Toxic Effects Of Nitric Oxide Research Articles

Expression of inducible nitric oxide synthase by neurones following exposure to endotoxin and cytokine.

In the CNS, nitric oxide (NO) has been implicated as both a mediator of neurotoxicity and a neuromodulator. The inducible NO synthase (iNOS), thought to mediate toxic effects of NO, has been attributed to glial cells in the CNS. We now report that cerebellar granule cell neurones can be stimulated by lipopolysaccharide and interferon-gamma to express iNOS in vitro, as demonstrated by reverse transcription-polymerase chain reaction and fluorescent in situ hybridisation. The expression of both constitutive NO synthase (cNOS) and iNOS by neurones suggests that NO has diverse functions in the brain, and supports the possibility that iNOS plays a role in neuronal damage and inflammation following activation of brain microglia and production of cytokines.

Inhaled nitric oxide as a therapy for pulmonary hypertension after operations for congenital heart defects

Seventeen infants were treated with inhaled nitric oxide for critical pulmonary artery hypertension after operations for congenital heart defects. In all 17 patients conventional medical therapy consisting of hyperventilation, deep sedation/analgesia, and correction of metabolic acidosis had failed. All children were monitored with a transthoracic pulmonary artery catheter inserted at operation. Pulmonary artery hypertension was defined as an acute rise in pulmonary pressure associated with a decrease in oxygen arterial or venous saturation. After failure of conventional medical therapy, 20 ppm of inhaled nitric oxide was administered to the patient. In all patients the pulmonary pressures decreased (mean pulmonary arterial pressure decreased by -34% +/- 21%) without significant change in systemic arterial pressure, whereas the oxygen arterial saturation and oxygen venous saturation increased by 9.7% +/- 12% and 37% +/- 28%, respectively. Fifteen children were discharged from the intensive care unit at 10 +/- 6 days (range 3 to 26 days) and two died. This study demonstrates that inhaled nitric oxide exerts a selective pulmonary vasodilation without decreasing systemic arterial pressure in children with congenital heart disease. The increased values of mixed venous oxygen saturation and urinary output suggest that this selective lowering of pulmonary vascular resistance improved the overall hemodynamics. The potential toxic effects of nitric oxide and nitrogen dioxide necessitate careful consideration of the risks and benefits of inhaled nitric oxide therapy.

Epithelial autotoxicity of nitric oxide: role in the respiratory cytopathology of pertussis.

Bordetella pertussis releases a specific peptidoglycan fragment known as tracheal cytotoxin (TCT) that reproduces the respiratory epithelial cytopathology of whooping cough (pertussis). In vitro, TCT inhibits DNA synthesis in hamster trachea epithelial cells and causes specific destruction of ciliated cells in explants of human and hamster respiratory epithelium. We have recently demonstrated that TCT triggers production of intracellular interleukin 1 by respiratory epithelial cells, and this cytokine may act as an intermediate signal in the generation of TCT toxicity. Here we report the identification of a subsequent critical step in this pathway: induction of nitric oxide synthesis in the respiratory epithelium. The toxic effects of nitric oxide are consistent with spectroscopic evidence of the formation of iron-dinitrosyl-dithiolate complexes in TCT-treated cells. Aconitase, with its iron-sulfur center, is one expected target of nitric oxide, and TCT inhibited 80% of the activity of this enzyme in respiratory epithelial cells. The deleterious effects of TCT and interleukin 1 were dramatically attenuated by the nitric oxide synthase inhibitors NG-monomethyl-L-arginine and aminoguanidine. These results indicate that nitric oxide mediates the toxicity of TCT for the respiratory epithelium, thus implicating a central role for nitric oxide in the pathogenesis of pertussis.