Comments for:
Abstract
Nitric oxide (NO) may be stabilized by binding to hemoglobin, by nitrosating thiol-containing plasma molecules, or by conversion to nitrite, all reactions potentially preserving its bioactivity in blood. Here we examined the contribution of blood-transported NO to regional vascular tone in humans before and during NO inhalation. While breathing room air and then room air with NO at 80 parts per million, forearm blood flow was measured in 16 subjects at rest and after blockade of forearm NO synthesis with NG-monomethyl-L-arginine (L-NMMA) followed by forearm exercise stress. L-NMMA reduced blood flow by 25% and increased resistance by 50%, an effect that was blocked by NO inhalation. With NO inhalation, resistance was significantly lower during L-NMMA infusion, both at rest and during repetitive hand-grip exercise. S-nitrosohemoglobin and plasma S-nitrosothiols did not change with NO inhalation. Arterial nitrite levels increased by 11% and arterial nitrosyl(heme)hemoglobin levels increased tenfold to the micromolar range, and both measures were consistently higher in the arterial than in venous blood. S-nitrosohemoglobin levels were in the nanomolar range, with no significant artery-to-vein gradients. These results indicate that inhaled NO during blockade of regional NO synthesis can supply intravascular NO to maintain normal vascular function. This effect may have application for the treatment of diseases characterized by endothelial dysfunction.
Authors
Richard O. Cannon III, Alan N. Schechter, Julio A. Panza, Frederick P. Ognibene, Margaret E. Pease-Fye, Myron A. Waclawiw, James H. Shelhamer, Mark T. Gladwin
Metabolic fate of inhaled NO in critically ill patients
Submitter: Jean-Charles Preiser and Jean-Louis Vincent | preiserj@ulb.ac.be
Erasme University Hospital, Brussels and CHNDRF, Charleroi, Belgium
Published August 6, 2001
Dear Sir, We read with interest the study by Cannon et al recently published in the Journal of Clinical Investigation (1) in which the authors describe the fate of a high concentration of nitric oxide (NO, 80 ppm) delivered to volunteers by inhalation. We reported similar findings in 13 critically ill patients with acute respiratory distress syndrome (ARDS) and right heart failure treated with inhaled NO (2). In these patients, long-term (median 3.5, range 2-32 days) inhalation of moderate concentrations of NO (6.3±1.1 ppm) was associated with a three-fold increase in the plasma nitrate concentrations. We also reported kinetic data on the elimination of nitrate. The total amount of nitrate excreted in the urine decreased dramatically already 24 hours after the inhaled NO was discontinued (203 ± 68 mmol), compared with the 24-h period immediately preceding the withdrawal of NO (852 ± 228 mmol). Our data and those of Cannon et al (1), indicate that nitrate is the major extra-pulmonary end-product of inhaled NO. Importantly, as pointed out by Cannon et al, nitrate is bioinactive, probably explaining why we did not observe any cardiovascular deterioration during NO inhalation. The reversal of the vasoconstrictor effects of a NO synthase inhibitor during inhalation of NO, described by Cannon et al (1), should be confirmed in clinical conditions (when low concentrations of NO are administered for long period). If this finding is still apparent, the combination of inhaled NO and NO synthase inhibitors, as proposed for patients with ARDS and septic shock (3), may be ineffective.
1. Cannon R.O., Schechter A.N., Panza J.A. et al., 2001. Effects of inhaled nitric oxide on regional blood flow are consistent with intravascular nitric oxide delivery. J. Clin. Invest. 108;279-287.
2. Preiser J.C., De Backer D., Debelle F., Vray B. and Vincent J.L., 1998. The metabolic fate of long-term inhaled nitric oxide. J. Crit. Care 13;97-103.
3. Moncada S. and Higgs A., 1993. The L-arginine-nitric oxide pathway. N. Engl. J. Med. 329;2002-2012.
Jean-Charles Preiser, M.D., Ph.D. and Jean-Louis Vincent, M.D., Ph.D.
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