The hydrogen sulfide donor IK‐1001 protects against hepatic reperfusion injury in a murine model: evidence for a gender difference

IK‐1001 is a parenteral sulfide donor that recently entered human trials. Published literature shows sulfide to be protective in myocardial ischemia. We explored the potential protective effects in hepatic ischemia. C57/B6 mice were anesthetized and a midline laparotomy was performed to expose the liver. Mice were treated with heparin to prevent clotting after which a micoaneurysm clip was applied to the hepatic artery and portal vein to create liver ischemia. In the last 5 minutes of a 45 minute occlusion, vehicle or IK‐1001 (2.3 mg/kg) was injected into inferior vena cava. The clips were removed to restore hepatic blood flow which was confirmed visually. The abdominal incision was closed and animals were recovered. At 5‐hours reperfusion, blood was collected to measure serum alanine aminotransferase (ALT). In vehicle treated male animals, ALT was 841 ± 261 U/L (n=10). With IK‐1001, ALT was reduced to 582 U/L ± 71 % (p<0.048) n=10. Interestingly, when studies were repeated in female mice, the degree of injury appeared reduced (497 ± 69 U/L, n=4) in comparison to male mice and no significant reduction in ALT was noted when female mice were treated with IK‐1001 (493 ± 185 U/L, n=8). We conclude that administration of IK‐1001 at the time of reperfusion results in liver protection as measured by ALT. In female mice, comparable ischemia did not appear to produce comparable injury and may explain a lack of benefit of IK‐1001 in females.