S-nitroso human serum albumin reduces ischaemia/reperfusion injury in the pig heart after unprotected warm ischaemia.

Abstract

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 micromol/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 degrees 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 micromol/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.

• Authors: Seth Hallström, Maximilian Franz, Harald Gasser, Martin Vodrazka, Severin Semsroth, Udo M Losert, Markus Haisjackl, Bruno K Podesser, Tadeusz Malinski
• Journal: Cardiovascular research (Cardiovasc Res) Vol. 77 Issue 3 Pg. 506-14 (Feb 01 2008) ISSN: 0008-6363 [Print] England
• PMID: 18006447 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Nitroso Compounds
• S-nitrosoalbumin
• Superoxides
• Peroxynitrous Acid
• Serum Albumin, Bovine
• Nitric Oxide

Topics

• Animals
• Blood Pressure (drug effects)
• Coronary Circulation
• Heart Rate (drug effects)
• Myocardial Ischemia (complications, physiopathology)
• Myocardial Reperfusion Injury (prevention & control)
• Nitric Oxide (biosynthesis)
• Nitroso Compounds (therapeutic use)
• Peroxynitrous Acid (metabolism)
• Serum Albumin, Bovine (therapeutic use)
• Superoxides (metabolism)
• Swine
• Ventricular Function, Left (drug effects)
• Warm Ischemia