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Soluble guanylate cyclase activation protects against postischemic inflammation and reduces nitrate tolerance in heme‐oxygenase‐1 knockout mice
Author(s) -
Wang Walter Zhuo,
Jones Allan,
Wang Meifang,
Zuidema Mozow,
Durante William,
Korthuis Ronald
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.678.2
Subject(s) - chemistry , heme oxygenase , heme , pharmacology , inflammation , nitric oxide , guanylate cyclase , sodium nitroprusside , knockout mouse , biochemistry , medicine , biology , enzyme , receptor , organic chemistry
In previous studies, we showed that unlike wild‐type animals, heme oxygenase‐1 knockout mice (HO‐1 (−/−)) demonstrated nitrate tolerance and were not protected from the inflammatory effects of ischemia/reperfusion (IR) when preconditioned with hydrogen sulfide or ethanol, stimuli that induce downstream signaling by soluble guanylate cyclase (sGC)‐dependent mechanisms. BAY 60‐2770 activates oxidized sGC while BAY 41‐2272 stimulates reduced sGC (JPET 335:85‐91, 2010). We hypothesized that pretreatment with either BAY compound would limit postischemic inflammation and reverse nitrate tolerance in HO‐1(−/−) mice. Intravital fluorescence microscopy was used to visualize leukocyte rolling (LR) and adhesion (LA) in single postcapillary venules of the small intestine. Vasodilator responses to acetylcholine (ACH) or nitroprusside (NP) were measured on superior mesenteric arterial (SMA) rings isolated after IR and from Sham IR mice. Preconditioning with either BAY compound 10 min before or 24 h prior to IR reduced postischemic LR and LA in both WT and HO‐1(−/−), and increased SMA responses to ACH and NP in HO‐1(−/−). It is concluded that preconditioning with the sGC active agents, BAY 60‐2770 and BAY 41‐2272, limits postischemic inflammation and reduces nitrate tolerance in HO‐1(−/−). Supported by grants from the NIH (AA‐014945, HL‐095486 & HL‐59976). BAY 60‐2770 was a gift from Bayer Schering Pharma AG.