ARTICLE
Cytokine-induced nitric oxide production inhibits mitochondrial energy production and impairs contractile function in rat cardiac myocytes
Tetsuya Tatsumi, MD, PhD*,
Satoaki Matoba, MD*,
Akira Kawahara, MD*,
Natsuya Keira, MD*,
Jun Shiraishi, MD*,
Kazuko Akashi, MD*,
Miyuki Kobara, MD*,
Tetsuya Tanaka, MD*,
Maki Katamura, MD*,
Chiaki Nakagawa, MD*,
Bon Ohta, MD, PhD*,
Takeshi Shirayama, MD, PhD*,
Kazuo Takeda, MD, PhD*,
Jun Asayama, MD, PhD ,
Henry Fliss, PhD and
Masao Nakagawa, MD, PhD*
* Second Department of Medicine, Kyoto Prefectural University of Medicine; Kyoto, Japan
Department of Clinical Pharmacology, Kyoto Pharmaceutical University, Kyoto, Japan
Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada
Manuscript received August 6, 1998;
revised manuscript received October 27, 1999,
accepted December 15, 1999.
Reprint requests and correspondence: Dr. Tetsuya Tatsumi, Second Department of Medicine, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
tatsumi{at}koto.kpu-m.ac.jp
OBJECTIVES
The present study examined whether nitric oxide (NO) produced by inducible nitric oxide synthase (iNOS) can directly inhibit aerobic energy metabolism and impair cell function in interleukin (IL)-1ß–stimulated cardiac myocytes.
BACKGROUND
Recent reports have indicated that excessive production of NO induced by cytokines can disrupt cellular energy balance through the inhibition of mitochondrial respiration in a variety of cells. However, it is still largely uncertain whether the NO-induced energy depletion affects myocardial contractility.
METHODS
Primary cultures of rat neonatal cardiac myocytes were prepared, and NO2–/NO3– (NOx) in the culture media was measured using Griess reagent.
RESULTS
Treatment with IL-1ß (10 ng/ml) increased myocyte production of NOx in a time-dependent manner. The myocytes showed a concomitant significant increase in glucose consumption, a marked increase in lactate production, and a significant decrease in cellular ATP (adenosine 5'-triphosphate). These metabolic changes were blocked by co-incubation with NG-monomethyl-L-arginine (L-NMMA), an inhibitor of NO synthesis. Sodium nitroprusside (SNP), a NO donor, induced similar metabolic changes in a dose-dependent manner, but 8-bromo-cyclic guanosine 3',5'-monophosphate (8-bromo-cGMP), a cGMP donor, had no effect on these parameters. The activities of the mitochondrial iron-sulfur enzymes, NADH-CoQ reductase and succinate-CoQ reductase, but not oligomycin-sensitive ATPase, were significantly inhibited in the IL-1ß or SNP-treated myocytes. Both IL-1ß and SNP significantly elevated maximum diastolic potential, reduced peak calcium current (ICa), and lowered contractility in the myocytes. KT5823, an inhibitor of cGMP-dependent protein kinase, did not block the electrophysiological and contractility effects.
CONCLUSIONS
These data suggest that IL-1ß–induced NO production in cardiac myocytes lowers energy production and myocardial contractility through a direct attack on the mitochondria, rather than through cGMP-mediated pathways.
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Abbreviations and Acronyms
| | ATP | = adenosine 5'-triphosphate | | 8-bromo-cGMP | = 8-bromo-cyclic guanosine 3',5'-monophosphate | | IL-1ß | = interleukin-1ß | | iNOS | = inducible nitric oxide synthase | | L-NMMA | = NG-monomethyl-L-arginine | | NO | = nitric oxide | | SNP | = sodium nitroprusside |
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