A nitric oxide processing defect of red blood cells created by hypoxia: deficiency of S-nitrosohemoglobin in pulmonary hypertension

McMahon TJ, Ahearn GS, Moya MP, Gow AJ, Huang YC, Luchsinger BP, Nudelman R, Yan Y, Krichman AD, Bashore TM, Califf RM, Singel DJ, Piantadosi CA, Tapson VF, Stamler JS. Proc Natl Acad Sci USA. 2005 Oct 11;102(41):14801-6. Epub 2005 Oct 3.

Reviewer: Theodore A. Alston, MD, PhD
Harvard Medical School
Boston, MA

Abstract: Red cells take up endothelium-derived nitric oxide (NO) and are generally thought to rapidly terminate the action of that vasodilator. However, red cells can release some of the NO that they pick up. From several directions, Stamler and colleagues assemble a compelling argument that NO release from red cells is a physiologically important process. Accordingly, impaired release of NO from red cells contributes to the pulmonary hypertension associated with hypoxemia.

The hemoglobin within red cells carries NO in two ways. The NO can attach to the iron atom of the heme, and it can attach to the sulfur atom of the amino acid cysteine of the hemoglobin polypeptide chain. The two types of NO are conveniently designated FeNO-Hb and SNO-Hb, respectively. The formation of FeNO-Hb is rapid, but the NO can transfer from the iron to the sulfur in a reaction that is stimulated by O2. It is the level of SNO-Hb that determines the ability of red cells to release NO (or a related nitroxy product).

The investigators found that freshly drawn venous human red cells (PO2 ∼ 40 mmHg) rapidly convert their FeNO-Hb to SNO-Hb upon promptexposureto21%O2(PO2∼150mmHg). Holding the PO2 at the hypoxic level for 30 min abolished the ability of 21% O2 to bring about this transfer of NO from iron to sulfur.

In isolated perfused rabbit lung, SNO-Hb itself, or red cells containing SNO-Hb, antagonized hypoxic pulmonary vasoconstriction, while unmodified hemoglobin augmented the vasoconstriction. In anesthetized pigs, infusion of red cells containing SNO-Hb into the pulmonary artery improved aortic oxygenation and reduced pulmonary vascular resistance.

In five patients with chronic hypoxemia and pulmonaryhypertension,redcellsweremarkedly depleted of SNO-Hb. These cells were impaired as hypoxic pulmonary vasodilators.

Most exciting, normal levels of SNO-Hb were achieved when hypoxic patients inhaled dilute ethyl nitrite vapor. That molecule can directly add NO to cysteine without the participation of heme or of O2. The drug lowered pulmonary vascular resistance and improved systemic oxygenation.

Comments: An intriguing aspect of this paper is that vasodilating red cells are found to improve systemic oxygenation. After all, the SNO-Hb cells are opposing the hypoxic pulmonary vasoconstriction expected to be important for the proper matching of alveolar perfusion to alveolar ventilation. A priori, an intravenous vasodilator would have been expected to worsen the matching.

Yet, hypoxia lowers SNO-Hb in red cells, and,despite its antagonism of hypoxic pulmonary vasoconstriction, SNO-Hb repletion can curiously improve oxygenation. Part of the story may be that, in the patients, SNO-Hb repletion was achieved by an inhaled drug, ethyl nitrite.

Inhaled NO itself, of course, is offered as a vasodilator that is short-acting and pulmonary selective because of rapidd estruction by red cells. In contrast, in this paper, ethyl nitrite is offered as an inhaled "NO donor" that causes a desirable ability of red cells to act as vasodilators. Further clinical study contrasting these two inhaled forms of NO will be very interesting.

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  • Anitricoxideprocessingdefectofredbloodcells created by hypoxia: deficiency of S-nitrosohemoglobin in pulmonary hypertension
  • Improving the Quality of Coronary Bypass Surgery With Intraoperative Angiography: Validation of a New Technique
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