Synergistic Effect of an Endothelin Type A Receptor Antagonist, S-0139, With rtPA on the Neuroprotection After Embolic Stroke
Using a model of embolic stroke, the present study tested the hypothesis that blockage of endothelin-1 with S-0139, a specific endothelin type A receptor (ET(A)) antagonist, enhances the neuroprotective effect of recombinant tissue plasminogen activator (rtPA) by suppressing molecules that mediate t...
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| Veröffentlicht in: | Stroke (1970) 2008-10, Vol.39 (10), p.2830-2836 |
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| creator | RUI LAN ZHANG CHUNLING ZHANG ZHENG GANG ZHANG CHOPP, Michael LI ZHANG ROBERTS, Cindi MEI LU KAPKE, Alissa YISHENG CUI NINOMIYA, Mitsuyoshi NAGAFUJI, Toshiaki ALBALA, Bruce |
| description | Using a model of embolic stroke, the present study tested the hypothesis that blockage of endothelin-1 with S-0139, a specific endothelin type A receptor (ET(A)) antagonist, enhances the neuroprotective effect of recombinant tissue plasminogen activator (rtPA) by suppressing molecules that mediate thrombosis and blood brain barrier (BBB) disruption induced by ischemia and rtPA.
Rats (n=104) subjected to embolic middle cerebral artery (MCA) occlusion were randomly divided into 1 of 4 infusion groups with 26 rats per group: (1) the control group in which rats were administered saline, (2) the monotherapy rtPA group in which rtPA was intravenously administered at a dose of 10 mg/kg 4 hours after MCA occlusion, (3) the monotherapy S-0139 group in which S-0139 was intravenously given 2 hours after MCA occlusion, and (4) the combination of rtPA +S-0139 group in which S-0139 and rtPA were given 2 and 4 hours after MCA occlusion, respectively. Measurements of infarct volume and parenchymal hemorrhage, behavioral outcome, and immunostaining were performed on rats euthanized 1 and 7 days after stroke.
The combination therapy of S-0139 and rtPA significantly (P |
| doi_str_mv | 10.1161/STROKEAHA.108.515684 |
| format | Article |
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Rats (n=104) subjected to embolic middle cerebral artery (MCA) occlusion were randomly divided into 1 of 4 infusion groups with 26 rats per group: (1) the control group in which rats were administered saline, (2) the monotherapy rtPA group in which rtPA was intravenously administered at a dose of 10 mg/kg 4 hours after MCA occlusion, (3) the monotherapy S-0139 group in which S-0139 was intravenously given 2 hours after MCA occlusion, and (4) the combination of rtPA +S-0139 group in which S-0139 and rtPA were given 2 and 4 hours after MCA occlusion, respectively. Measurements of infarct volume and parenchymal hemorrhage, behavioral outcome, and immunostaining were performed on rats euthanized 1 and 7 days after stroke.
The combination therapy of S-0139 and rtPA significantly (P<0.01) reduced infarct volume (24.8+/-0.9% versus 33.8+/-1.5% in control) and hemorrhagic area (7.1+/-6.1 microm(2) versus 36.5+/-19.2 microm(2) in control) and improved functional recovery compared with control saline-treated animals. Immunostaining analysis revealed that the combination therapy had the synergistically suppressed ischemia- and rtPA-induced ICAM-1, protease-activated receptor 1 (PAR-1), as well as accumulation of platelets in cerebral microvessels. Furthermore, the combination treatment synergistically reduced loss of laminin, ZO1, and occludin in cerebral vessels.
These data suggest that S-0139 provides the neuroprotection by suppressing ischemia- and rtPA-triggered molecules that evoke thrombosis and BBB disruption.</description><identifier>ISSN: 0039-2499</identifier><identifier>EISSN: 1524-4628</identifier><identifier>DOI: 10.1161/STROKEAHA.108.515684</identifier><identifier>PMID: 18669895</identifier><identifier>CODEN: SJCCA7</identifier><language>eng</language><publisher>Hagerstown, MD: Lippincott Williams & Wilkins</publisher><subject><![CDATA[Animals ; Biological and medical sciences ; Blood Platelets - drug effects ; Blood-Brain Barrier - drug effects ; Brain - drug effects ; Brain - pathology ; Caffeic Acids - administration & dosage ; Collagen Type IV - biosynthesis ; Collagen Type IV - drug effects ; Drug Synergism ; Endothelin Receptor Antagonists ; Fibrinolytic Agents - administration & dosage ; Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy ; Immunohistochemistry ; Infarction, Middle Cerebral Artery - drug therapy ; Infarction, Middle Cerebral Artery - pathology ; Intercellular Adhesion Molecule-1 - biosynthesis ; Intercellular Adhesion Molecule-1 - drug effects ; Male ; Medical sciences ; Nervous system (semeiology, syndromes) ; Neurology ; Neuroprotective Agents - administration & dosage ; Oleanolic Acid - administration & dosage ; Oleanolic Acid - analogs & derivatives ; Rats ; Rats, Wistar ; Receptor, PAR-1 - biosynthesis ; Receptor, PAR-1 - drug effects ; Recovery of Function - drug effects ; Tight Junctions - drug effects ; Tissue Plasminogen Activator - administration & dosage ; Vascular diseases and vascular malformations of the nervous system]]></subject><ispartof>Stroke (1970), 2008-10, Vol.39 (10), p.2830-2836</ispartof><rights>2008 INIST-CNRS</rights><rights>2008 American Heart Association, Inc. 2008</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c473t-2a8d833c1fc77c0c0ca0f4bca6ce5eb967eb427de81f7a64af6e07d7b5023e623</citedby><cites>FETCH-LOGICAL-c473t-2a8d833c1fc77c0c0ca0f4bca6ce5eb967eb427de81f7a64af6e07d7b5023e623</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,777,781,882,3674,27905,27906</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=20715110$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18669895$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>RUI LAN ZHANG</creatorcontrib><creatorcontrib>CHUNLING ZHANG</creatorcontrib><creatorcontrib>ZHENG GANG ZHANG</creatorcontrib><creatorcontrib>CHOPP, Michael</creatorcontrib><creatorcontrib>LI ZHANG</creatorcontrib><creatorcontrib>ROBERTS, Cindi</creatorcontrib><creatorcontrib>MEI LU</creatorcontrib><creatorcontrib>KAPKE, Alissa</creatorcontrib><creatorcontrib>YISHENG CUI</creatorcontrib><creatorcontrib>NINOMIYA, Mitsuyoshi</creatorcontrib><creatorcontrib>NAGAFUJI, Toshiaki</creatorcontrib><creatorcontrib>ALBALA, Bruce</creatorcontrib><title>Synergistic Effect of an Endothelin Type A Receptor Antagonist, S-0139, With rtPA on the Neuroprotection After Embolic Stroke</title><title>Stroke (1970)</title><addtitle>Stroke</addtitle><description>Using a model of embolic stroke, the present study tested the hypothesis that blockage of endothelin-1 with S-0139, a specific endothelin type A receptor (ET(A)) antagonist, enhances the neuroprotective effect of recombinant tissue plasminogen activator (rtPA) by suppressing molecules that mediate thrombosis and blood brain barrier (BBB) disruption induced by ischemia and rtPA.
Rats (n=104) subjected to embolic middle cerebral artery (MCA) occlusion were randomly divided into 1 of 4 infusion groups with 26 rats per group: (1) the control group in which rats were administered saline, (2) the monotherapy rtPA group in which rtPA was intravenously administered at a dose of 10 mg/kg 4 hours after MCA occlusion, (3) the monotherapy S-0139 group in which S-0139 was intravenously given 2 hours after MCA occlusion, and (4) the combination of rtPA +S-0139 group in which S-0139 and rtPA were given 2 and 4 hours after MCA occlusion, respectively. Measurements of infarct volume and parenchymal hemorrhage, behavioral outcome, and immunostaining were performed on rats euthanized 1 and 7 days after stroke.
The combination therapy of S-0139 and rtPA significantly (P<0.01) reduced infarct volume (24.8+/-0.9% versus 33.8+/-1.5% in control) and hemorrhagic area (7.1+/-6.1 microm(2) versus 36.5+/-19.2 microm(2) in control) and improved functional recovery compared with control saline-treated animals. Immunostaining analysis revealed that the combination therapy had the synergistically suppressed ischemia- and rtPA-induced ICAM-1, protease-activated receptor 1 (PAR-1), as well as accumulation of platelets in cerebral microvessels. Furthermore, the combination treatment synergistically reduced loss of laminin, ZO1, and occludin in cerebral vessels.
These data suggest that S-0139 provides the neuroprotection by suppressing ischemia- and rtPA-triggered molecules that evoke thrombosis and BBB disruption.</description><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Blood Platelets - drug effects</subject><subject>Blood-Brain Barrier - drug effects</subject><subject>Brain - drug effects</subject><subject>Brain - pathology</subject><subject>Caffeic Acids - administration & dosage</subject><subject>Collagen Type IV - biosynthesis</subject><subject>Collagen Type IV - drug effects</subject><subject>Drug Synergism</subject><subject>Endothelin Receptor Antagonists</subject><subject>Fibrinolytic Agents - administration & dosage</subject><subject>Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy</subject><subject>Immunohistochemistry</subject><subject>Infarction, Middle Cerebral Artery - drug therapy</subject><subject>Infarction, Middle Cerebral Artery - pathology</subject><subject>Intercellular Adhesion Molecule-1 - biosynthesis</subject><subject>Intercellular Adhesion Molecule-1 - drug effects</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Nervous system (semeiology, syndromes)</subject><subject>Neurology</subject><subject>Neuroprotective Agents - administration & dosage</subject><subject>Oleanolic Acid - administration & dosage</subject><subject>Oleanolic Acid - analogs & derivatives</subject><subject>Rats</subject><subject>Rats, Wistar</subject><subject>Receptor, PAR-1 - biosynthesis</subject><subject>Receptor, PAR-1 - drug effects</subject><subject>Recovery of Function - drug effects</subject><subject>Tight Junctions - drug effects</subject><subject>Tissue Plasminogen Activator - administration & dosage</subject><subject>Vascular diseases and vascular malformations of the nervous system</subject><issn>0039-2499</issn><issn>1524-4628</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkUFv1DAQhS0EokvhHyDkC7dmsR3Hdi5IUZVSRNWi7iKOkeOMdw1ZO3JcpD3w3zHa1baVD5Zm3vdGMw-h95QsKRX002p9f_etba6bJSVqWdFKKP4CLWjFeMEFUy_RgpCyLhiv6zP0Zp5_EUJYqarX6IwqIWpVVwv0d7X3EDduTs7g1lowCQeLtcetH0Lawug8Xu8nwA2-BwNTChE3PulN8Bm6wKuC0LK-wD9d2uKYvjc4eJw5fAsPMUwxpGzpcq2xCSJud30Y86hViuE3vEWvrB5neHf8z9GPq3Z9eV3c3H35etncFIbLMhVMq0GVpaHWSGlIfppY3hstDFTQ10JCz5kcQFErteDaCiBykH2VFwbBynP0-eA7PfQ7GAz4FPXYTdHtdNx3Qbvuece7bbcJfzomOREVyQb8YGBimOcI9sRS0v2PozvFkSuqO8SRsQ9P5z5Cx_tnwcejQM9GjzZqb9x80jEiaUUpKf8BdAqWNA</recordid><startdate>20081001</startdate><enddate>20081001</enddate><creator>RUI LAN ZHANG</creator><creator>CHUNLING ZHANG</creator><creator>ZHENG GANG ZHANG</creator><creator>CHOPP, Michael</creator><creator>LI ZHANG</creator><creator>ROBERTS, Cindi</creator><creator>MEI LU</creator><creator>KAPKE, Alissa</creator><creator>YISHENG CUI</creator><creator>NINOMIYA, Mitsuyoshi</creator><creator>NAGAFUJI, Toshiaki</creator><creator>ALBALA, Bruce</creator><general>Lippincott Williams & Wilkins</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>5PM</scope></search><sort><creationdate>20081001</creationdate><title>Synergistic Effect of an Endothelin Type A Receptor Antagonist, S-0139, With rtPA on the Neuroprotection After Embolic Stroke</title><author>RUI LAN ZHANG ; CHUNLING ZHANG ; ZHENG GANG ZHANG ; CHOPP, Michael ; LI ZHANG ; ROBERTS, Cindi ; MEI LU ; KAPKE, Alissa ; YISHENG CUI ; NINOMIYA, Mitsuyoshi ; NAGAFUJI, Toshiaki ; ALBALA, Bruce</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c473t-2a8d833c1fc77c0c0ca0f4bca6ce5eb967eb427de81f7a64af6e07d7b5023e623</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Blood Platelets - drug effects</topic><topic>Blood-Brain Barrier - drug effects</topic><topic>Brain - drug effects</topic><topic>Brain - pathology</topic><topic>Caffeic Acids - administration & dosage</topic><topic>Collagen Type IV - biosynthesis</topic><topic>Collagen Type IV - drug effects</topic><topic>Drug Synergism</topic><topic>Endothelin Receptor Antagonists</topic><topic>Fibrinolytic Agents - administration & dosage</topic><topic>Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy</topic><topic>Immunohistochemistry</topic><topic>Infarction, Middle Cerebral Artery - drug therapy</topic><topic>Infarction, Middle Cerebral Artery - pathology</topic><topic>Intercellular Adhesion Molecule-1 - biosynthesis</topic><topic>Intercellular Adhesion Molecule-1 - drug effects</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Nervous system (semeiology, syndromes)</topic><topic>Neurology</topic><topic>Neuroprotective Agents - administration & dosage</topic><topic>Oleanolic Acid - administration & dosage</topic><topic>Oleanolic Acid - analogs & derivatives</topic><topic>Rats</topic><topic>Rats, Wistar</topic><topic>Receptor, PAR-1 - biosynthesis</topic><topic>Receptor, PAR-1 - drug effects</topic><topic>Recovery of Function - drug effects</topic><topic>Tight Junctions - drug effects</topic><topic>Tissue Plasminogen Activator - administration & dosage</topic><topic>Vascular diseases and vascular malformations of the nervous system</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>RUI LAN ZHANG</creatorcontrib><creatorcontrib>CHUNLING ZHANG</creatorcontrib><creatorcontrib>ZHENG GANG ZHANG</creatorcontrib><creatorcontrib>CHOPP, Michael</creatorcontrib><creatorcontrib>LI ZHANG</creatorcontrib><creatorcontrib>ROBERTS, Cindi</creatorcontrib><creatorcontrib>MEI LU</creatorcontrib><creatorcontrib>KAPKE, Alissa</creatorcontrib><creatorcontrib>YISHENG CUI</creatorcontrib><creatorcontrib>NINOMIYA, Mitsuyoshi</creatorcontrib><creatorcontrib>NAGAFUJI, Toshiaki</creatorcontrib><creatorcontrib>ALBALA, Bruce</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>PubMed Central (Full Participant titles)</collection><jtitle>Stroke (1970)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>RUI LAN ZHANG</au><au>CHUNLING ZHANG</au><au>ZHENG GANG ZHANG</au><au>CHOPP, Michael</au><au>LI ZHANG</au><au>ROBERTS, Cindi</au><au>MEI LU</au><au>KAPKE, Alissa</au><au>YISHENG CUI</au><au>NINOMIYA, Mitsuyoshi</au><au>NAGAFUJI, Toshiaki</au><au>ALBALA, Bruce</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synergistic Effect of an Endothelin Type A Receptor Antagonist, S-0139, With rtPA on the Neuroprotection After Embolic Stroke</atitle><jtitle>Stroke (1970)</jtitle><addtitle>Stroke</addtitle><date>2008-10-01</date><risdate>2008</risdate><volume>39</volume><issue>10</issue><spage>2830</spage><epage>2836</epage><pages>2830-2836</pages><issn>0039-2499</issn><eissn>1524-4628</eissn><coden>SJCCA7</coden><abstract>Using a model of embolic stroke, the present study tested the hypothesis that blockage of endothelin-1 with S-0139, a specific endothelin type A receptor (ET(A)) antagonist, enhances the neuroprotective effect of recombinant tissue plasminogen activator (rtPA) by suppressing molecules that mediate thrombosis and blood brain barrier (BBB) disruption induced by ischemia and rtPA.
Rats (n=104) subjected to embolic middle cerebral artery (MCA) occlusion were randomly divided into 1 of 4 infusion groups with 26 rats per group: (1) the control group in which rats were administered saline, (2) the monotherapy rtPA group in which rtPA was intravenously administered at a dose of 10 mg/kg 4 hours after MCA occlusion, (3) the monotherapy S-0139 group in which S-0139 was intravenously given 2 hours after MCA occlusion, and (4) the combination of rtPA +S-0139 group in which S-0139 and rtPA were given 2 and 4 hours after MCA occlusion, respectively. Measurements of infarct volume and parenchymal hemorrhage, behavioral outcome, and immunostaining were performed on rats euthanized 1 and 7 days after stroke.
The combination therapy of S-0139 and rtPA significantly (P<0.01) reduced infarct volume (24.8+/-0.9% versus 33.8+/-1.5% in control) and hemorrhagic area (7.1+/-6.1 microm(2) versus 36.5+/-19.2 microm(2) in control) and improved functional recovery compared with control saline-treated animals. Immunostaining analysis revealed that the combination therapy had the synergistically suppressed ischemia- and rtPA-induced ICAM-1, protease-activated receptor 1 (PAR-1), as well as accumulation of platelets in cerebral microvessels. Furthermore, the combination treatment synergistically reduced loss of laminin, ZO1, and occludin in cerebral vessels.
These data suggest that S-0139 provides the neuroprotection by suppressing ischemia- and rtPA-triggered molecules that evoke thrombosis and BBB disruption.</abstract><cop>Hagerstown, MD</cop><pub>Lippincott Williams & Wilkins</pub><pmid>18669895</pmid><doi>10.1161/STROKEAHA.108.515684</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Stroke (1970), 2008-10, Vol.39 (10), p.2830-2836 |
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| source | MEDLINE; American Heart Association Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Journals@Ovid Complete; Alma/SFX Local Collection |
| subjects | Animals Biological and medical sciences Blood Platelets - drug effects Blood-Brain Barrier - drug effects Brain - drug effects Brain - pathology Caffeic Acids - administration & dosage Collagen Type IV - biosynthesis Collagen Type IV - drug effects Drug Synergism Endothelin Receptor Antagonists Fibrinolytic Agents - administration & dosage Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy Immunohistochemistry Infarction, Middle Cerebral Artery - drug therapy Infarction, Middle Cerebral Artery - pathology Intercellular Adhesion Molecule-1 - biosynthesis Intercellular Adhesion Molecule-1 - drug effects Male Medical sciences Nervous system (semeiology, syndromes) Neurology Neuroprotective Agents - administration & dosage Oleanolic Acid - administration & dosage Oleanolic Acid - analogs & derivatives Rats Rats, Wistar Receptor, PAR-1 - biosynthesis Receptor, PAR-1 - drug effects Recovery of Function - drug effects Tight Junctions - drug effects Tissue Plasminogen Activator - administration & dosage Vascular diseases and vascular malformations of the nervous system |
| title | Synergistic Effect of an Endothelin Type A Receptor Antagonist, S-0139, With rtPA on the Neuroprotection After Embolic Stroke |
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