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INTERACTIONS OF HEMOGLOBIN WITH NITRIC OXIDE
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ACQUIRED (TOXIC) METHEMOGLOBINEMIA
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In a rural region of the state, a 4-month-old infant was seen at the local emergency room for episodes of seizures, breathing difficulty, and vomiting. The infant's skin and mucous membranes were bluish, indicating cyanosis. Analysis of arterial blood revealed a chocolate brown color, a normal pO2, an O2 saturation of 60%, and a ferric-heme methemoglobin level of 35%. The tentative cause of the acute toxic methemoglobinemia was found to be well water contaminated by a nitrate/nitrite concentration of 34 mg/L. The infant was treated successfully by intravenous administration of methylene blueView drug information (1-2 mg/kg), a potent reducing agent.
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Comment: Methylene blueView drug information reduces ferric hemoglobin (methemoglobin) to normal (ferrous) hemoglobin. Methemoglobin is an oxidation product of Hb; it is produced spontaneously at a low rate and more rapidly in the presence of certain drugs, nitrites, and aniline dyes. Mutation of either the proximal or distal His to Tyr also makes heme iron more susceptible to oxidation (Table 4.1). Erythrocytes contain an NADH-cytochrome b5 reductase that catalyzes the reduction of methemoglobin to Hb. Infants are particularly vulnerable to methemoglobinemia. Not only do they have a diminished activity of the reductase, but their HbF is more sensitive to oxidants compared to HbA.
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Integration link: Organic nitrates - methemoglobin formationIntegration Link
Taken from Pharmacology 5E

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Notwithstanding its well-established role as an important mediator of vascular signal transduction (see Chapter 6), NO (nitric oxideView drug information) is a highly reactive, gaseous free radical that can modify biological macromolecules. NO has been shown to react reversibly with Hb in two rather different ways: binding to heme Fe2+, a process comparable to the binding of O2, and forming an adduct with surface-exposed Cys93 β side chains. The physiological significance of either nitrosyl-Hb or S-nitroso-Hb remains controversial. Some investigators favor a hypothesis that the interaction of Hb with NO is sensitive to pO2 and the T-state/R-state conformational transition and that Hb has a role in transport and delivery of a third gas, NO. Others argue that the level of S-nitroso-Hb in blood is too low (∼5 nM) and unchanged between the arterial and venous compartments to participate in an allosterically mediated release of NO (see also p 235).
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