Soluble guanylate cyclase activation prevents postischemic inflammation in wild type and heme oxygenase‐1 KO mice

It was observed that heme oxygenase‐1 KO mice (H mox 1(−/−)), do not exhibit protection from ischemia/reperfusion (IR) inflammation afforded by hydrogen sulfide or ethanol, preconditioning stimuli that limit postischemic inflammation via soluble guanylate cyclase (sGC)‐dependent mechanisms in wild‐type mice (WT). BAY 60‐2770 activates oxidized/heme‐free sGC, while BAY 41‐2272 stimulates reduced sGC (JPET 335:85‐91, 2010). We hypothesized that pretreatment with the BAY compounds would limit postischemic inflammation & reverse nitrate tolerance in H mox 1(−/− ). Intravital fluorescence microscopy was used to visualize leukocyte rolling (LR) and adhesion (LA) in single postcapillary venules of the small intestine. Drug responses were measured on superior mesenteric arterial (SMA) rings isolated after IR. Preconditioning with either Bay compound 10 min prior to IR reduced postischemic LR and LA in both WT and H mox 1(−/−), and was associated with increased SMA responses to acetylcholine and sodium nitroprusside. Preconditioning 24 h prior to IR attenuated IR‐induced LR and LA in WT. 24 h experiments on H mox 1(−/−) are in progress. It is concluded that the sGC active agents, BAY 60‐2770 and BAY 41‐2272, limit postischemic inflammation and may also reduce nitrate tolerance in H mox 1(−/−). Supported by HL59976, HL82816 & AA14945. BAY 60‐2770 was a gift from Bayer Schering Pharma AG.