title: S-nitroso human serum albumin attenuates pulmonary hypertension, improves right ventricular-arterial coupling, and reduces oxidative stress in a chronic right ventricle volume overload model.
abstract: BACKGROUND
  This study examined the acute effect of intravenous S-nitroso human serum albumin (S-NO-HSA) infusion on overall hemodynamics and oxidative stress in a chronic left-to-right shunt-induced pulmonary arterial hypertension model with right ventricle (RV) failure.
  
  
  METHODS
  An aortocaval fistula (pulmonary-to-systemic blood flow ratio [Qp/Qs] > 2.0) was surgically created in 50 male Wistar rats. After 10 weeks, they were randomly treated with S-NO-HSA (n = 20) or human serum albumin (HSA; n = 25) infusion (0.5 µmol/kg/h) for 60 minutes. A sham group (n = 10) received S-NO-HSA. RV contractility, RV-vascular coupling, and ventricular interdependence were assessed in vivo at different pre-loads by biventricular conductance catheters. Heart and lung biopsy specimens were obtained for determination of high-energy phosphates, oxidative stress (oxidized glutathione/reduced glutathione), and endothelial nitric oxide synthase protein expression.
  
  
  RESULTS
  S-NO-HSA, compared with HSA infusion, reduced RV afterload expressed by effective pulmonary arterial elastance (Ea; 0.49 ± 0.3 vs 1.2 ± 0.2 mm Hg/ml; p = 0.0005) and improved RV diastolic function (slope of end-diastolic pressure-volume relationship) as well as contractility indicated by slope of end-systolic pressure-volume relationship (Ees). Therefore an increase in efficiency of ventricular-vascular coupling (Ees/Ea) occurred after S-NO-HSA (0.35 ± 0.17 to 0.94 ± 0.21; p = 0.005), but not HSA infusion, leading to positive effect on ventricular interdependence with increased left ventricular stroke volume (56% ± 4% vs 19% ± 5%; p = 0.0013). S-NO-HSA, compared with HSA, treatment improved adenosine 5'-triphosphate (13.9 ± 1.1 vs 7.0 ± 1.8 µmol/g protein) and phosphocreatine (5.9 ± 3.3 vs 1.9 ± 0.6 µmol/g protein; p = 0.01) RV content and decreased the tissue oxidized glutathione/reduced glutathione ratio (p = 0.001).
  
  
  CONCLUSIONS
  S-NO-HSA reduces pulmonary hypertension and improves RV systolic and diastolic function and RV-arterial coupling, with a positive effect on ventricular interdependence by increasing energetic reserve and reducing oxidative stress.
authors.affiliation: Division of Cardiac Surgery, Department of Surgery, University of Verona, Verona, Italy; Division of Cardiac Surgery, Department of Surgery, University of Verona, Verona, Italy. Electronic address: alessio.rungatscher@univr.it.
authors.forename: Alessio
authors.initials: A
authors.lastname: Rungatscher
authors.affiliation: Institute of Physiological Chemistry, Medical University of Graz, Graz, Austria. Electronic address: seth.hallstroem@medunigraz.at.
authors.forename: Seth
authors.initials: S
authors.lastname: Hallström
authors.affiliation: Division of Cardiac Surgery, Department of Surgery, University of Verona, Verona, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Linardi
authors.affiliation: Division of Cardiac Surgery, Department of Surgery, University of Verona, Verona, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Milani
authors.affiliation: Ludwig Boltzmann Cluster for Cardiovascular Research, Medical University of Vienna. Vienna, Austria.
authors.forename: Harald
authors.initials: H
authors.lastname: Gasser
authors.affiliation: Ludwig Boltzmann Cluster for Cardiovascular Research, Medical University of Vienna. Vienna, Austria.
authors.forename: Bruno K
authors.initials: BK
authors.lastname: Podesser
authors.affiliation: Center for Heart and Vessel Preclinical Studies, St. John Hospital and Medical Center, Wayne State University Medical School. Detroit, Michigan.
authors.forename: Tiziano M
authors.initials: TM
authors.lastname: Scarabelli
authors.affiliation: Division of Cardiac Surgery, Department of Surgery, University of Verona, Verona, Italy.
authors.forename: Giovanni B
authors.initials: GB
authors.lastname: Luciani
authors.affiliation: Division of Cardiac Surgery, Department of Surgery, University of Verona, Verona, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Faggian
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002908:Chronic Disease; D004195:Disease Models, Animal; D006352:Heart Ventricles / Q000378:metabolism / Q000503:physiopathology*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D009603:Nitroso Compounds / Q000097:blood*; D018384:Oxidative Stress; D051381:Rats; D017208:Rats, Wistar; D012709:Serum Albumin; D000075462:Serum Albumin, Human; D018497:Ventricular Dysfunction, Right / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D016278:Ventricular Function, Right
chemical_list: D009603:Nitroso Compounds; C511514:S-nitrosoalbumin, human; D012709:Serum Albumin; D000075462:Serum Albumin, Human
keywords: S-nitroso human serum albumin; animal model; high-energy phosphates; oxidative stress; pressure-volume; pulmonary hypertension; right ventricle; ventricular-arterial coupling