CLINICAL STUDIES
Inducible nitric oxide synthase in skeletal muscle of patients with chronic heart failure
Urs N. Riede, MD*,
Ulrich Förstermann, MD ,
Helmut Drexler, MD with the technical assistance of Brigitte Freudenberg-Plessow
* Department of Pathology, University of Freiburg, Freiburg, Germany
Department of Pharmacology, Johannes-Gutenberg-University, Mainz, Germany
Department of Medicine, Hannover Medical University, Hannover, Germany
Manuscript received March 4, 1998;
revised manuscript received May 20, 1998,
accepted June 4, 1998.
Address for correspondence: Dr. Helmut Drexler, Medizinische Hochschule Hannover, Abteilung Kardiologie, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany
drexler.helmut{at}mh-hannover.de
Objectives. The expression and localization of inducible nitric oxide (NO) synthase (NOS II) was evaluated as a source of NO which has been shown to affect muscle contraction.
Background. Advanced stages of chronic heart failure are associated with systemic activation of cytokines which have been shown to stimulate the expression of NOS II in various cell types, including myocytes. We hypothesized that systemic cytokine activation could lead to expression of NOS II in skeletal muscle of patients with chronic heart failure.
Methods. Skeletal muscle specimens were obtained by percutaneous needle biopsy in six normal volunteers and eight patients with heart failure (New York Heart Association class III). Electron microscopy immunocytochemistry (immunogold labeling) with specific anti-NOS antibodies was utilized to elucidate the intracellular localization of NOS II and neuronal NO synthase (NOS I) in myocytes of skeletal muscle. Reverse transcriptase, competitive polymerase chain reaction (PCR) was applied to quantify NOS II mRNA in skeletal muscle.
Results. Inducible nitric oxide synthase was readily expressed in the cytosol of skeletal muscle myocytes; NOS I expression was sparse. Polymerase chain reaction results indicated that NOS II gene expression is increased in patients with chronic heart failure.
Conclusions. Inducible NO synthase is expressed in human skeletal muscle and its gene expression is increased in patients with severe heart failure. Given the experimental evidence that NO can attenuate contractile performance of skeletal muscle and can mediate muscle wasting, an increased local production of NO in skeletal muscle by NOS II may have important implications for patients with severe heart failure.
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Abbreviations and Acronyms
| | CHF | = chronic heart failure | | EM | = electron microscopy | | NO | = nitric oxide | | NOS | = NO synthase | | NOS I | = neuronal nitric oxide synthase | | NOS II | = inducible nitric oxide synthase | | PCR | = polymerase chain reaction | | RT | = reverse transcriptase | | TNF | = tumor necrosis factor |
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