Cardiovascular Research Advance Access [Accepted Manuscript] published online on October 30, 2007
Cardiovascular Research, doi:10.1093/cvr/cvm052
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S-Nitroso human serum albumin reduces ischemia/reperfusion injury in the pig heart after unprotected warm ischemia
a Institute of Physiological Chemistry, Center for Physiological Medicine, Medical University Graz, Austria
b Ludwig Boltzmann Cluster for Cardiovascular Research, Medical University of Vienna, Austria
c Institute for Biomedical Research, Medical University of Vienna, Austria
d Department of Chemistry and Biochemistry, Ohio University, Athens, Ohio, USA
* Corresponding authors: Bruno K. Podesser, MD/ Seth Hallström, PhD Ludwig Boltzmann Cluster for Cardiovascular Research, Währinger Gürtel 18-20, Medical University of Vienna, A-1090 Vienna, Austria Tel.: +43-1-40400-5229, Fax: +43-1-40400-5221 E-mail addresses: b.k.podesser{at}cardiovascular-research.at seth.hallstroem{at}meduni-graz.at
Aim: Uncoupled endothelial nitric oxide synthase (eNOS) is a major contributor to vascular reactive oxygen species generation in ischemia/reperfusion (I/R) injury. Supplementation of NO by the novel NO donor S-nitroso human serum albumin (S-NO-HSA) may inhibit uncoupling of eNOS (feedback inhibition).
Methods: Pigs (n=14; 33.1±1.7 kg) were continuously monitored for heart rate (HR), mean arterial pressure (MAP), left ventricular systolic pressure (LVSP), and coronary flow (CF). Infusion of either human serum albumin (n=8; controls) or S-NO-HSA (n=6) lasted 60 min (0.1 µmol/kg/h) starting 15 min prior to ischemia. After clamping the aorta under cardiopulmonary bypass (CPB), the hearts underwent 15 min of warm, unprotected ischemia (37°C). Reperfusion lasted 150 min (30 min under CPB; 15 min weaning; additional 105 min reperfusion). In biopsies from non-ischemic hearts and myocardial biopsies taken after 150 min of reperfusion, high-energy phosphates were measured and the calcium ionophore-stimulated release of NO, superoxide and peroxynitrite (ONOO–) were monitored with nanosensors.
Results: Compared to non-ischemic hearts, the NO level decreased from 930±25 to 600±15 nmol/L (P<0.001) while the superoxide level increased from 45±5 to 110±10 nmol/L (P<0.001) after ischemia. S-NO-HSA restored the NO level to 825±20 nmol/L, shifted favorably the [NO]/[ONOO–] balance (a marker of eNOS uncoupling) from 1.36±0.06 (ischemia) to 3.59±0.18, significantly improved CF (65±10 vs. control, 43±5 mL/min, P<0.05), MAP (57±5 vs. 39±3 mm Hg, P<0.01), LVSP (106±5 vs.81±4 mm Hg, P<0.01) and phosphocreatine content (41.5±7.3 vs. 18.0±5.6 µmol/g protein; P<0.01) at 150 min of reperfusion.
Conclusions: Long-lasting release of NO by S-NO-HSA prevented uncoupling of eNOS and thereby improved systolic and diastolic function, myocardial perfusion, and the energetic reserve of the heart after I/R injury.
Time for primary review: 19
1 These authors contributed equally to this work.
deceased.
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