptor antagonist, GR82334, was a potent, specific, competitive antagonist of the relaxant effects of substance P. In contrast, the selective NK2 receptor antagonist, R396 (10 μm) had no effect on the response to substance P.
4
Electrical field stimulation of dog isolated middle cerebral artery, contracted with prostaglandin F2α, caused neurogenically mediated, non‐adrenergic non‐cholinergic (NANC) relaxations. These NANC relaxations were unaffected by endothelium removal, GR82334 (10 μm) or by capsaicin (10 μm) treatment. However, the nitric oxide synthesis inhibitor, L‐NG‐monomethyl arginine methyl ester (L‐NMMA) (100 μm) markedly attenuated the response to electrical stimulation.
5
These results suggest that substance P causes relaxation of dog isolated middle cerebral artery via activation of NK1 receptors. However, substance P does not appear to be involved in NANC neurotransmission. In contrast, the marked inhibitory effect of L‐NMMA on NANC relaxations implicates nitric oxide in NANC neurotransmission in this vessel.</description><identifier>ISSN: 0007-1188</identifier><identifier>EISSN: 1476-5381</identifier><identifier>DOI: 10.1111/j.1476-5381.1992.tb09071.x</identifier><identifier>PMID: 1380374</identifier><identifier>CODEN: BJPCBM</identifier><language>eng</language><publisher>Oxford, UK: Blackwell Publishing Ltd</publisher><subject>Animals ; Arginine - analogs & derivatives ; Arginine - pharmacology ; Biological and medical sciences ; Capsaicin - pharmacology ; Cerebral Arteries - drug effects ; Cerebral Arteries - innervation ; Cerebral Arteries - physiology ; Dogs ; Electric Stimulation ; Endothelium, Vascular - physiology ; Fundamental and applied biological sciences. Psychology ; Heart ; In Vitro Techniques ; neurogenic relaxation ; nitric oxide ; NK1 receptors ; omega-N-Methylarginine ; Peptide Fragments - pharmacology ; Receptors, Neurokinin-2 ; Receptors, Neurotransmitter - antagonists & inhibitors ; Receptors, Neurotransmitter - drug effects ; Receptors, Neurotransmitter - physiology ; Substance P ; Substance P - analogs & derivatives ; Substance P - pharmacology ; Substance P - physiology ; Synaptic Transmission - drug effects ; Synaptic Transmission - physiology ; Vasodilation - drug effects ; Vasodilation - physiology ; Vertebrates: cardiovascular system</subject><ispartof>British journal of pharmacology, 1992-04, Vol.105 (4), p.875-880</ispartof><rights>1992 British Pharmacological Society</rights><rights>1992 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5371-ba0e4aea9e77dd04f6c859e28c09568a5d1f31c6c31c711b108d9b74afe648993</citedby><cites>FETCH-LOGICAL-c5371-ba0e4aea9e77dd04f6c859e28c09568a5d1f31c6c31c711b108d9b74afe648993</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC1908684/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC1908684/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27903,27904,53769,53771</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=5214048$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/1380374$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Stubbs, C.M.</creatorcontrib><creatorcontrib>Waldron, G.J.</creatorcontrib><creatorcontrib>Connor, H.E.</creatorcontrib><creatorcontrib>Feniuk, W.</creatorcontrib><title>Characterization of the receptor mediating relaxation to substance P in canine middle cerebral artery: no evidence for involvement of substance P in neurogenically mediated relaxation</title><title>British journal of pharmacology</title><addtitle>Br J Pharmacol</addtitle><description>1
The aim of this study was to characterize the neurokinin receptor which mediates relaxation of dog isolated middle cerebral artery by the use of selective agonists and antagonists and to establish whether substance P is involved in the neurogenically mediated relaxant response in this vessel.
2
Substance P caused concentration‐related, endothelium‐dependent relaxations of dog isolated middle cerebral artery, contracted with prostaglandin F2α. The selective NK1 receptor agonists, GR73632 and substance P methyl ester (SPOMe), also caused relaxation with similar maximum effects to those of substance P. GR73632 and SPOMe were approximately 20 times and 6 times less potent respectively than substance P. The selective NK2 and NK3 receptor agonists, GR64349 and senktide, were only weakly active in causing relaxation being at least 425 times and 245 times less potent respectively than substance P.
3
The selective NK1 receptor antagonist, GR82334, was a potent, specific, competitive antagonist of the relaxant effects of substance P. In contrast, the selective NK2 receptor antagonist, R396 (10 μm) had no effect on the response to substance P.
4
Electrical field stimulation of dog isolated middle cerebral artery, contracted with prostaglandin F2α, caused neurogenically mediated, non‐adrenergic non‐cholinergic (NANC) relaxations. These NANC relaxations were unaffected by endothelium removal, GR82334 (10 μm) or by capsaicin (10 μm) treatment. However, the nitric oxide synthesis inhibitor, L‐NG‐monomethyl arginine methyl ester (L‐NMMA) (100 μm) markedly attenuated the response to electrical stimulation.
5
These results suggest that substance P causes relaxation of dog isolated middle cerebral artery via activation of NK1 receptors. However, substance P does not appear to be involved in NANC neurotransmission. In contrast, the marked inhibitory effect of L‐NMMA on NANC relaxations implicates nitric oxide in NANC neurotransmission in this vessel.</description><subject>Animals</subject><subject>Arginine - analogs & derivatives</subject><subject>Arginine - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Capsaicin - pharmacology</subject><subject>Cerebral Arteries - drug effects</subject><subject>Cerebral Arteries - innervation</subject><subject>Cerebral Arteries - physiology</subject><subject>Dogs</subject><subject>Electric Stimulation</subject><subject>Endothelium, Vascular - physiology</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Heart</subject><subject>In Vitro Techniques</subject><subject>neurogenic relaxation</subject><subject>nitric oxide</subject><subject>NK1 receptors</subject><subject>omega-N-Methylarginine</subject><subject>Peptide Fragments - pharmacology</subject><subject>Receptors, Neurokinin-2</subject><subject>Receptors, Neurotransmitter - antagonists & inhibitors</subject><subject>Receptors, Neurotransmitter - drug effects</subject><subject>Receptors, Neurotransmitter - physiology</subject><subject>Substance P</subject><subject>Substance P - analogs & derivatives</subject><subject>Substance P - pharmacology</subject><subject>Substance P - physiology</subject><subject>Synaptic Transmission - drug effects</subject><subject>Synaptic Transmission - physiology</subject><subject>Vasodilation - drug effects</subject><subject>Vasodilation - physiology</subject><subject>Vertebrates: cardiovascular system</subject><issn>0007-1188</issn><issn>1476-5381</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1992</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqVUtGO1CAUbYxmHVc_wYQY41srTGmBfXCjE3VNNnEf9JlQejvDhIER2nHGH_P3pGkzrr4YeQDCOfdwLpwse0FwQdJ4vS0IZXVelZwURIhl0TdYYEaK44NscYYeZguMMcsJ4fxx9iTGLcYJZNVFdkFKjktGF9nP1UYFpXsI5ofqjXfId6jfAAqgYd_7gHbQmoS4dTqy6jiReo_i0MReOQ3oDhmHtHLGAdqZtrWANARogrJIhSR9ukLOIziYFkZ-l1SNO3h7gB24frzxLzEHQ_BrcEYra0-zBWjvOXiaPeqUjfBsXi-zrx_ef1nd5LefP35avb3NdVUykjcKA1WgBDDWtph2teaVgCXXWFQ1V1VLupLoWqeJEdIQzFvRMKo6qCkXorzM3ky6-6FJNnTym9qS-2B2KpykV0b-iTizkWt_kERgXnOaBF7NAsF_GyD2cmeiBmuVAz9EyUpC65rhfxJJTXFF8ah4NRF18DEG6M5uCJZjPuRWjiGQYwjkmA8550MeU_Hz-_38Lp0CkfCXM65ievwupE8x8UyrliRZ4Il2PdG-Gwun_zAg393djLvyF4pU3iY</recordid><startdate>199204</startdate><enddate>199204</enddate><creator>Stubbs, C.M.</creator><creator>Waldron, G.J.</creator><creator>Connor, H.E.</creator><creator>Feniuk, W.</creator><general>Blackwell Publishing Ltd</general><general>Nature Publishing</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TK</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>199204</creationdate><title>Characterization of the receptor mediating relaxation to substance P in canine middle cerebral artery: no evidence for involvement of substance P in neurogenically mediated relaxation</title><author>Stubbs, C.M. ; Waldron, G.J. ; Connor, H.E. ; Feniuk, W.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5371-ba0e4aea9e77dd04f6c859e28c09568a5d1f31c6c31c711b108d9b74afe648993</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1992</creationdate><topic>Animals</topic><topic>Arginine - analogs & derivatives</topic><topic>Arginine - pharmacology</topic><topic>Biological and medical sciences</topic><topic>Capsaicin - pharmacology</topic><topic>Cerebral Arteries - drug effects</topic><topic>Cerebral Arteries - innervation</topic><topic>Cerebral Arteries - physiology</topic><topic>Dogs</topic><topic>Electric Stimulation</topic><topic>Endothelium, Vascular - physiology</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Heart</topic><topic>In Vitro Techniques</topic><topic>neurogenic relaxation</topic><topic>nitric oxide</topic><topic>NK1 receptors</topic><topic>omega-N-Methylarginine</topic><topic>Peptide Fragments - pharmacology</topic><topic>Receptors, Neurokinin-2</topic><topic>Receptors, Neurotransmitter - antagonists & inhibitors</topic><topic>Receptors, Neurotransmitter - drug effects</topic><topic>Receptors, Neurotransmitter - physiology</topic><topic>Substance P</topic><topic>Substance P - analogs & derivatives</topic><topic>Substance P - pharmacology</topic><topic>Substance P - physiology</topic><topic>Synaptic Transmission - drug effects</topic><topic>Synaptic Transmission - physiology</topic><topic>Vasodilation - drug effects</topic><topic>Vasodilation - physiology</topic><topic>Vertebrates: cardiovascular system</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Stubbs, C.M.</creatorcontrib><creatorcontrib>Waldron, G.J.</creatorcontrib><creatorcontrib>Connor, H.E.</creatorcontrib><creatorcontrib>Feniuk, W.</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>British journal of pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Stubbs, C.M.</au><au>Waldron, G.J.</au><au>Connor, H.E.</au><au>Feniuk, W.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Characterization of the receptor mediating relaxation to substance P in canine middle cerebral artery: no evidence for involvement of substance P in neurogenically mediated relaxation</atitle><jtitle>British journal of pharmacology</jtitle><addtitle>Br J Pharmacol</addtitle><date>1992-04</date><risdate>1992</risdate><volume>105</volume><issue>4</issue><spage>875</spage><epage>880</epage><pages>875-880</pages><issn>0007-1188</issn><eissn>1476-5381</eissn><coden>BJPCBM</coden><abstract>1
The aim of this study was to characterize the neurokinin receptor which mediates relaxation of dog isolated middle cerebral artery by the use of selective agonists and antagonists and to establish whether substance P is involved in the neurogenically mediated relaxant response in this vessel.
2
Substance P caused concentration‐related, endothelium‐dependent relaxations of dog isolated middle cerebral artery, contracted with prostaglandin F2α. The selective NK1 receptor agonists, GR73632 and substance P methyl ester (SPOMe), also caused relaxation with similar maximum effects to those of substance P. GR73632 and SPOMe were approximately 20 times and 6 times less potent respectively than substance P. The selective NK2 and NK3 receptor agonists, GR64349 and senktide, were only weakly active in causing relaxation being at least 425 times and 245 times less potent respectively than substance P.
3
The selective NK1 receptor antagonist, GR82334, was a potent, specific, competitive antagonist of the relaxant effects of substance P. In contrast, the selective NK2 receptor antagonist, R396 (10 μm) had no effect on the response to substance P.
4
Electrical field stimulation of dog isolated middle cerebral artery, contracted with prostaglandin F2α, caused neurogenically mediated, non‐adrenergic non‐cholinergic (NANC) relaxations. These NANC relaxations were unaffected by endothelium removal, GR82334 (10 μm) or by capsaicin (10 μm) treatment. However, the nitric oxide synthesis inhibitor, L‐NG‐monomethyl arginine methyl ester (L‐NMMA) (100 μm) markedly attenuated the response to electrical stimulation.
5
These results suggest that substance P causes relaxation of dog isolated middle cerebral artery via activation of NK1 receptors. However, substance P does not appear to be involved in NANC neurotransmission. In contrast, the marked inhibitory effect of L‐NMMA on NANC relaxations implicates nitric oxide in NANC neurotransmission in this vessel.</abstract><cop>Oxford, UK</cop><pub>Blackwell Publishing Ltd</pub><pmid>1380374</pmid><doi>10.1111/j.1476-5381.1992.tb09071.x</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0007-1188 |
| ispartof | British journal of pharmacology, 1992-04, Vol.105 (4), p.875-880 |
| issn | 0007-1188 1476-5381 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_1908684 |
| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Alma/SFX Local Collection |
| subjects | Animals Arginine - analogs & derivatives Arginine - pharmacology Biological and medical sciences Capsaicin - pharmacology Cerebral Arteries - drug effects Cerebral Arteries - innervation Cerebral Arteries - physiology Dogs Electric Stimulation Endothelium, Vascular - physiology Fundamental and applied biological sciences. Psychology Heart In Vitro Techniques neurogenic relaxation nitric oxide NK1 receptors omega-N-Methylarginine Peptide Fragments - pharmacology Receptors, Neurokinin-2 Receptors, Neurotransmitter - antagonists & inhibitors Receptors, Neurotransmitter - drug effects Receptors, Neurotransmitter - physiology Substance P Substance P - analogs & derivatives Substance P - pharmacology Substance P - physiology Synaptic Transmission - drug effects Synaptic Transmission - physiology Vasodilation - drug effects Vasodilation - physiology Vertebrates: cardiovascular system |
| title | Characterization of the receptor mediating relaxation to substance P in canine middle cerebral artery: no evidence for involvement of substance P in neurogenically mediated relaxation |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-27T03%3A49%3A02IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Characterization%20of%20the%20receptor%20mediating%20relaxation%20to%20substance%20P%20in%20canine%20middle%20cerebral%20artery:%20no%20evidence%20for%20involvement%20of%20substance%20P%20in%20neurogenically%20mediated%20relaxation&rft.jtitle=British%20journal%20of%20pharmacology&rft.au=Stubbs,%20C.M.&rft.date=1992-04&rft.volume=105&rft.issue=4&rft.spage=875&rft.epage=880&rft.pages=875-880&rft.issn=0007-1188&rft.eissn=1476-5381&rft.coden=BJPCBM&rft_id=info:doi/10.1111/j.1476-5381.1992.tb09071.x&rft_dat=%3Cproquest_pubme%3E73146670%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=16405404&rft_id=info:pmid/1380374&rfr_iscdi=true |