O2 free radical-mediated myocardial and vascular dysfunction

Abstract

In the present investigation electrolysis of a physiological buffer solution for 2 min with a constant current (20 mA, DC stainless steel anode) was observed to generate free radicals, determined by a luminol assay. Rabbit isolated hearts perfused with physiological buffer subjected to electrolysis were observed to undergo an increase in coronary artery perfusion pressure (PP) and in left ventricular end-diastolic pressure (LVEDP), 80 +/- 4 and 52 +/- 7 mmHg, respectively. Immediately after electrolysis of the physiological buffer, the hearts were observed to accumulate and retain (8-fold) more 125I-labeled albumin than hearts perfused with normal buffer without electrolysis, indicating an increased vascular permeability. The free radical scavengers, dimethyl sulfoxide (DMSO) and catalase (CAT), provided significant protection of the hearts against the changes in PP, LVEDP, and vascular permeability. This study demonstrates that toxic oxygen species generated independently of circulating blood elements or enzymatic reactions can have a direct effect on the vasculature of an isolated heart leading to alterations in cardiac function. The protection afforded by the addition of DMSO or CAT to the perfusion system would suggest that the OH. radical and H2O2 were the reactive oxygen species involved in producing the observed vascular and cardiac effects.

Effects of exogenous free radicals on electromechanical function and metabolism in isolated rabbit and guinea pig ventricle. Implications for ischemia and reperfusion injury.

“…Specific targets that are damaged by free radical-induced lipid peroxides include mitochondria, Na+-K+ ATPase, myofibrillar ATPase, and sarcoplasmic reticulum (6)(7)(8)(9). Free radicals may also damage vascular endothelium (31), secondarily affecting cardiac function by impairing blood flow.…”

“…CAT prevents * OH formation by degrading hydrogen peroxide to water. The concentrations were chosen based on previous studies demonstrating beneficial effects on free radical-induced cardiac dysfunction (31,32 …”

Myocardial glutathione depletion impairs recovery after short periods of ischemia.

“…Superoxide dismutase administered before the radical generating systems or during reperfusion largely prevented the ultrastructural changes. 24 The lower glutathione levels in our DEM-treated hearts may have reduced the capacity of endothelial cells to modulate levels of peroxide arising from the superoxide radicals generated during reperfusion. Either the peroxide itself or hydroxyl radicals formed from the peroxide might cause cell injury and swelling, leading to increased coronary vascular resistance.…”

Glycolytic inhibition and calcium overload as consequences of exogenously generated free radicals in rabbit hearts.

“…Exogenous free radicals would be expected to enhance cellular calcium loading by the known inhibition ofNa'-K+ ATPase in the surface membrane and of Ca2+-ATPase in both the sarcolemma and the sarcoplasmic reticulum (20,22,23,(62)(63)(64)(65). Free radicals are also capable ofinjuring mitochondrial Ca2+-ATPase (34).…”