Cardiovascular Research Advance Access first published online on October 30, 2007
This version [Corrected Proof] published online on November 22, 2007
Cardiovascular Research, doi:10.1093/cvr/cvm052
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S-nitroso human serum albumin reduces ischaemia/reperfusion injury in the pig heart after unprotected warm ischaemia
1 Institute of Physiological Chemistry, Center for Physiological Medicine, Medical University Graz, Austria
2 Ludwig Boltzmann Cluster for Cardiovascular Research, Medical University of Vienna, Austria
3 Institute for Biomedical Research, Medical University of Vienna, Austria
4 Department of Chemistry and Biochemistry, Ohio University, Athens, Ohio, USA
* Corresponding author. Tel: +43 1 40400 5229; fax: +43 1 40400 5221. E-mail address: b.k.podesser{at}cardiovascular-research.at (Bruno K. Podesser); seth.hallstroem{at}meduni-graz.at (Seth Hallström)
Aims: Uncoupled endothelial nitric oxide synthase (eNOS) is a major contributor to vascular reactive oxygen species generation in ischaemia/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 and results: 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 ischaemia. After clamping the aorta under cardiopulmonary bypass (CPB), the hearts underwent 15 min of warm, unprotected ischaemia (37°C). Reperfusion lasted 150 min (30 min under CPB; 15 min weaning; additional 105 min reperfusion). In biopsies from non-ischaemic 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. Compared with non-ischaemic 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 ischaemia. S-NO-HSA restored the NO level to 825 ± 20 nmol/L, shifted favourably the [NO]/[ONOO–] balance (a marker of eNOS uncoupling) from 1.36 ± 0.06 (ischaemia) 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 (PCr) content (41.5 ± 7.3 vs. 18.0 ± 5.6 µmol/g protein; P < 0.01) at 150 min of reperfusion.
Conclusion: 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.
KEYWORDS Ischaemia; Reperfusion; Nitric oxide; Oxygen radicals; Contractile function
Time for primary review: 19 days
These authors contributed equally to this work. 
Deceased.