{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T12:57:19Z","timestamp":1781787439802,"version":"3.54.5"},"reference-count":77,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"12","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Stroke"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>Overall, 75% of patients with acute stroke have elevated mean arterial pressure (MAP). In randomized stroke trials, the indirect NO donor glyceryl trinitrate lowered MAP but improved neither regional cerebral blood flow (rCBF) nor functional outcomes. One probable reason is that the microcirculation cannot bioactivate glyceryl trinitrate. In contrast, the direct NO donor 3-morpholinosydnonimine (SIN-1), not requiring bioactivation, should also release NO in small vessels, where it supports eNOS (endothelial NO synthase)\u2013derived NO in maintaining rCBF in the hypotensive portion of Lassen autoregulatory curve. In a meta-analysis, SIN-1 reduced infarct volume in ischemia models, but the effects of SIN-1 on early pathophysiology are unknown.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>Here, we investigated SIN-1 during a 60-minute bilateral common carotid artery occlusion and reperfusion in forty-eight 12- to 14-week-old Wistar-Kyoto rat (WKY) controls and 48 stroke-prone spontaneously hypertensive rats. We calculated the difference between the median values of each variable in the last 5 minutes of bilateral common carotid artery occlusion and baseline and compared them between treatment (SIN-1\/control) and strain (stroke-prone spontaneously hypertensive rat\/WKY) using 2-way ANOVA. We proceeded in the same way regarding reperfusion.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      Strain\u00d7intervention interaction was only found for MAP during bilateral common carotid artery occlusion. SIN-1 lowered MAP within stroke-prone spontaneously hypertensive rats (\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      &lt;0.001) and within WKY (\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      &lt;0.001), whereas MAP increased only in untreated stroke-prone spontaneously hypertensive rats versus untreated WKY (\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      =0.038). Across stroke-prone spontaneously hypertensive rat and WKY, SIN-1 increased rCBF (\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      &lt;0.001), increased spontaneous brain activity (\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      =0.002), lowered extracellular potassium concentration (\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      =0.009) and area under the curve of potassium (\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      =0.025), and reduced the direct current\u2013amplitude (\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      =0.028) and cumulative direct current\u2013shift duration (\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      =0.001), consistent with milder ischemia and less severe spreading depolarization load in SIN-1\u2013treated animals. During reperfusion, SIN-1 lowered MAP (\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      &lt;0.001), decreased the no-reflow area (\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      =0.002), increased rCBF (\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      &lt;0.001), increased spontaneous brain activity (\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      &lt;0.001), and decreased extracellular potassium (\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      =0.008) and direct current potential (\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      =0.022) in both strains, consistent with less no-reflow and better recovery in SIN-1\u2013treated animals.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>SIN-1 emerges as a promising antihypertensive in acute stroke as it paradoxically increases rCBF in ischemic tissue and reduces no-reflow.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/strokeaha.125.052917","type":"journal-article","created":{"date-parts":[[2025,9,4]],"date-time":"2025-09-04T09:01:13Z","timestamp":1756976473000},"page":"3484-3499","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":2,"title":["SIN-1 Improves Cerebral Blood Flow and Reduces Deviation From Brain Homeostasis During Ischemia and Reperfusion in Rats"],"prefix":"10.1161","volume":"56","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8323-3296","authenticated-orcid":true,"given":"Coline L.","family":"Lemale","sequence":"first","affiliation":[{"name":"Center for Stroke Research Berlin (C.L.L., B.B., S.M., J.P.D.), Charit\u00e9 Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin and Humboldt-Universit\u00e4t zu Berlin, Germany."},{"name":"Department of Experimental Neurology (C.L.L., S.M., J.P.D.), Charit\u00e9 Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin and Humboldt-Universit\u00e4t zu Berlin, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5182-8295","authenticated-orcid":true,"given":"Lina M.","family":"Serna-Higuita","sequence":"additional","affiliation":[{"name":"Institute for Clinical Epidemiology and Applied Biometry, University of T\u00fcbingen, Germany (L.M.S.-H., P.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7917-9645","authenticated-orcid":true,"given":"Baptiste","family":"Balan\u00e7a","sequence":"additional","affiliation":[{"name":"Center for Stroke Research Berlin (C.L.L., B.B., S.M., J.P.D.), Charit\u00e9 Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin and Humboldt-Universit\u00e4t zu Berlin, Germany."},{"name":"Inserm U1028, CNRS UMR 5292, Lyon Neuroscience Research Center, Team TIGER, Lyon, France (B.B.)."},{"name":"Universit\u00e9 Claude Bernard Lyon1, France (B.B.)."},{"name":"Department of Neurological Anesthesiology and Intensive Care Medicine, Hospices Civils de Lyon, France (B.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0950-0629","authenticated-orcid":true,"given":"Sara","family":"Simula","sequence":"additional","affiliation":[{"name":"Aix Marseille Univ, INSERM, INS, Int Neurosci Syst, France (S.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0970-1308","authenticated-orcid":true,"given":"Sebastian","family":"Major","sequence":"additional","affiliation":[{"name":"Center for Stroke Research Berlin (C.L.L., B.B., S.M., J.P.D.), Charit\u00e9 Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin and Humboldt-Universit\u00e4t zu Berlin, Germany."},{"name":"Department of Experimental Neurology (C.L.L., S.M., J.P.D.), Charit\u00e9 Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin and Humboldt-Universit\u00e4t zu Berlin, Germany."},{"name":"Department of Neurology (S.M., J.P.D.), Charit\u00e9 Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin and Humboldt-Universit\u00e4t zu Berlin, Germany."},{"name":"QUEST Center for Responsible Research, Berlin Institute of Health at Charit\u00e9 Universit\u00e4tsmedizin Berlin, Germany (S.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Martus","sequence":"additional","affiliation":[{"name":"Institute for Clinical Epidemiology and Applied Biometry, University of T\u00fcbingen, Germany (L.M.S.-H., P.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3454-6576","authenticated-orcid":true,"given":"Ingemar","family":"Fredriksson","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Link\u00f6ping University, Sweden (I.F.)."},{"name":"Perimed AB, J\u00e4rf\u00e4lla, Stockholm, Sweden (I.F.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7459-2828","authenticated-orcid":true,"given":"Jens P.","family":"Dreier","sequence":"additional","affiliation":[{"name":"Center for Stroke Research Berlin (C.L.L., B.B., S.M., J.P.D.), Charit\u00e9 Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin and Humboldt-Universit\u00e4t zu Berlin, Germany."},{"name":"Department of Experimental Neurology (C.L.L., S.M., J.P.D.), Charit\u00e9 Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin and Humboldt-Universit\u00e4t zu Berlin, Germany."},{"name":"Department of Neurology (S.M., J.P.D.), Charit\u00e9 Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin and Humboldt-Universit\u00e4t zu Berlin, Germany."},{"name":"Bernstein Center for Computational Neuroscience Berlin, Germany (J.P.D.)."},{"name":"Einstein Center for Neurosciences Berlin, Germany 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