ELECTROPHYSIOLOGICAL EFFECTS OF 4-HYDROXYNONENAL, AN ALDEHYDIC PRODUCT OF LIPID-PEROXIDATION, ON ISOLATED RAT VENTRICULAR MYOCYTES

被引:76
|
作者
BHATNAGAR, A [1 ]
机构
[1] UNIV TEXAS, MED BRANCH, DEPT HUMAN BIOL CHEM & GENET, GALVESTON, TX 77555 USA
关键词
4-HYDROXYNONENAL; MYOCYTES; OXIDATIVE STRESS;
D O I
10.1161/01.RES.76.2.293
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Aldehydic products of lipid peroxidation, such as 4-hydroxynonenal (4-HNE), have been implicated in the etiology of pathological changes under oxidative stress. To identify the mechanism by which 4-HNE alters cellular excitability, its effects on isolated rat ventricular myocytes were studied. Superfusion with 100 to 880 mu mol/L 4-HNE led to a time- and concentration-dependent rigor shortening of myocytes. A reduction in [Ca2+](o) and inhibition of transsarcolemmal Ca2+ transport by 1 mmol/L La3+ did not affect either the magnitude or the time course of 4-HNE-induced myocyte rigor. Superfusion of myocytes with 400 mu mol/L 4-HNE led to an increase in the action potential duration, progressive depolarization of the resting membrane potential, and an increase in the input resistance (R(in)) of the myocyte (phase I), followed by a loss of electrical excitability. Continued superfusion with 4-HNE re sulted in membrane hyperpolarization and a prominent decrease in the R(in) (phase II), The decrease in R(in) coincided with myocyte rigor. In whole-cell voltage-clamp experiments, superfusion with 4-HNE inhibited current through the inward rectifier K+ channel (I-K1). 4-HNE had no effect on either the magnitude or the rate of ''rundown'' of L-type Ca2+ currents. Exposure to 4-HNE led to an increase in the magnitude of the fast inward Na+ current (I-Na). The voltage dependence of the steady state parameters for activation and inactivation of I-Na shifted to more positive potentials, with a resultant increase in the window current. 4-HNE-induced myocyte rigor was accompanied by a large increase in time-independent currents that displayed linear dependence on the membrane potential and were inhibited by glibenclamide, suggesting activation of the ATP-sensitive K+ channel. Steady state currents recorded in Cs+-containing Ringer's solution with La3+ and tetrodotoxin and Cs+-containing internal solution (leak currents) were not affected by 4-HNE. Superfusion with 4-HNE resulted in a significant decrease in the cellular concentration of nonprotein thiols and a severe decrease in [ATP](i). The energy charge of the myocytes fell from 0.9 to 0.3. These observations indicate that 4-HNE-induced membrane depolarization may be due to an inhibition of I-K1. Changes in voltage dependence of I-Na, inhibition of I-K1 and membrane depolarization appear to contribute to the prolongation of the action potential, observed during phase I. Depletion of [ATP], may be responsible for changes observed during phase II, ie, activation of the ATP-sensitive K+ channels, membrane hyperpolarization, decrease in R(in), and rigor shortening of the myocytes. These results suggest that stable products of lipid peroxidation, such as 4-HNE, are proarrhythmic and may contribute to the cytotoxic effects of oxidative stress.
引用
收藏
页码:293 / 304
页数:12
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