The Role of a Hydroxyl Radical Scavenger (Nicaraven) in Recovery of Cardiac Function Following Preservation and Reperfusion1

Abstract

We investigated the efficacy in reducing myocardial preservation and reperfusion (P/R) injury of direct hydroxyl radical scavenging by nicaraven as compared with scavenging of both superoxide radicals and hydrogen peroxides by superoxide dismutase (SOD) and catalase (CAT), respectively. Isolated rat hearts were mounted on a Langendorff (L) apparatus to estimate the baseline aortic flow (AF), coronary flow (CF), cardiac output (CO), systolic pressure (SP), aortic mean pressure (MP), rate pressure product, and LV dp/dt. They were divided into 3 groups: group 1, 12 hr storage in HTK solution; group 2, 12 hr storage in HTK solution containing 2.5x10(5) U/L SOD and 2x10(5) U/L mg/L CAT; and Group 3, 12 hr storage in HTK solution containing 10(-3) M nicaraven. SOD, CAT, and nicaraven were administered intraperitoneally before harvesting. Hearts were stored in each preservation solution at 4, and then reperfused. Postpreservative function and concentrations of leaked enzymes were measured. The hearts were switched back to the L-mode and paced at 330 beats/min. CF following perfusion with Krebs-Henseleit bicarbonate buffer (KHB) solution containing 10(-6) M 5-hydroxytryptamine (5-HT) or 10(-5) M nitroglycerin (NTG) then evaluated. The myocardial water content also was measured. The recovery of CF, CO, SP, MP, and LV dp/dt was significantly greater in group 3 than in group 1. The recovery of CF was superior to that in group 2 (P<0.05). There were no significant differences in the recovery of cardiac function between groups 1 and 2. 5-HT caused a decrease in CF in each group, however, CF in group 3 was higher than that in group 1 (P<0.05). NTG caused no significant differences among the groups. There were no significant differences in leaked enzymes and myocardial water content among the three groups. These results suggest that nicaraven protects against myocardial P/R injury through its hydroxyl radical scavenging activity, and that therapy with oxygen-free radical scavengers should be directed toward inactivation of hydroxyl radicals rather than superoxide radicals and/or hydrogen peroxides.

Cardioprotective Effects of Lowering Oxygen Tension After Aortic Unclamping on Cardiopulmonary Bypass During Coronary Artery Bypass Grafting

“…1,14 The cell protects itself by ubiquitous endogenous free radical scavengers, which may be depleted by ischemia and additionally overwhelmed by the burst of free radical production that occurs with the onset of reoxygenation or hyperoxia after reperfusion with aortic unclamping during CPB. 15 Prasad et al have shown that superoxide dismutase and catalase, which are scavengers of superoxide anion and hydrogen peroxide, respectively, are effective in preventing postpump cardiac dysfunction, 14 16 The present study showed that lowering the reperfusate PO2 after aortic unclamping on CPB reduced oxidative myocardial damage and the effects on the hemodynamics and myocardial enzyme release persisted for approximately 3 h after discontinuation of CPB. In fact, the CI in the lowering reperfusate PO2 group was higher than in the hyperoxic reperfusion groups at 30 min and 3 h after discontinuation of CPB.…”

ROS scavenging before 27°C ischemia protects hearts and reduces mitochondrial ROS, Ca2+ overload, and changes in redox state

“…Consistent with this notion, Ku et al (27,28) reported that formation of OH ⅐ from O 2 •Ϫ and H 2 O 2 is likely responsible for injury due to cold storage, and addition of nicaraven (OH ⅐ scavenger) to the preservation solution protected against the injury.…”

Postischemic Reperfusion Injury Can Be Attenuated by Oxygen Tension Control

“…2,8 Beckman et al reported that superoxide anion and NO interact to form cytotoxic oxygen species, 12 and NO generation is also dependent on the PO2. 13 Some studies have shown that free radical scavengers attenuate reperfusion injury following ischemia, [8][9][10][11][14][15][16] so we hypothesized that as an alternative to treatment with antioxidants, it is conceivable that the production of oxygen-derived free radicals could be avoided by lowering the PO2 after ischemia. Carla et al reported that hyperoxic reperfusion did not increase myocardial infarct size as an irreversible change, but they did not mention arrythmias or myocardial functional stunning as reversible changes.…”

“…5 In the case of myocardial stunning, the phenomenon may be mediated, at least in part, by a burst of free radicals formed during the early phase of reperfusion and improved by free radical scavengers at the time of reperfusion. [6][7][8][9][10] As an alternative treatment to antioxidants, it is conceivable that adequate physiologic oxygen tension during reperfusion following ischemia may limit oxidative injury. Thus, we hypothesized that the production of oxygenderived free radicals may be attenuated by sustaining a more physiologic oxygen tension (PO2) during reperfusion following ischemia.…”