Role of nitric oxide and cGMP in human septic serum-induced depression of cardiac myocyte contractility
| Autor: | Joseph E. Parrillo, Peter Wang, Greg Skorupa, Richard Schulz, Anand Kumar, Fadi H. Khadour, Linda Dee, Rupinder Brar |
|---|---|
| Rok vydání: | 1999 |
| Předmět: |
medicine.medical_specialty
Nitric Oxide Synthase Type III Physiology Arginine Nitric Oxide Nitric oxide Contractility chemistry.chemical_compound Physiology (medical) Internal medicine medicine Animals Humans Myocyte Enzyme Inhibitors Cyclic GMP omega-N-Methylarginine Tumor Necrosis Factor-alpha business.industry Septic shock Myocardium Cardiac myocyte Myocardial depressant factor Blood Physiological Phenomena medicine.disease Myocardial Contraction Shock Septic Rats Methylene Blue Drug Combinations Endocrinology chemistry Shock (circulatory) Nitric Oxide Synthase Nucleotides Cyclic medicine.symptom business Interleukin-1 |
| Zdroj: | ResearcherID |
| ISSN: | 1522-1490 0363-6119 |
| Popis: | Previous studies have demonstrated the existence of a circulating myocardial depressant substance during human septic shock. We have recently identified this substance as a synergistic combination of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta). This study utilized an in vitro cardiac myocyte assay to evaluate the potential mechanistic role of nitric oxide (NO) and cGMP in depression of myocyte contractility induced by TNF-alpha, IL-1beta, TNF-alpha + IL-1beta (at low concentrations), and human septic shock serum (HSS). TNF-alpha, IL-1beta, TNF-alpha + IL-1beta, and each of 5 sera from patients with acute septic shock caused depression of both maximum extent and peak velocity of cardiac myocyte shortening and an increase in intracellular cGMP concentration during 30 min of exposure (minimum P0.01). NO synthetase (NOS) and guanylate cyclase inhibitors such as N-methyl-L-arginine (L-NMA) and methylene blue prevented these effects; an excess of L-arginine with L-NMA restored them (minimum P0.01). In contrast, D-arginine failed to reestablish cytokine-induced myocyte depression and cGMP accumulation prevented by L-NMA. Exposure of myocytes to TNF-alpha, IL-1beta, or TNF-alpha + IL-1beta produced a concentration-dependent increase in intracellular cGMP that paralleled the depression of cardiac myocyte contractility (minimum P0.001). In addition, TNF-alpha, IL-1beta, TNF-alpha + IL-1beta, or HSS application to cardiac myocytes resulted in increased NO gas generation, which was inhibited by L-NMA (minimum P0.01). Furthermore, unstimulated cardiac myocytes were shown to harbor constitutive but not inducible NOS activity. These data suggest that the sequential generation of NO by a constitutive NOS and cGMP by guanylate cyclase represents an important mechanism of cardiac myocyte depression by TNF-alpha, IL-1beta, TNF-alpha + IL-1beta, and the myocardial depressant substance(s) of septic shock. |
| Databáze: | OpenAIRE |
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