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

HS-donors are cardioprotective in ischemia/reperfusion (I/R) injury. Some HS-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 HS-donors with distinct pharmacodynamic properties act synergistically in I/R injury and (ii) determine if HS-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 (NaS: 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 NaS/GYY4137, as well as NaS/AP39 reduced further the I/R injury, beyond what was observed with each individual donor. Since inhibition of the HS-producing enzyme 3-mercaptopyruvate sulfurtransferase is known to reduce infarct size, we co-administered C3 with NaS to determine possible additive effects between the two agents. In this case, combination of C3 with NaS did not yield superior results compared to the individual treatments. Similarly, to what was observed in healthy mice, administration of a HS-donor (NaS 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 HS-donor leads to enhanced cardioprotection and that HS-donors remain effective in obese animals.