Hydrogen peroxide-induced intracellular acidosis and electromechanical inhibition in the diseased human ventricular myocardium.
Accumulation of oxygen free radicals is an important mediator of post-ischemia/reperfusion cardiac dysfunction. However, oxidative injury has not been well characterized in human cardiac tissues. In the present study, we superfused hydrogen peroxide (H(2)O(2)) into the diseased human ventricle in order to assess the effects of oxygen free radicals on the electromechanical parameters and the intracellular pH (pH(i)), and to test the ability of certain potential cardioprotective agents, including scavengers of hydrogen peroxide (dibenzamidostilbene disulfonic acid; DBDS), the.OH free radical (N-(mercaptopropionyl)-glycine; N-MPG), and the HOCl free radical (L-methionine), to protect against oxidative injury. Disease human ventricular tissues were obtained from patients undergoing heart transplantation. Electrophysiological experiments were performed using a traditional micropipette, while the pH(i) was measured by microspectrofluorimetry. We found that (a) H(2)O(2) (30 microM-3 mM) induced a significant dose-dependent intracellular acidosis, (b) H(2)O(2) (30 microM-3 mM) had a notable dose-dependent biphasic effect on the contractile force (an increase, followed by a decrease), while moderate concentrations of H(2)O(2) also inhibited the generation of action potential and increased the diastolic resting force significantly, and (c) N-MPG caused significant block of both the intracellular acidosis and the electromechanical inhibition induced by 3 mM H(2)O(2), whereas L-methionine and DBDS did not. Our data suggest that the toxic effects of H(2)O(2) are caused mainly through the generation of.OH, which is attributed to the intracellular acidosis seen in the diseased human ventricle.
Loh
Shih-Hurng
SH
Department of Pharmacology, National Defense Medical Center, Neifu P.O. Box 90048-504, Republic of China, Taipei, Taiwan, republic of China. shloh@ndmctsgh.edu.tw
Tsai
Chien-Sung
CS
Tsai
Yin
Y
Chen
Wei-Hwa
WH
Hong
Guo-Jiueng
GJ
Wei
Jeng
J
Cheng
Tzi-Hurng
TH
Lin
Cheng-I
CI
D000138:Acidosis / Q000139:chemically induced / Q000378:metabolism*; D000975:Antioxidants / Q000494:pharmacology; D001696:Biomechanical Phenomena; D002311:Cardiomyopathy, Dilated / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D004594:Electrophysiology; D005260:Female; D016166:Free Radical Scavengers / Q000494:pharmacology; D005609:Free Radicals / Q000378:metabolism; D006321:Heart / Q000503:physiopathology*; D006352:Heart Ventricles / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D017665:Hydroxyl Radical / Q000378:metabolism; D006997:Hypochlorous Acid / Q000378:metabolism; D007424:Intracellular Fluid / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008839:Microelectrodes; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D013050:Spectrometry, Fluorescence; D013997:Time Factors
D000975:Antioxidants; D016166:Free Radical Scavengers; D005609:Free Radicals; D017665:Hydroxyl Radical; D006997:Hypochlorous Acid; D006861:Hydrogen Peroxide