{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,3]],"date-time":"2026-04-03T12:22:45Z","timestamp":1775218965300,"version":"3.50.1"},"reference-count":34,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2020,9,5]],"date-time":"2020-09-05T00:00:00Z","timestamp":1599264000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["IJMS"],"abstract":"<jats:p>Background: Cerebral vasospasm (CVS) remains a major cause of delayed cerebral ischaemia following aneurysmal subarachnoid haemorrhage (SAH), making it a life-threatening type of stroke with high morbidity and mortality. Endothelin-1 is known as key player mediating a strong vasocontractile effect. Interestingly, losartan restores the impaired vasorelaxative ET(B1) receptor function in a non-competitive direct fashion. With this study, we aimed to investigate a potential losartan-dependent vasodilatory effect vice versa by inhibiting NO release through L-NAME, thus pushing forward concepts to alleviate vasospasm and possibly prevent ischaemia and neurodegeneration. Methods: Cerebral vasospasm was induced by the use of an established double-injection rat model. Sprague-Dawley rats were culled on Day 3 after the ictus, and the vasospastic basilar artery was harvested for isometric investigations of the vessel tone. Ring segments were preincubated with and without L-NAME and\/or losartan. Results: Preincubation with L-NAME induced dose-dependent vasoconstriction via endothelin-1 in the non-SAH cohort, which was dose-dependently reduced by losartan. After SAH and dose-dependent endothelin-1 administration, maximal contraction was achieved in the control group without losartan. Furthermore, this maximal contraction was significantly decreased in the losartan group and was reversed by L-NAME. Conclusions: After SAH, losartan was shown to positively influence the ET(B1) receptor pathway in a non-competitive direct agonistic and indirect fashion. Losartan alleviated the maximum contraction triggered by endothelin-1. This effect was resolved due to NO inhibition by L-NAME. Considering this spasmolytic effect of losartan besides its already well-known effects (attenuating cerebral inflammation, restoring cerebral autoregulation and reducing epileptogenic activity) and alleviating early brain injury, losartan seems to have potential as a promising pharmacological agent after SAH.<\/jats:p>","DOI":"10.3390\/ijms21186496","type":"journal-article","created":{"date-parts":[[2020,9,6]],"date-time":"2020-09-06T23:12:49Z","timestamp":1599433969000},"page":"6496","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["The Role of Losartan as a Potential Neuroregenerative Pharmacological Agent after Aneurysmal Subarachnoid Haemorrhage"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4510-5741","authenticated-orcid":false,"given":"Stefan","family":"Wanderer","sequence":"first","affiliation":[{"name":"Department of Neurosurgery, Kantonsspital Aarau, Tellstrasse 25, 5001 Aarau, Switzerland"},{"name":"Cerebrovascular Research Group, Department for BioMedical Research, University of Bern, 3008 Bern, Switzerland"},{"name":"Department of Neurosurgery, Goethe-University Hospital, Schleusenweg 2 \u2013 16, 60528 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1764-688X","authenticated-orcid":false,"given":"Lukas","family":"Andereggen","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Kantonsspital Aarau, Tellstrasse 25, 5001 Aarau, Switzerland"},{"name":"Cerebrovascular Research Group, Department for BioMedical Research, University of Bern, 3008 Bern, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan","family":"Mrosek","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Goethe-University Hospital, Schleusenweg 2 \u2013 16, 60528 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0052-9073","authenticated-orcid":false,"given":"Sepide","family":"Kashefiolasl","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Goethe-University Hospital, Schleusenweg 2 \u2013 16, 60528 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6305-7571","authenticated-orcid":false,"given":"Serge","family":"Marbacher","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Kantonsspital Aarau, Tellstrasse 25, 5001 Aarau, Switzerland"},{"name":"Cerebrovascular Research Group, Department for BioMedical Research, University of Bern, 3008 Bern, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9771-7806","authenticated-orcid":false,"given":"J\u00fcrgen","family":"Konczalla","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Goethe-University Hospital, Schleusenweg 2 \u2013 16, 60528 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,9,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2391","DOI":"10.1161\/STROKEAHA.110.589275","article-title":"Definition of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage as an outcome event in clinical trials and observational studies: Proposal of a multidisciplinary research group","volume":"41","author":"Vergouwen","year":"2010","journal-title":"Stroke"},{"key":"ref_2","first-page":"131","article-title":"Endothelins and the cerebral circulation","volume":"7","author":"Salom","year":"1995","journal-title":"Cereb. Brain Metab. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.3171\/jns.2005.102.6.1101","article-title":"Cerebrovascular characterization of clazosentan, the first nonpeptide endothelin receptor antagonist clinically effective for the treatment of cerebral vasospasm. Part I: Inhibitory effect on endothelin(A) receptor-mediated contraction","volume":"102","author":"Vatter","year":"2005","journal-title":"J. Neurosurg."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"561","DOI":"10.3174\/ajnr.A5024","article-title":"Feasibility and Safety of Repeat Instant Endovascular Interventions in Patients with Refractory Cerebral Vasospasms","volume":"38","author":"Andereggen","year":"2017","journal-title":"AJNR Am. J. Neuroradiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1007\/978-3-7091-1192-5_42","article-title":"Inflammation in subarachnoid hemorrhage and delayed deterioration associated with vasospasm: A review","volume":"115","author":"Provencio","year":"2013","journal-title":"Acta Neurochir. Suppl."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1007\/s12975-013-0257-2","article-title":"Early brain injury, an evolving frontier in subarachnoid hemorrhage research","volume":"4","author":"Fujii","year":"2013","journal-title":"Transl. Stroke Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1007\/978-3-7091-1192-5_26","article-title":"Spreading ischemia after aneurysmal subarachnoid hemorrhage","volume":"115","author":"Dreier","year":"2013","journal-title":"Acta Neurochir. Suppl."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3230","DOI":"10.1161\/STROKEAHA.112.669788","article-title":"Impairment of cerebral autoregulation predicts delayed cerebral ischemia after subarachnoid hemorrhage: A prospective observational study","volume":"43","author":"Budohoski","year":"2012","journal-title":"Stroke"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1016\/S0031-6997(25)06809-7","article-title":"Endothelins: Molecular biology, biochemistry, pharmacology, physiology, and pathophysiology","volume":"46","author":"Rubanyi","year":"1994","journal-title":"Pharmacol. Rev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1159\/000231974","article-title":"Mechanisms underlying the vascular actions of endothelin 1, angiotensin II and bradykinin in the rat carotid","volume":"84","author":"Tirapelli","year":"2009","journal-title":"Pharmacology"},{"key":"ref_11","first-page":"1064","article-title":"Alteration of the cerebrovascular function of endothelin B receptor after subarachnoidal hemorrhage in the rat","volume":"231","author":"Konczalla","year":"2006","journal-title":"Exp. Biol. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"H3750","DOI":"10.1152\/ajpheart.00857.2007","article-title":"Cerebrovascular ETB, 5-HT1B, and AT1 receptor upregulation correlates with reduction in regional CBF after subarachnoid hemorrhage","volume":"293","author":"Ansar","year":"2007","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1007\/s10571-006-9009-0","article-title":"Mechanisms of the Anti-Ischemic Effect of Angiotensin II AT( 1 ) Receptor Antagonists in the Brain","volume":"26","author":"Saavedra","year":"2006","journal-title":"Cell Mol. Neurobiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"335","DOI":"10.2174\/15672026113109990030","article-title":"Crosstalk between the angiotensin and endothelin-system in the cerebrovasculature","volume":"10","author":"Konczalla","year":"2013","journal-title":"Curr. Neurovasc. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e301","DOI":"10.1016\/j.wneu.2018.07.138","article-title":"Intra-Arterial Papaverine-Hydrochloride and Transluminal Balloon Angioplasty for Neurointerventional Management of Delayed-Onset Post-Aneurysmal Subarachnoid Hemorrhage Vasospasm","volume":"119","author":"Hosmann","year":"2018","journal-title":"World Neurosurg."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1007\/s10143-017-0887-z","article-title":"Crosstalk between the angiotensin and endothelin system in the cerebrovasculature after experimental induced subarachnoid hemorrhage","volume":"41","author":"Wanderer","year":"2018","journal-title":"Neurosurg. Rev."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1139\/y11-032","article-title":"Human recombinant erythropoietin alters the flow-dependent vasodilatation of in vitro perfused rat mesenteric arteries with unbalanced endothelial endothelin-1 \/ nitric oxide ratio","volume":"89","author":"Barhoumi","year":"2011","journal-title":"Can. J. Physiol. Pharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1007\/s00701-017-3419-2","article-title":"Vasomodulatory effects of the angiotensin II type 1 receptor antagonist losartan on experimentally induced cerebral vasospasm after subarachnoid haemorrhage","volume":"160","author":"Wanderer","year":"2018","journal-title":"Acta Neurochir."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.pbb.2014.10.005","article-title":"Antiepileptogenic and neuroprotective effects of losartan in kainate model of temporal lobe epilepsy","volume":"127","author":"Tchekalarova","year":"2014","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1149","DOI":"10.1161\/HYPERTENSIONAHA.106.084939","article-title":"Cerebral hemodynamics after short- and long-term reduction in blood pressure in mild and moderate hypertension","volume":"49","author":"Zhang","year":"2007","journal-title":"Hypertension"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Wanderer, S., Gruter, B.E., Strange, F., Sivanrupan, S., Di Santo, S., Widmer, H.R., Fandino, J., Marbacher, S., and Andereggen, L. (2020). The Role of Sartans in the Treatment of Stroke and Subarachnoid Hemorrhage: A Narrative Review of Preclinical and Clinical Studies. Brain Sci., 10.","DOI":"10.3390\/brainsci10030153"},{"key":"ref_22","first-page":"585","article-title":"Telmisartan regulates the development of cerebral ischemia by alleviating endoplasmic reticulum stress","volume":"73","author":"Li","year":"2018","journal-title":"Pharmazie"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1007\/s10571-015-0278-3","article-title":"Long-Term Treatment with Losartan Attenuates Seizure Activity and Neuronal Damage Without Affecting Behavioral Changes in a Model of Co-morbid Hypertension and Epilepsy","volume":"36","author":"Tchekalarova","year":"2016","journal-title":"Cell Mol. Neurobiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1016\/S0140-6736(07)60153-6","article-title":"Subarachnoid haemorrhage","volume":"369","author":"Kerr","year":"2007","journal-title":"Lancet"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"H1989","DOI":"10.1152\/ajpheart.00839.2004","article-title":"Angiogenic protection from focal ischemia with angiotensin II type 1 receptor blockade in the rat","volume":"288","author":"Forder","year":"2005","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"864","DOI":"10.1002\/ana.24147","article-title":"Losartan prevents acquired epilepsy via TGF-beta signaling suppression","volume":"75","author":"Cacheaux","year":"2014","journal-title":"Ann. Neurol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.vph.2018.08.006","article-title":"Post-stroke losartan and captopril treatments arrest hemorrhagic expansion in SHRsp without lowering blood pressure","volume":"111","author":"Smeda","year":"2018","journal-title":"Vascul. Pharmacol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1291\/hypres.28.43","article-title":"Hemodynamic influences of losartan on the brain in hypertensive patients","volume":"28","author":"Oku","year":"2005","journal-title":"Hypertens. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1577","DOI":"10.1111\/j.1476-5381.2010.00872.x","article-title":"Animal research: Reporting in vivo experiments: The ARRIVE guidelines","volume":"160","author":"Kilkenny","year":"2010","journal-title":"Br. J. Pharmacol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1190","DOI":"10.1227\/01.NEU.0000199346.74649.66","article-title":"Time course in the development of cerebral vasospasm after experimental subarachnoid hemorrhage: Clinical and neuroradiological assessment of the rat double hemorrhage model","volume":"58","author":"Vatter","year":"2006","journal-title":"Neurosurgery"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1161\/01.STR.17.3.472","article-title":"Rat middle cerebral artery occlusion: Evaluation of the model and development of a neurologic examination","volume":"17","author":"Bederson","year":"1986","journal-title":"Stroke"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1358\/mf.2004.26.4.831333","article-title":"Experimental approaches to evaluate endothelin-A receptor antagonists","volume":"26","author":"Vatter","year":"2004","journal-title":"Methods Find Exp. Clin. Pharmacol."},{"key":"ref_33","first-page":"652","article-title":"Interactions between extracellular and intracellular administered angiotensin II in isolated rat portal vein rings","volume":"108","author":"Gurzu","year":"2004","journal-title":"Rev. Med. Chir. Soc. Med. Nat. Iasi"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1100","DOI":"10.1227\/01.NEU.0000255471.75752.4B","article-title":"Characterization of the endothelin-B receptor expression and vasomotor function during experimental cerebral vasospasm","volume":"60","author":"Vatter","year":"2007","journal-title":"Neurosurgery"}],"updated-by":[{"DOI":"10.3390\/ijms26052312","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2020,9,5]],"date-time":"2020-09-05T00:00:00Z","timestamp":1599264000000}}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/18\/6496\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,3]],"date-time":"2025-08-03T22:22:42Z","timestamp":1754259762000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/18\/6496"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,9,5]]},"references-count":34,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2020,9]]}},"alternative-id":["ijms21186496"],"URL":"https:\/\/doi.org\/10.3390\/ijms21186496","relation":{"correction":[{"id-type":"doi","id":"10.3390\/ijms26052312","asserted-by":"object"}]},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,9,5]]}}}