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

Abstract

Oxygen-derived free radicals have been implicated in the pathogenesis of cardiac dysfunction during ischemia, postischemic myocardial "stunning," and reperfusion injury. We investigated the effects of oxygen-derived free radicals on cardiac function in intact isolated rabbit hearts and single guinea pig ventricular myocytes. In the intact rabbit ventricle, exposure to free radical-generating systems caused increased cellular K+ efflux, shortening of the action potential duration, changes in tension, and depletion of high energy phosphates similar to ischemia and metabolic inhibition. In patch-clamped single ventricular myocytes, free radical-generating systems activated ATP-sensitive K+ channels, decreased the calcium current, and caused cell shortening by irreversibly inhibiting glycolytic and oxidative metabolism. The results suggest that free radicals generated during ischemia and reperfusion may contribute to electrophysiologic abnormalities and contractile dysfunction by inhibiting glycolysis and oxidative phosphorylation. Inhibition of metabolism by free radicals may be an important factor limiting functional recovery from an ischemic insult after reestablishment of effective blood flow.

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

“…The generation by the physiological mechanism of Ca2+-activated cross-bridge cycling (24). ATP depletion has been reported as a consequence ofexposure to exogenous free radicals (9,19), but the reported depletion in bulk ATP to -50% of control levels would not in itself suffice to produce contracture (45 (33). Metabolism: effect offree radicals on high energy phosphates.…”

“…Direct recordings of membrane potential (14,15) and ionic currents (9,16) during and after exposure to free radicals reveal surprisingly specific effects on ion transport pathways, with no evidence for the creation of nonspecific leaks. Goldhaber et al (9) have found that radicals generated either by hydrogen peroxide or by xanthine + xanthine oxidase turn on ATP-sensitive potassium channels in the sarcolemma. Since these channels are thought to be preferentially regulated by ATP derived from glycolysis (rather than from oxidative phosphorylation), the observation that they are activated by exogenous free radicals is suggestive of glycolytic inhibition (17).…”

“…Radicals are generated upon restoration of flow to ischemic myocardium (1)(2)(3)(4); scavengers and enzymes that destroy radicals have been found to improve functional and metabolic recovery (5)(6)(7)(8); and, finally, exogenous radical generation mim-ics various features of reperfusion injury, notably contractile dysfunction and ATP depletion (9,10). Despite important exceptions to many of these observations (1 [1][2][3][4][5][6][7][8][9][10][11][12][13], interest in the effects of free radicals remains great. Nevertheless, relatively little is known about the precise mechanisms by which radicals damage cells.…”

Effects of Oxidative Stress on the Electrophysiological Function of Neuronal Membranes

“…For example, the inward rectifying K + current has been reported to be either unaffected (Cerbai et al, 1991) or decreased (Tarr & Valenzeno, 1991). The electrophysiological effects of ROS generally consist of a reduction in action potential amplitude and an increase in action potential duration followed by a reduction (Tarr and Valenzeno, 1989;Barrington, 1994;Satoh and Matsui, 1997), although either only a reduction (Goldhaber et al, 1989;Hayashi et al, 1989;Coetzee et al, 1990) or only an increase in action potential duration (Barrington, 1994) have also been reported. Nakaya et al (1991) reported that ROS-induced shortening of the action potential duration of guinea-pig isolated ventricular myocytes.…”

“…For example, voltagedependent Na + , K + and Ca 2+ channels, Ca 2+ -activated K + channels, and K ATP channels have all been identified as targets for ROS (Hool, 2006). Several previous studies indicate that H 2 O 2 alters energy metabolism, ATP-sensitive K + currents, L-type Ca 2+ currents (Goldhaber & Liu, 1994;Racay et al, 1997), as well as delayed rectifier K + currents (Goldhaber et al, 1989). However in literature the data concerning the effect of ROS on potassium current are controversal.…”