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Using mechanism-based combinations of H2S-donors to maximize the cardioprotective action of H2S

Stella Ravani,A. Chatzianastasiou,A. Papapetropoulos

Published 2023 in Naunyn-Schmiedeberg's Archives of Pharmacology

ABSTRACT

H_2S-donors are cardioprotective in ischemia/reperfusion (I/R) injury. Some H_2S-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_2S-donors with distinct pharmacodynamic properties act synergistically in I/R injury and (ii) determine if H_2S-donors remain cardioprotective in obese mice. C57BL/6 mice were subjected to 30 min of ischemia followed by 120 min of reperfusion. Donors were administered intravenously at the end of ischemia (Na_2S: 1 μmol/kg, GYY4137: 25 μmol/kg, AP39: 0,25 μmol/kg), while the 3-mercaptopyruvate sulfurtransferase (10 mg/kg) inhibitor was given intraperitonially 1 h 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_2S/GYY4137, as well as Na_2S/AP39 reduced further the I/R injury, beyond what was observed with each individual donor. Since inhibition of the H_2S-producing enzyme 3-mercaptopyruvate sulfurtransferase is known to reduce infarct size, we co-administered C3 with Na_2S to determine possible additive effects between the two agents. In this case, combination of C3 with Na_2S did not yield superior results compared to the individual treatments. Similarly, to what was observed in healthy mice, administration of a H_2S-donor (Na_2S 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_2S-donor leads to enhanced cardioprotection and that H_2S-donors remain effective in obese animals.

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