title: Preconditioning with soluble guanylate cyclase activation prevents postischemic inflammation and reduces nitrate tolerance in heme oxygenase-1 knockout mice.
abstract: Previously we have shown that, unlike wild-type mice (WT), heme oxygenase-1 knockout (HO-1-/-) mice developed nitrate tolerance and were not protected from inflammation caused by ischemia-reperfusion (I/R) when preconditioned with a H2S donor. We hypothesized that stimulation (with BAY 41-2272) or activation (with BAY 60-2770) of soluble guanylate cyclase (sGC) would precondition HO-1-/- mice against an inflammatory effect of I/R and increase arterial nitrate responses. Intravital fluorescence microscopy was used to visualize leukocyte rolling and adhesion to postcapillary venules of the small intestine in anesthetized mice. Relaxation to ACh and BAY compounds was measured on superior mesenteric arteries isolated after I/R protocols. Preconditioning with either BAY compound 10 min (early phase) or 24 h (late phase) before I/R reduced postischemic leukocyte rolling and adhesion to sham control levels and increased superior mesenteric artery responses to ACh, sodium nitroprusside, and BAY 41-2272 in WT and HO-1-/- mice. Late-phase preconditioning with BAY 60-2770 was maintained in HO-1-/- and endothelial nitric oxide synthase knockout mice pretreated with an inhibitor (dl-propargylglycine) of enzymatically produced H2S. Pretreatment with BAY compounds also prevented the I/R increase in small intestinal TNF-α. We speculate that increasing sGC activity and related PKG acts downstream to H2S and disrupts signaling processes triggered by I/R in part by maintaining low cellular Ca²⁺. In addition, BAY preconditioning did not increase sGC levels, yet increased the response to agents that act on reduced heme-containing sGC. Collectively these actions would contribute to increased nitrate sensitivity and vascular function.
authors.affiliation: Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, Missouri; and.
authors.forename: Walter Z
authors.initials: WZ
authors.lastname: Wang
authors.forename: Allan W
authors.initials: AW
authors.lastname: Jones
authors.forename: Meifang
authors.initials: M
authors.lastname: Wang
authors.forename: William
authors.initials: W
authors.lastname: Durante
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Korthuis
mesh_terms: D000818:Animals; D001565:Benzoates / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000494:pharmacology*; D006162:Guanylate Cyclase / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000172:deficiency* / Q000235:genetics; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology*; D006862:Hydrogen Sulfide / Q000378:metabolism; D007249:Inflammation / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control*; D018836:Inflammation Mediators / Q000378:metabolism; D007421:Intestine, Small / Q000098:blood supply*; D007511:Ischemia / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D036904:Leukocyte Rolling / Q000187:drug effects; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics; D017538:Mesenteric Artery, Superior / Q000187:drug effects / Q000201:enzymology / Q000601:surgery; D065666:Mesenteric Ischemia; D008641:Mesenteric Vascular Occlusion / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000378:metabolism; D015427:Reperfusion Injury / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control*; D015398:Signal Transduction / Q000187:drug effects; D000071756:Soluble Guanylyl Cyclase; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014652:Vascular Diseases / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D014664:Vasodilation / Q000187:drug effects; D014699:Venules / Q000187:drug effects / Q000201:enzymology
chemical_list: C423582:3-(4-Amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo(3,4-b)pyridine; C528797:4-(((4-carboxybutyl) (2- (5-fluoro-2-((4'-(trifluoromethyl) biphenyl-4-yl)methoxy)phenyl)ethyl) amino)methyl)benzoic acid; D001565:Benzoates; D001713:Biphenyl Compounds; D020536:Enzyme Activators; D006845:Hydrocarbons, Fluorinated; D018836:Inflammation Mediators; D008565:Membrane Proteins; D011720:Pyrazoles; D011725:Pyridines; D018160:Receptors, Cytoplasmic and Nuclear; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D017869:Cyclic GMP-Dependent Protein Kinases; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006862:Hydrogen Sulfide
keywords: BAY 41-2272; BAY 60-2770; endothelial nitric oxide synthase; ischemia-reperfusion; leukocyte rolling and adhesion; protein kinase G; vascular smooth muscle