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Some H<jats:sub>2<\/jats:sub>S-donors exert their beneficial effects in a nitric oxide (NO)-dependent manner, while others act using NO-independent pathways. The aims of the present study were to (i) evaluate whether H<jats:sub>2<\/jats:sub>S-donors with distinct pharmacodynamic properties act synergistically in I\/R injury and (ii) determine if H<jats:sub>2<\/jats:sub>S-donors remain cardioprotective in obese mice. C57BL\/6 mice were subjected to 30\u00a0min of ischemia followed by 120\u00a0min of reperfusion. Donors were administered intravenously at the end of ischemia (Na<jats:sub>2<\/jats:sub>S: 1\u00a0\u03bcmol\/kg, GYY4137: 25\u00a0\u03bcmol\/kg, AP39: 0,25\u00a0\u03bcmol\/kg), while the 3-mercaptopyruvate sulfurtransferase (10\u00a0mg\/kg) inhibitor was given intraperitonially 1\u00a0h prior to ischemia. Infarct size was estimated by 2,3,5-triphenyltetrazolium staining, while the area at risk was calculated using Evans blue. All three donors reduced infarct size when administered as a sole treatment. Co-administration of Na<jats:sub>2<\/jats:sub>S\/GYY4137, as well as Na<jats:sub>2<\/jats:sub>S\/AP39 reduced further the I\/R injury, beyond what was observed with each individual donor. Since inhibition of the H<jats:sub>2<\/jats:sub>S-producing enzyme 3-mercaptopyruvate sulfurtransferase is known to reduce infarct size, we co-administered C3 with Na<jats:sub>2<\/jats:sub>S to determine possible additive effects between the two agents. In this case, combination of C3 with Na<jats:sub>2<\/jats:sub>S did not yield superior results compared to the individual treatments. Similarly, to what was observed in healthy mice, administration of a H<jats:sub>2<\/jats:sub>S-donor (Na<jats:sub>2<\/jats:sub>S or AP39) reduced I\/R injury in mice rendered obese by consumption of a high fat diet. We conclude that combining a NO-dependent with a NO-independent H<jats:sub>2<\/jats:sub>S-donor leads to enhanced cardioprotection and that H<jats:sub>2<\/jats:sub>S-donors remain effective in obese animals.<\/jats:p>","DOI":"10.1007\/s00210-023-02729-6","type":"journal-article","created":{"date-parts":[[2023,9,29]],"date-time":"2023-09-29T11:02:13Z","timestamp":1695985333000},"page":"1853-1864","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Using mechanism-based combinations of H2S-donors to maximize the cardioprotective action of H2S"],"prefix":"10.1007","volume":"397","author":[{"given":"Stella","family":"Ravani","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Athanasia","family":"Chatzianastasiou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Papapetropoulos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,9,29]]},"reference":[{"key":"2729_CR1","doi-asserted-by":"publisher","first-page":"1649","DOI":"10.1039\/C5MD00170F","volume":"6","author":"B Alexander","year":"2015","unstructured":"Alexander B, Coles SJ, Fox BC, Khan TF, Maliszewi J, Perry A, Pitak MP, Whiteman M, Wood ME (2015) Investigating the generation of hydrogen sulfide from the phosphinodithioate slow-release donor GYY4137. 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