Alessio Rungatscher1, Seth Hallström2, Daniele Linardi3, Elisabetta Milani3, Harald Gasser4, Bruno K Podesser4, Tiziano M Scarabelli5, Giovanni B Luciani3, Giuseppe Faggian3. 1. 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. 2. Institute of Physiological Chemistry, Medical University of Graz, Graz, Austria. Electronic address: seth.hallstroem@medunigraz.at. 3. Division of Cardiac Surgery, Department of Surgery, University of Verona, Verona, Italy. 4. Ludwig Boltzmann Cluster for Cardiovascular Research, Medical University of Vienna. Vienna, Austria. 5. Center for Heart and Vessel Preclinical Studies, St. John Hospital and Medical Center, Wayne State University Medical School. Detroit, Michigan.
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.
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: Gobinath Shanmugam; Madhusudhanan Narasimhan; Robbie L Conley; Thiagarajan Sairam; Ashutosh Kumar; Ronald P Mason; Ramalingam Sankaran; John R Hoidal; Namakkal S Rajasekaran Journal: Front Physiol Date: 2017-05-03 Impact factor: 4.566