Hypoxic reperfusion of the ischemic heart and oxygen radical generation

Abstract

Postischemic myocardial contractile dysfunction is in part mediated by the burst of reactive oxygen species (ROS), which occurs with the reintroduction of oxygen. We hypothesized that tissue oxygen tension modulates this ROS burst at reperfusion. After 20 min of global ischemia, isolated rat hearts were reperfused with temperature-controlled (37.4°C) Krebs-Henseleit buffer saturated with one of three different O2 concentrations (95, 20, or 2%) for the first 5 min of reperfusion and then changed to 95% O 2. Additional hearts were loaded with 1) allopurinol (1 mM), a xanthine oxidase inhibitor, 2) diphenyleneiodonium (DPI; 1 M), an NAD(P)H oxidase inhibitor, or 3) Tiron (10 mM), a superoxide scavenger, and were then reperfused with either 95 or 2% O 2 for the first 5 min. ROS production and tissue oxygen tension were quantitated using electron paramagnetic resonance spectroscopy. Tissue oxygen tension was significantly higher in the 95% O2 group. However, the largest radical burst occurred in the 2% O 2 reperfusion group (P Ͻ 0.001). Recovery of left ventricular (LV) contractile function and aconitase activity during reperfusion were inversely related to the burst of radical production and were significantly higher in hearts initially reperfused with 95% O2 (P Ͻ 0.001). Allopurinol, DPI, and Tiron reduced the burst of radical formation in the 2% O2 reperfusion groups (P Ͻ 0.05). Hypoxic reperfusion generates an increased ROS burst originating from multiple pathways. Recovery of LV function during reperfusion is inversely related to this oxygen radical burst, highlighting the importance of myocardial oxygen tension during initial reperfusion.reactive oxygen species; contractile function; cardiac arrest REPERFUSION, FOLLOWING GLOBAL ISCHEMIA of the heart, restores oxygen delivery to the ischemic tissue. During ischemia, there is a strong reductive pressure, which, with the reintroduction of oxygen, results in the burst of reactive oxygen species (ROS), which are thought to primarily be responsible for the postischemic myocardial contractile dysfunction (2, 4, 5). This phenomenon of postischemic contractile dysfunction may result from either cell injury or myocardial stunning (6), or a combination of both. This postischemic myocardial dysfunction is seen after a number of clinical syndromes including both regional (acute myocardial infarction) and global (cardiac arrest) myocardial ischemia (15,20).ROS, particularly superoxide, may be generated from multiple sources and mechanisms depending on the duration of preceding ischemia. Earlier studies identified endothelial cells as a major source of ROS at reperfusion that could be inhibited by xanthine oxidase blockers (31) and react with iron to form the very reactive hydroxyl radical (30). After prolonged periods of ischemia sufficient to result in necrosis, a major source of ROS appears to be neutrophils, which can be blocked with anti-neutrophil interventions causing a reduction of infarct size (7). However, after shorter periods of ischemia resulting in myocardial s...

Markers of oxidative stress in acute myocardial infarction treated by percutaneous coronary intervention

“…Gradual thrombolytic reperfusion could therefore lead to higher ROS production. Indeed, Angelos [25] recently reported that in isolated rat hearts the highest level of ROS is produced following reperfusion at the lowest blood oxygen saturation. However, there is a lack of clinical or experimental data comparing ROS production following thrombolytic reperfusion and PCI.…”

Skeletal myoblasts transplanted in the ischemic myocardium enhance in situ oxygenation and recovery of contractile function

“…Thus the VEGF expression, observed in the infarct region of SM-treated hearts, could explain the higher capillary density and vessel formation. It is likely that the newly formed vessels might improve tissue perfusion in and around the ischemic zone, resulting in increased blood flow and myocardial PO 2 . Several studies have demonstrated that expression of certain growth factors, including VEGF, by the transplanted cells is a possible mechanism for functional improvement in the heart (19,25,34).…”

“…The particulate probes measure PO 2 in the tissue milieu. Lithium octa-n-butoxy-substituted naphthalocyanine radical (LiNc-BuO) is a particulate oximetry spin probe that we have recently synthesized and validated for in vivo oximetry (2,15,27,42,43). The LiNc-BuO crystals are composed of stacks of neutral radicals of lithiated naphthalocyanine macrocycles (28).…”

O2delivery and redox state are determinants of compartment-specific reactive O2species in myocardial reperfusion

“…Recently, we noted a paradoxical ROS response at the onset of reperfusion when O 2 concentration was varied (2). The burst of ROS at the onset of reperfusion was significantly increased under hypoxic reperfusion conditions in the isolated perfused heart, compared with reperfusion with 95% O 2 saturated buffer.…”