title: Metabolic, Cardiac, and Renal Effects of the Slow Hydrogen Sulfide-Releasing Molecule GYY4137 During Resuscitated Septic Shock in Swine with Pre-Existing Coronary Artery Disease.
abstract: Decreased levels of endogenous hydrogen sulfide (H2S) contribute to atherosclerosis, whereas equivocal data are available on H2S effects during sepsis. Moreover, H2S improved glucose utilization in anaesthetized, ventilated, hypothermic mice, but normothermia and/or sepsis blunted this effect. The metabolic effects of H2S in large animals are controversial. Therefore, we investigated the effects of the H2S donor GYY4137 during resuscitated, fecal peritonitis-induced septic shock in swine with genetically and diet-induced coronary artery disease (CAD). Twelve and 18 h after peritonitis induction, pigs received either GYY4137 (10 mg kg, n = 9) or vehicle (n = 8). Before, at 12 and 24 h of sepsis, we assessed left ventricular (pressure-conductance catheters) and renal (creatinine clearance, blood NGAL levels) function. Endogenous glucose production and glucose oxidation were derived from the plasma glucose isotope and the expiratory CO2/CO2 enrichment during continuous i.v. 1,2,3,4,5,6-C6-glucose infusion. GYY4137 significantly increased aerobic glucose oxidation, which coincided with higher requirements of exogenous glucose to maintain normoglycemia, as well as significantly lower arterial pH and decreased base excess. Apart from significantly lower cardiac eNOS expression and higher troponin levels, GYY4137 did not significantly influence cardiac and kidney function or the systemic inflammatory response. During resuscitated septic shock in swine with CAD, GYY4137 shifted metabolism to preferential carbohydrate utilization. Increased troponin levels are possibly due to reduced local NO availability. Cautious dosing, the timing of GYY4137 administration, and interspecies differences most likely account for the absence of any previously described anti-inflammatory or organ-protective effects of GYY4137 in this model.
authors.affiliation: *Department of Anesthesiology, University Hospital Ulm, Ulm, Germany †Institute of Anesthesiological Pathophysiology and Process Engineering, University Hospital Ulm, Ulm, Germany ‡Department of Biosciences, College of Life and Environmental Science, University of Exeter, Exeter, UK §University of Exeter Medical School, St. Luke's Campus, Exeter, UK.
authors.forename: Benedikt L
authors.initials: BL
authors.lastname: Nußbaum
authors.forename: Josef
authors.initials: J
authors.lastname: Vogt
authors.forename: Ulrich
authors.initials: U
authors.lastname: Wachter
authors.forename: Oscar
authors.initials: O
authors.lastname: McCook
authors.forename: Martin
authors.initials: M
authors.lastname: Wepler
authors.forename: José
authors.initials: J
authors.lastname: Matallo
authors.forename: Enrico
authors.initials: E
authors.lastname: Calzia
authors.forename: Michael
authors.initials: M
authors.lastname: Gröger
authors.forename: Michael
authors.initials: M
authors.lastname: Georgieff
authors.forename: Mark E
authors.initials: ME
authors.lastname: Wood
authors.forename: Matthew
authors.initials: M
authors.lastname: Whiteman
authors.forename: Peter
authors.initials: P
authors.lastname: Radermacher
authors.forename: Sebastian
authors.initials: S
authors.lastname: Hafner
mesh_terms: D000818:Animals; D003324:Coronary Artery Disease / Q000097:blood / Q000188:drug therapy / Q000503:physiopathology; D003692:Delayed-Action Preparations / Q000493:pharmacokinetics / Q000494:pharmacology; D004195:Disease Models, Animal; D006321:Heart / Q000503:physiopathology*; D006862:Hydrogen Sulfide / Q000493:pharmacokinetics / Q000494:pharmacology; D007668:Kidney / Q000378:metabolism / Q000503:physiopathology; D009025:Morpholines / Q000493:pharmacokinetics / Q000494:pharmacology; D009946:Organothiophosphorus Compounds / Q000493:pharmacokinetics / Q000494:pharmacology; D012151:Resuscitation; D012772:Shock, Septic / Q000097:blood / Q000188:drug therapy / Q000503:physiopathology; D013552:Swine
chemical_list: D003692:Delayed-Action Preparations; C529376:GYY 4137; D009025:Morpholines; D009946:Organothiophosphorus Compounds; D006862:Hydrogen Sulfide