Effect of mild carboxy-hemoglobin on exercising skeletal muscle: intravascular and intracellular evidence

Abstract

. Effect of mild carboxy-hemoglobin on exercising skeletal muscle: intravascular and intracellular evidence. Am J Physiol Regul Integr Comp Physiol 283: R1131-R1139, 2002. First published July 11, 2002 10.1152/ ajpregu.00226.2002We studied muscle blood flow, muscle oxygen uptake (V O2), net muscle CO uptake, Mb saturation, and intracellular bioenergetics during incremental single leg knee-extensor exercise in five healthy young subjects in conditions of normoxia, hypoxia (H; 11% O2), normoxia ϩ CO (COnorm), and 100% O2 ϩ CO (COhyper). Maximum work rates and maximal oxygen uptake (V O2 max) were equally reduced by Ϸ14% in H, COnorm, and COhyper. The reduction in arterial oxygen content (CaO 2 ) (Ϸ20%) resulted in an elevated blood flow (Q) in the CO and H trials. Net muscle CO uptake was attenuated in the CO trials. Suprasystolic cuff measurements of the deoxy-Mb signal were not different in terms of the rate of signal rise or maximum signal attained with and without CO. At maximal exercise, calculated mean capillary PO2 was most reduced in H and resulted in the lowest Mbassociated PO2. Reductions in ATP, PCr, and pH during H, COnorm, and COhyper occurred earlier during progressive exercise than in normoxia. Thus the effects of reduced CaO 2 due to mild CO poisoning are similar to H. exercise; metabolism; CO toxicity; magnetic resonance spectroscopy; 31 P; maximal O2 consumption; intracellular partial pressure of O2 THE STRONG AFFINITY of carbon monoxide (CO) for Hb has afforded researchers the opportunity to measure Hb mass and blood volume (5), examine O 2 transport (12, 18), and most recently to manipulate blood Hb levels while independently manipulating arterial PO 2 to study the control of skeletal muscle blood flow (9). Additionally, mild CO poisoning is an unavoidable consequence of cigarette smoking (36). The usefulness of CO as a tool is enhanced by the fact that unlike hypoxia (H), mild CO exposure does not stimulate the carotid body and does not result in an increase in cardiac output or ventilation (33). However, the validity of using CO in vascular research and the clinical consequences of mild CO poisoning are highly dependent on the magnitude of the diffusive movement of CO from the vascular to intracellular space and the subsequent intracellular consequences of any such movement.In favor of limited CO movement and consistent with the normal physiological function of CO disposal (as a catalytic byproduct of heme), the ligand affinities for CO are the reverse of those for O 2 . Hence, Mb has a higher CO affinity than cytochrome oxidase and Hb has a higher affinity than myoglobin (Mb). Additionally, on the basis of the high affinity Hb has for CO, the major driving force for CO movement (CO partial pressure in the blood) should theoretically remain low with a mild level of Hb-CO. Despite this concept, both researchers and clinicians concern's regarding the exposure of muscle to CO have revolved around the effect of CO on O 2 transport by interfering with Mb-facilitated O 2 diffusion and the metabol...

Erythrocyte and the Regulation of Human Skeletal Muscle Blood Flow and Oxygen Delivery

“…20 Flow-or shear stress-induced increase in ATP from endothelial cells cannot explain our results either, because COϩnormoxia resulted in lower [ATP] than hypoxia, despite the somewhat higher TBF than in hypoxia. Lastly, the strikingly constant creatine kinase concentration throughout the entire protocol clearly argues against a noticeable leakage of ATP from interstitium.…”

“…[11][12][13][14][15][16][17][18][19][20] The main difference compared with our recent studies was that with greater herein COHb levels in the COϩnormoxia trial (22% versus 18%) thigh O 2 delivery did not increase significantly, and that with lower herein F I O 2 levels in the hypoxia trial (10% versus 12%) thigh O 2 delivery tended to decline somewhat at high work rates. 19,20 In every study, however, thigh V O 2 was remarkably similar among conditions owing to compensatory adjustments in TBF and a-vO 2 diff. These hemodynamic data illustrate the ability of the circulatory system in adjusting skeletal muscle blood flow so that total O 2 flux from muscle capillaries to mitochondria is maintained in conditions of vastly different O 2 gradients.…”

“…It is worth noting that intracellular O 2 markers such as PO 2 and MbO 2 saturation cannot explain the profound increases in TBF with CO inhalation because quadriceps muscle PO 2 and MbO 2 saturation have been shown to be similar in normoxia, COϩnormoxia, and COϩhyperoxia. 20 A central question then relates to how the red blood cell signals the vascular endothelium to increase or decrease skeletal muscle blood flow in direct proportion to O 2 Hb. According to the model proposed by Ellsworth et al, 3 the erythrocyte would release ATP in proportion to the offloading of O 2 from hemoglobin.…”

Superoxide scavengers augment contractile but not energetic responses to hypoxia in rat diaphragm

“…These measurements are extremely difficult to make accurately and should be viewed with some caution; nevertheless they suggest that, in a hypoxic tissue bath, PO 2 reductions in the muscle core can be substantial. Normal PO 2 in perfused skeletal muscle is believed to be ϳ10 Torr at rest and 3-5 Torr during intense exercise (38), not reaching a "critical" cell PO 2 where respiration is limited until ϳ1.5 Torr (39). The present study likely resulted in relatively severe hypoxia in the muscle core with more moderate hypoxia in the study by Heunks et al (23).…”

Metabolic Control of Microvascular Networks: Oxygen Sensing and Beyond

“…Under resting conditions, replacing blood, and thus RBCs, by saline did not affect vascular responses to changes in pO 2 [20,120,125]. In physical exercise, however, blood flow in the skeletal muscle in humans has been shown to primarily respond to a reduction in arterial Hb-sO 2 , and not in pO 2 [126,127,128], suggesting that a main contribution to O 2 -dependent signaling for blood flow control under these conditions originates from erythrocytes, rather than vascular endothelium, vascular smooth-muscle or skeletal muscle [129]. …”