{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T11:22:42Z","timestamp":1764069762358,"version":"3.45.0"},"reference-count":55,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T00:00:00Z","timestamp":1764028800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001807","name":"S\u00e3o Paulo Research Foundation","doi-asserted-by":"publisher","award":["2019\/18886-1","2017\/08122-9"],"award-info":[{"award-number":["2019\/18886-1","2017\/08122-9"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Intravascular hemolysis, a hallmark of sickle cell disease (SCD), leads to elevated plasma heme levels. Although heme is essential for physiological processes, its excess can be deleterious. Heme oxygenase (HO) degrades heme into carbon monoxide (CO), which activates the soluble guanylate cyclase (sGC)\u2013cyclic guanosine monophosphate (cGMP) signaling cascade and can modulate smooth muscle tone. However, the direct effects of heme on bladder function remain unknown. This study investigated whether heme regulates detrusor smooth muscle contractility through the HO\u2013CO\u2013sGC\u2013cGMP pathway. Detrusor strips from C57BL\/6 mice were mounted on a myograph for functional analysis. Heme induced a significant, concentration-dependent relaxation of detrusor smooth muscle compared with vehicle-treated tissues. To elucidate the underlying mechanism, tissues were pre-incubated with the sGC inhibitor ODQ (10 \u00b5M) or the HO inhibitor 1J (100 \u00b5M) before heme exposure. Both inhibitors markedly attenuated heme-induced relaxation, reducing the maximal relaxation response. Moreover, pre-incubation with heme (100 \u00b5M) significantly decreased the maximal contractile responses (Emax) to carbachol, KCl, and electrical field stimulation (EFS), effects that were abolished by ODQ or 1J. In parallel, biochemical assays showed that heme markedly increased cGMP levels in detrusor tissue, an effect prevented by both inhibitors, confirming the role of the HO\u2013CO\u2013sGC\u2013cGMP signaling cascade in this response. These findings demonstrate that heme modulates bladder contractility by activating the HO\u2013CO\u2013sGC\u2013cGMP pathway, promoting detrusor relaxation. This mechanism suggests that excessive circulating heme, as occurs in hemolytic disorders such as SCD, may contribute to detrusor hypocontractility and voiding dysfunctions, identifying this pathway as a potential therapeutic target.<\/jats:p>","DOI":"10.3390\/antiox14121398","type":"journal-article","created":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T10:46:18Z","timestamp":1764067578000},"page":"1398","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Heme Modulates Bladder Contractility Through the HO\u2013CO\u2013sGC\u2013cGMP Pathway: Insights into Sickle Cell Disease-Associated Bladder Dysfunction"],"prefix":"10.3390","volume":"14","author":[{"given":"Dalila Andrade","family":"Pereira","sequence":"first","affiliation":[{"name":"Laboratory of Pharmacology, S\u00e3o Francisco University Medical School, Bragan\u00e7a Paulista 12916-900, SP, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fernando Ferreira","family":"Costa","sequence":"additional","affiliation":[{"name":"Hematology and Hemotherapy Center, University of Campinas, Campinas 13083-970, SP, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3374-5570","authenticated-orcid":false,"given":"F\u00e1bio Henrique","family":"Silva","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacology, S\u00e3o Francisco University Medical School, Bragan\u00e7a Paulista 12916-900, SP, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1001\/jama.2022.10233","article-title":"Sickle Cell Disease: A Review","volume":"328","author":"Kavanagh","year":"2022","journal-title":"JAMA"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1111\/j.1537-2995.2006.00679.x","article-title":"Hyperhemolysis during the Evolution of Uncomplicated Acute Painful Episodes in Patients with Sickle Cell Anemia","volume":"46","author":"Ballas","year":"2006","journal-title":"Transfusion"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.urology.2008.02.006","article-title":"Enuresis Is a Common and Persistent Problem among Children and Young Adults with Sickle Cell Anemia","volume":"72","author":"Field","year":"2008","journal-title":"Urology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.1016\/j.juro.2011.10.171","article-title":"Prevalence of Enuresis and Daytime Urinary Incontinence in Children and Adolescents with Sickle Cell Disease","volume":"187","author":"Portocarrero","year":"2012","journal-title":"J. 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