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Few effective treatments exist that attenuate IR injury. The augmentation of nitric oxide (NO) signaling remains a promising therapeutic target for IR injury. NO binds to soluble guanylyl cyclase (sGC) to regulate vasodilation, maintain endothelial barrier integrity, and modulate inflammation through the production of cyclic-GMP in vascular smooth muscle. Pharmacologic sGC stimulators and activators have recently been developed. In preclinical studies, sGC stimulators, which augment the reduced form of sGC, and activators, which activate the oxidized non-NO binding form of sGC, increase vasodilation and decrease cardiac, cerebral, renal, pulmonary, and hepatic injury following IR. These effects may be a result of the improved regulation of perfusion and decreased oxidative injury during IR. sGC stimulators are now used clinically to treat some chronic conditions such as heart failure and pulmonary hypertension. Clinical trials of sGC activators have been terminated secondary to adverse side effects including hypotension. Additional clinical studies to investigate the effects of sGC stimulation and activation during acute conditions, such as IR, are warranted.<\/jats:p>","DOI":"10.3390\/cells12141903","type":"journal-article","created":{"date-parts":[[2023,7,24]],"date-time":"2023-07-24T01:08:11Z","timestamp":1690160891000},"page":"1903","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Targeting Soluble Guanylyl Cyclase during Ischemia and Reperfusion"],"prefix":"10.3390","volume":"12","author":[{"given":"Eric H.","family":"Mace","sequence":"first","affiliation":[{"name":"Department of Surgery, Vanderbilt University Medical Center, Medical Center North, Suite CCC-4312, 1161 21st Avenue South, Nashville, TN 37232-2730, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa J.","family":"Kimlinger","sequence":"additional","affiliation":[{"name":"Vanderbilt University School of Medicine, 428 Eskind Family Biomedical Library and Learning Center, Nashville, TN 37240-0002, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"IV","given":"Frederic T.","family":"Billings","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Division of Critical Care Medicine, Vanderbilt University Medical Center, Medical Arts Building, Suite 422, 1211 21st Avenue South, Nashville, TN 37212-1750, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2622-4267","authenticated-orcid":false,"given":"Marcos G.","family":"Lopez","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Division of Critical Care Medicine, Vanderbilt University Medical Center, Medical Arts Building, Suite 422, 1211 21st Avenue South, Nashville, TN 37212-1750, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,7,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3659","DOI":"10.3892\/mmr.2015.3170","article-title":"A-lipoic Acid Protects against Cerebral Ischemia\/Reperfusion-induced Injury in Rats","volume":"11","author":"Deng","year":"2015","journal-title":"Mol. 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