Exposure to free radicals causes a distinct sequence of changes in the cardiocyte action potential including increased plateau potential, action potential duration and after-depolarization. These changes suggest that free radicals initially alter function of the sarcolemmal membrane in a manner that is expected to increase intracellular calcium activity. Several possible mechanisms involving changes in the different ionic currents or altered function of the ionic pumps or exchange proteins could explain the observed changes in the action potential and ultimately underlie increased intracellular calcium activity. I propose to determine and characterize mechanism(s) that could underlie an increase in cellular calcium. To do this the effects of free radicals on the current-voltage relationship for the sodium, calcium and potassium currents will be determined in canine cardiocytes using single whole cell voltage clamp techniques. If free radicals alter the current-voltage curves of a particular current under study, then experiments will be performed to determine which of the following aspects of channel function might be changed: voltage and time dependency of channel kinetics and the ionic dependencies of channel function (when appropriate). The effects of free radicals on the Na-pump, Na:H exchange and Na:Ca exchange will be assessed using microelectrode techniques in single, enzymatically dissociated cells. The proposed research should enable the mechanism by which free radicals alter intracellular calcium levels in isolated cardiocytes to be identified. Such information will assist in identifying pharmacologic agents that could prevent or moderate free radical injury. Free radical injury has been implicated in the myocardial injury which results from diverse conditions ranging from ischemia and the oxygen paradox to adriamycin toxicity and aging. A more complete understanding of the mechanisms of free radical-induced changes should have important clinical implications.
| Barrington, P L; Martin, R L; Zhang, K (1997) Slowly inactivating sodium currents are reduced by exposure to oxidative stress. J Mol Cell Cardiol 29:3251-65 |
| Barrington, P L (1994) Interactions of H2O2, EGTA and patch pipette recording methods in feline ventricular myocytes. J Mol Cell Cardiol 26:557-68 |
| Barrington, P L; Lai, E; McCay, P B (1993) Lack of myocardial lipid peroxidation during acute reperfusion injury in perfused guinea pig hearts. Cardiovasc Res 27:1339-45 |
| Barrington, P L; Ten Eick, R E (1990) Characterization of the electrophysiological effects of metoprolol on isolated feline ventricular myocytes. J Pharmacol Exp Ther 252:1043-52 |
