No abstract

The hallmark of sickle cell disease (SCD) is the polymerization of deoxygenated sickle hemoglobin (HbS). In SCD patients, one strategy to reduce red blood cell (RBC) sickling is to increase HbS oxygen affinity. Our objective was to determine if low concentrations of nitric oxide (NO) gas would augment the oxygen affinity of RBCs containing homozygous HbS (SS). Blood containing normal adult hemoglobin (AA) or SS RBCs was incubated in vitro in the presence of varying concentrations of NO up to 80 ppm, and oxygen dissociation curves (ODCs) were measured. In addition, blood was obtained from three AA and nine SS volunteers, before and after breathing 80 ppm NO in air for 45 min, and the ODCs were measured. Exposure of SS RBCs to 80 ppm NO in vitro for 5 min or longer decreased the partial pressure of oxygen at which hemoglobin is 50% saturated with oxygen (P 50 ), an average of 15% (4.8 Ϯ 1.7 mmHg mean Ϯ SE; P Ͻ 0.001). The increase in SS RBC oxygen affinity correlated with the NO concentration. The P 50 of AA RBCs was unchanged ( P Ͼ 0.1) by 80 ppm NO. In SS volunteers breathing 80 ppm NO for 45 min, the P 50 decreased ( P Ͻ 0.001) by 4.6 Ϯ 2.0 mmHg. 60 min after NO breathing was discontinued, the RBC P 50 remained decreased in five of seven volunteers in whom the ODC was measured. There was no RBC P 50 change ( P Ͼ 0.1) in AA volunteers breathing NO. Methemoglobin (Mhb) remained low in all subjects breathing NO (SS Mhb 1.4 Ϯ 0.5%), and there was no correlation ( r ϭ 0.02) between the reduction in P 50 and the change in Mhb. Thus, low concentrations of NO augment the oxygen affinity of sickle erythrocytes in vitro and in vivo without significant Mhb production. These results suggest that low concentrations of NO gas may offer an attractive new therapeutic model for the treatment of SCD. ( J. Clin. Invest. 1997. 100: 1193-1198.)

We tested the importance of aerobic metabolism to human running speed directly by altering inspired oxygen concentrations and comparing the maximal speeds attained at different rates of oxygen uptake. Under both normoxic (20.93% O2) and hypoxic (13.00% O2) conditions, four fit adult men completed 15 all-out sprints lasting from 15 to 180 s as well as progressive, discontinuous treadmill tests to determine maximal oxygen uptake and the metabolic cost of steady-state running. Maximal aerobic power was lower by 30% (1.00 +/- 0.15 vs. 0.77 +/- 0.12 ml O2. kg-1. s-1) and sprinting rates of oxygen uptake by 12-25% under hypoxic vs. normoxic conditions while the metabolic cost of submaximal running was the same. Despite reductions in the aerobic energy available for sprinting under hypoxic conditions, our subjects were able to run just as fast for sprints of up to 60 s and nearly as fast for sprints of up to 120 s. This was possible because rates of anaerobic energy release, estimated from oxygen deficits, increased by as much as 18%, and thus compensated for the reductions in aerobic power. We conclude that maximal metabolic power outputs during sprinting are not limited by rates of anaerobic metabolism and that human speed is largely independent of aerobic power during all-out runs of 60 s or less.

Breathing NO produced a rapid, protective effect to severe hypoxic stress in SAD mice. There appears to be a required loading period between NO breathing and its beneficial effect during hypoxic stress, possibly because of the total amount of NO delivered to SAD hemoglobin, blood cell components, and endothelium. NO breathing may be beneficial as a therapeutic intervention in SCD.