Inhaled nitric oxide augments nitric oxide transport on sickle cell hemoglobin without affecting oxygen affinity
Mark T. Gladwin, Alan N. Schechter, James H. Shelhamer, Lewis K. Pannell, Deirdre A. Conway, Borys W. Hrinczenko, James S. Nichols, Margaret E. Pease-Fye, Constance T. Noguchi, Griffin P. Rodgers, Frederick P. Ognibene
Mark T. Gladwin, Alan N. Schechter, James H. Shelhamer, Lewis K. Pannell, Deirdre A. Conway, Borys W. Hrinczenko, James S. Nichols, Margaret E. Pease-Fye, Constance T. Noguchi, Griffin P. Rodgers, Frederick P. Ognibene
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Inhaled nitric oxide augments nitric oxide transport on sickle cell hemoglobin without affecting oxygen affinity

Abstract

Nitric oxide (NO) inhalation has been reported to increase the oxygen affinity of sickle cell erythrocytes. Also, proposed allosteric mechanisms for hemoglobin, based on S-nitrosation of β-chain cysteine 93, raise the possibilty of altering the pathophysiology of sickle cell disease by inhibiting polymerization or by increasing NO delivery to the tissue. We studied the effects of a 2-hour treatment, using varying concentrations of inhaled NO. Oxygen affinity, as measured by P50, did not respond to inhaled NO, either in controls or in individuals with sickle cell disease. At baseline, the arterial and venous levels of nitrosylated hemoglobin were not significantly different, but NO inhalation led to a dose-dependent increase in mean nitrosylated hemoglobin, and at the highest dosage, a significant arterial-venous difference emerged. The levels of nitrosylated hemoglobin are too low to affect overall hemoglobin oxygen affinity, but augmented NO transport to the microvasculature seems a promising strategy for improving microvascular perfusion.

Authors

Mark T. Gladwin, Alan N. Schechter, James H. Shelhamer, Lewis K. Pannell, Deirdre A. Conway, Borys W. Hrinczenko, James S. Nichols, Margaret E. Pease-Fye, Constance T. Noguchi, Griffin P. Rodgers, Frederick P. Ognibene

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Effect of inhaled NO on the oxygen affinity (P50) of SS and AA erythrocy...
Effect of inhaled NO on the oxygen affinity (P50) of SS and AA erythrocytes. (a) The AA ODCs (expressed as P50) at baseline before NO inhalation (hours 1 and 2) demonstrated minimal hysteresis when measured during sample deoxygenation or during sample oxygenation. The baseline SS ODCs measured at 1 and 2 hours before NO inhalation, as expected, demonstrated significant hysteresis during sample deoxygenation and during sample oxygenation. There was no significant change in any of the P50 measurements after 1 and 2 hours of inhaled NO at 80 ppm in either the AA or SS individuals (hours 3 and 4; filled horizontal bar), measured either during sample deoxygenation (for SS individuals; P = 0.63) or reoxygenation (for SS individuals; P = 1.00). There was no significant change in any of the P50 measurements for up to 3 hours after NO inhalation in any of the individuals tested (10/10 tested in the first hour after NO; 7/10 in the second hour; and 3/10 in the third hour). (b) During dose escalation of inhaled NO in 3 SS individuals, there is no significant change in P50 measured during sample deoxygenation or reoxygenation after 1 hour inhalation each of 40, 60, and 80 ppm NO gas.