Isoflurane Conditioning‐Induced Delayed Cerebral Ischemia Protection in Subarachnoid Hemorrhage—Role of Inducible Nitric Oxide Synthase
Background Recent evidence implicates inflammation as a key driver in delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage (SAH). Inducible nitric oxide synthase (iNOS) is one of the known major mediators of inflammation. We previously showed that an inhalational anesthetic, isoflurane...
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| Format: | Article |
| Language: | English |
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Wiley
2023-07-01
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| Series: | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| Subjects: | |
| Online Access: | https://www.ahajournals.org/doi/10.1161/JAHA.123.029975 |
| _version_ | 1797742628485201920 |
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| author | Meizi Liu Keshav Jayaraman Aaron J. Norris Ahmed Hussein James W. Nelson Jogender Mehla Deepti Diwan Ananth Vellimana Yousef Abu‐Amer Gregory J. Zipfel Umeshkumar Athiraman |
| author_facet | Meizi Liu Keshav Jayaraman Aaron J. Norris Ahmed Hussein James W. Nelson Jogender Mehla Deepti Diwan Ananth Vellimana Yousef Abu‐Amer Gregory J. Zipfel Umeshkumar Athiraman |
| author_sort | Meizi Liu |
| collection | DOAJ |
| description | Background Recent evidence implicates inflammation as a key driver in delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage (SAH). Inducible nitric oxide synthase (iNOS) is one of the known major mediators of inflammation. We previously showed that an inhalational anesthetic, isoflurane, provides strong protection against delayed cerebral ischemia after SAH. Our current study aims to define the role of iNOS in isoflurane conditioning‐induced protection against delayed cerebral ischemia in a mouse model of SAH. Methods and Results The experiments used 10‐ to 14‐week‐old male wild‐type (C57BL/6) and iNOS global knockout mice. Anesthetic conditioning was initiated 1 hour after SAH with isoflurane 2% for 1 hour. Isoflurane‐induced changes in iNOS expression were measured. N‐(3‐(aminomethyl) benzyl) acetamidine, a highly selective iNOS inhibitor, was injected intraperitoneally immediately after SAH and then daily. Vasospasm, microvessel thrombosis, and neurological assessment was performed. Data were analyzed by 1‐way ANOVA and 2‐way repeated measures ANOVA followed by Student Newman Keuls comparison test. Statistical significance was set at P<0.05. Isoflurane conditioning downregulated iNOS expression in naïve and SAH mice. N‐(3‐(aminomethyl) benzyl) acetamidine attenuated large artery vasospasm and microvessel thrombosis and improved neurological deficits in wild‐type animals. iNOS knockout mice were significantly resistant to vasospasm, microvessel thrombosis, and neurological deficits induced by SAH. Combining isoflurane with N‐(3‐(aminomethyl) benzyl) acetamidine did not offer extra protection, nor did treating iNOS knockout mice with isoflurane. Conclusions Isoflurane conditioning‐induced delayed cerebral ischemia protection appears to be mediated by downregulating iNOS. iNOS is a potential therapeutic target to improve outcomes after SAH. |
| first_indexed | 2024-03-12T14:43:21Z |
| format | Article |
| id | doaj.art-bdf8c2085ff84924a699b42cb9ad5e00 |
| institution | Directory Open Access Journal |
| issn | 2047-9980 |
| language | English |
| last_indexed | 2024-03-12T14:43:21Z |
| publishDate | 2023-07-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| spelling | doaj.art-bdf8c2085ff84924a699b42cb9ad5e002023-08-16T04:54:43ZengWileyJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-99802023-07-01121410.1161/JAHA.123.029975Isoflurane Conditioning‐Induced Delayed Cerebral Ischemia Protection in Subarachnoid Hemorrhage—Role of Inducible Nitric Oxide SynthaseMeizi Liu0Keshav Jayaraman1Aaron J. Norris2Ahmed Hussein3James W. Nelson4Jogender Mehla5Deepti Diwan6Ananth Vellimana7Yousef Abu‐Amer8Gregory J. Zipfel9Umeshkumar Athiraman10Department of Anesthesiology Washington University St. Louis MO USADepartment of Anesthesiology Washington University St. Louis MO USADepartment of Anesthesiology Washington University St. Louis MO USADepartment of Neurological Surgery Washington University St. Louis MO USADepartment of Neurological Surgery Washington University St. Louis MO USADepartment of Neurological Surgery Washington University St. Louis MO USADepartment of Neurological Surgery Washington University St. Louis MO USADepartment of Neurological Surgery Washington University St. Louis MO USADepartment of Orthopedics Washington University St. Louis MO USADepartment of Neurological Surgery Washington University St. Louis MO USADepartment of Anesthesiology Washington University St. Louis MO USABackground Recent evidence implicates inflammation as a key driver in delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage (SAH). Inducible nitric oxide synthase (iNOS) is one of the known major mediators of inflammation. We previously showed that an inhalational anesthetic, isoflurane, provides strong protection against delayed cerebral ischemia after SAH. Our current study aims to define the role of iNOS in isoflurane conditioning‐induced protection against delayed cerebral ischemia in a mouse model of SAH. Methods and Results The experiments used 10‐ to 14‐week‐old male wild‐type (C57BL/6) and iNOS global knockout mice. Anesthetic conditioning was initiated 1 hour after SAH with isoflurane 2% for 1 hour. Isoflurane‐induced changes in iNOS expression were measured. N‐(3‐(aminomethyl) benzyl) acetamidine, a highly selective iNOS inhibitor, was injected intraperitoneally immediately after SAH and then daily. Vasospasm, microvessel thrombosis, and neurological assessment was performed. Data were analyzed by 1‐way ANOVA and 2‐way repeated measures ANOVA followed by Student Newman Keuls comparison test. Statistical significance was set at P<0.05. Isoflurane conditioning downregulated iNOS expression in naïve and SAH mice. N‐(3‐(aminomethyl) benzyl) acetamidine attenuated large artery vasospasm and microvessel thrombosis and improved neurological deficits in wild‐type animals. iNOS knockout mice were significantly resistant to vasospasm, microvessel thrombosis, and neurological deficits induced by SAH. Combining isoflurane with N‐(3‐(aminomethyl) benzyl) acetamidine did not offer extra protection, nor did treating iNOS knockout mice with isoflurane. Conclusions Isoflurane conditioning‐induced delayed cerebral ischemia protection appears to be mediated by downregulating iNOS. iNOS is a potential therapeutic target to improve outcomes after SAH.https://www.ahajournals.org/doi/10.1161/JAHA.123.029975DCIiNOSisofluraneneurovascular protectionsubarachnoid hemorrhage |
| spellingShingle | Meizi Liu Keshav Jayaraman Aaron J. Norris Ahmed Hussein James W. Nelson Jogender Mehla Deepti Diwan Ananth Vellimana Yousef Abu‐Amer Gregory J. Zipfel Umeshkumar Athiraman Isoflurane Conditioning‐Induced Delayed Cerebral Ischemia Protection in Subarachnoid Hemorrhage—Role of Inducible Nitric Oxide Synthase Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease DCI iNOS isoflurane neurovascular protection subarachnoid hemorrhage |
| title | Isoflurane Conditioning‐Induced Delayed Cerebral Ischemia Protection in Subarachnoid Hemorrhage—Role of Inducible Nitric Oxide Synthase |
| title_full | Isoflurane Conditioning‐Induced Delayed Cerebral Ischemia Protection in Subarachnoid Hemorrhage—Role of Inducible Nitric Oxide Synthase |
| title_fullStr | Isoflurane Conditioning‐Induced Delayed Cerebral Ischemia Protection in Subarachnoid Hemorrhage—Role of Inducible Nitric Oxide Synthase |
| title_full_unstemmed | Isoflurane Conditioning‐Induced Delayed Cerebral Ischemia Protection in Subarachnoid Hemorrhage—Role of Inducible Nitric Oxide Synthase |
| title_short | Isoflurane Conditioning‐Induced Delayed Cerebral Ischemia Protection in Subarachnoid Hemorrhage—Role of Inducible Nitric Oxide Synthase |
| title_sort | isoflurane conditioning induced delayed cerebral ischemia protection in subarachnoid hemorrhage role of inducible nitric oxide synthase |
| topic | DCI iNOS isoflurane neurovascular protection subarachnoid hemorrhage |
| url | https://www.ahajournals.org/doi/10.1161/JAHA.123.029975 |
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