© 1995 American Heart Association, Inc.
Articles |
Electrophysiological Effects of 4-Hydroxynonenal, an Aldehydic Product of Lipid Peroxidation, on Isolated Rat Ventricular Myocytes
From the Department of Physiology and Biophysics and the Department of Human Biological Chemistry and Genetics, University of Texas Medical Branch, Galveston.
Correspondence to Dr Aruni Bhatnagar, Department of Physiology and Biophysics and Department of Human Biological Chemistry and Genetics, University of Texas Medical Branch, Galveston, TX 77555.
Abstract 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 µmol/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 µmol/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 (Rin) of the myocyte (phase I), followed by a loss of electrical excitability. Continued superfusion with 4-HNE resulted in membrane hyperpolarization and a prominent decrease in the Rin (phase II). The decrease in Rin coincided with myocyte rigor. In whole-cell voltage-clamp experiments, superfusion with 4-HNE inhibited current through the inward rectifier K+ channel (IK1). 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 (INa). The voltage dependence of the steady state parameters for activation and inactivation of INa 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 IK1. Changes in voltage dependence of INa, inhibition of IK1, and membrane depolarization appear to contribute to the prolongation of the action potential, observed during phase I. Depletion of [ATP]i may be responsible for changes observed during phase II, ie, activation of the ATP-sensitive K+ channels, membrane hyperpolarization, decrease in Rin, 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.
Key Words: 4-hydroxynonenal • myocytes • oxidative stress
This article has been cited by other articles:
 |
|
 |
|
  K. Fukuda, S. S. Davies, T. Nakajima, B.-H. Ong, S. Kupershmidt, J. Fessel, V. Amarnath, M. E. Anderson, P. A. Boyden, P. C. Viswanathan, et al. Oxidative Mediated Lipid Peroxidation Recapitulates Proarrhythmic Effects on Cardiac Sodium Channels Circ. Res., December 9, 2005; 97(12): 1262 - 1269. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Zorn-Pauly, P. Schaffer, B. Pelzmann, E. Bernhart, G. Wei, P. Lang, G. Ledinski, J. Greilberger, B. Koidl, and G. Jurgens Oxidized LDL induces ventricular myocyte damage and abnormal electrical activity-role of lipid hydroperoxides Cardiovasc Res, April 1, 2005; 66(1): 74 - 83. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Y. Oudit, M. G. Trivieri, N. Khaper, T. Husain, G. J. Wilson, P. Liu, M. J. Sole, and P. H. Backx Taurine Supplementation Reduces Oxidative Stress and Improves Cardiovascular Function in an Iron-Overload Murine Model Circulation, April 20, 2004; 109(15): 1877 - 1885. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. J. Brame, O. Boutaud, S. S. Davies, T. Yang, J. A. Oates, D. Roden, and L. J. Roberts II Modification of Proteins by Isoketal-containing Oxidized Phospholipids J. Biol. Chem., April 2, 2004; 279(14): 13447 - 13451. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Bhatnagar Cardiovascular pathophysiology of environmental pollutants Am J Physiol Heart Circ Physiol, February 1, 2004; 286(2): H479 - H485. [Full Text] [PDF]
|
|
|
|
|
|
S. Srivastava, B. Chandrasekar, A. Bhatnagar, and S. D. Prabhu Lipid peroxidation-derived aldehydes and oxidative stress in the failing heart: role of aldose reductase Am J Physiol Heart Circ Physiol, December 1, 2002; 283(6): H2612 - H2619. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Shinmura, R. Bolli, S.-Q. Liu, X.-L. Tang, E. Kodani, Y.-t. Xuan, S. Srivastava, and A. Bhatnagar Aldose Reductase Is an Obligatory Mediator of the Late Phase of Ischemic Preconditioning Circ. Res., August 9, 2002; 91(3): 240 - 246. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Nakamura, K. Kusano, Y. Nakamura, M. Kakishita, K. Ohta, S. Nagase, M. Yamamoto, K. Miyaji, H. Saito, H. Morita, et al. Carvedilol Decreases Elevated Oxidative Stress in Human Failing Myocardium Circulation, June 18, 2002; 105(24): 2867 - 2871. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Eaton, J.-M. Li, D. J. Hearse, and M. J. Shattock Formation of 4-hydroxy-2-nonenal-modified proteins in ischemic rat heart Am J Physiol Heart Circ Physiol, March 1, 1999; 276(3): H935 - H943. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Srivastava, A. Chandra, L.-F. Wang, W. E. Seifert Jr., B. B. DaGue, N. H. Ansari, S. K. Srivastava, and A. Bhatnagar Metabolism of the Lipid Peroxidation Product, 4-Hydroxy-trans-2-nonenal, in Isolated Perfused Rat Heart J. Biol. Chem., May 1, 1998; 273(18): 10893 - 10900. [Abstract] [Full Text] [PDF]
|
|