S-Nitroso Human Serum Albumin Enhances Left Ventricle Hemodynamic Performance and Reduces Myocardial Damage after Local Ischemia-Reperfusion Injury

Abstract

Endothelial nitric oxide (NO) production is crucial in maintaining vascular homeostasis. However, in the context of ischemia-reperfusion (I/R) injury, uncoupled endothelial nitric oxide synthase (eNOS) can exacerbate reactive oxygen species (ROS) generation. Supplementation with S-nitroso human serum albumin (S-NO-HSA) offers a potential solution by mitigating eNOS uncoupling, thereby enhancing NO bioavailability. In a study conducted at the University of Verona, male rats underwent thoracotomy followed by 30 min left anterior descendant coronary (LAD) occlusion and subsequent reperfusion. Hemodynamic parameters were meticulously assessed using a conductance catheter inserted via the carotid artery. The rats were stratified into two main groups based on reperfusion duration and the timing of drug infusion, with the effects of S-NO-HSA evaluated after 2 or 24 h. Remarkably, intravenous administration of S-NO-HSA, initiated before or during ischemia, exhibited notable benefits. It significantly improved left ventricular function, safeguarded energetic substrates such as phosphocreatine and ATP, and sustained glutathione levels akin to basal conditions, indicative of diminished oxidative stress. The data from this study strongly suggest a protective role for S-NO-HSA in mitigating I/R injury induced by LAD artery occlusion, a phenomenon observed at both 2 and 24 h post-reperfusion. These findings underscore the promising therapeutic potential of NO supplementation in alleviating myocardial damage subsequent to ischemic insult.

Keywords: NO donor; acute myocardial infarction; ischemia–reperfusion damage; nitric oxide; nitrosylated albumin.

Figure 1

LAD ligation with 6.0 stitch (A) and temporary occlusion (ischemic time 30 min) with a tourniquet (B).

Figure 2

Experimental protocol of the study. Rats were divided into two main groups: one received pretreatment with HSA or SNOHSA 15 min before ischemia induction; the other group received post-treatment with HSA or SNOHSA 15 min after ischemia induction.

Figure 3

Left ventricle hemodynamic parameters in pretreated rats with HSA or S-NO-HSA at different time points (T0, basal; T1, ischemia; T2, 2 h of reperfusion; T3, 24 h of reperfusion); * p < 0.05 pre-S-NO-HSA vs. pre-HSA. SV = stroke volume; EF = ejection fraction; max PWR = maximal power; PAMP = preload adjusted maximal power; dP/dt max = maximum increase in systolic pressure; LVEDP = left ventricular end-diastolic pressure; dP/dt min = maximum decrease in diastolic pressure; tau-Weiss = tau-Weiss time constant.

Figure 4

Left ventricle hemodynamic parameters in post-treated rats with HSA or S-NO-HSA at different time points (T0, basal; T1, ischemia; T2, 2 h of reperfusion; T3, 24 h of reperfusion). * p < 0.05 post-S-NO-HSA vs. post-HSA. SV = stroke volume; EF = ejection fraction; max PWR = maximal power; PAMP = preload adjusted maximal power; dP/dt max = maximum increase in systolic pressure; LVEDP = left ventricular end-diastolic pressure; dP/dt min = maximum decrease in diastolic pressure; tau-Weiss = tau-Weiss time constant.

Figure 5

Left ventricle hemodynamic parameters pretreated S-NO-HSA and post-treated S-NO-HSA at different time points (T0, basal; T1, ischemia; T2, 2 h of reperfusion; T3, 24 h of reperfusion); * p < 0.05 pre-S-NO-HSA vs. post-S-NO-HSA. SV = stroke volume; EF = ejection fraction; max PWR = maximal power; PAMP = preload adjusted maximal power; dP/dt max = maximum increase in systolic pressure; LVEDP = left ventricular end-diastolic pressure; dP/dt min = maximum decrease in diastolic pressure; tau-Weiss = tau-Weiss time constant.

Figure 6

High-energy phosphates in biopsies of the left ventricle in the treatment group receiving pre-S-NO-HSA and post-S-NO-HSA compared with the control group (HSA) in two different time points: T2 (2 h reperfusion) and T3 (24 h reperfusion). Changes in PCr and adenine nucleotide levels (A,B) and energy charge (C,D) in S-NO-HSA vs. control group; * p < 0.05 vs. HSA.

Figure 7

GSH and GSSG content in biopsies of the left ventricle in the treatment group receiving pre-S-NO-HSA and post-S-NO-HSA compared with the control group (HSA) at two different time points: T2 (2 h reperfusion) and T3 (24 h reperfusion). Changes in GSSG/GSH content (A,B) and the percentage of oxidized glutathione (GSSG) are illustrated (C,D); * p < 0.05 vs. HSA.