T. E. J. Gayeski

O2 transport and its interaction with metabolism ; a systems view of aerobic capacity

This commentary demonstrates that VO2max depends, in part, on diffusive O2 transport; exercise hyperemia is necessary but not sufficient. Experiments and new mathematical models place the principal site of resistance to O2 diffusion between the surface of a red cell and the sarcolemma. The large drop in PO2 over this short distance is caused by high flux density and absence of heme protein O2 carrier in this region. PO2 gradients within red myocytes are shallow at high VO2 because myoglobin acts as O2 carrier and PO2 buffer. At high VO2 cell PO2 is less than 5 torr, the myoglobin P50. Low cell PO2 relative to blood PO2 is essential to a) maintain the driving force on diffusion as capillary PO2 falls, and b) to increase myoglobin-facilitated diffusion and the overall O2 conductance. O2 per se does not limit mitochondrial ATP production under normal circumstances because the low O2 drive on electron transport is compensated by greater phosphorylation and redox drives. These metabolic adaptations support transcapillary diffusion by defending VO2 at the low cell PO2 required to extract O2 from blood. Thus aerobic capacity is a distributed property, dependent on the interaction of transport and metabolism as a system.

Lack of Lung Hemorrhage in Humans After Intraoperative Transesophageal Echocardiography with Ultrasound Exposure Conditions Similar to Those Causing Lung Hemorrhage in Laboratory Animals

This study investigated the phenomenon of ultrasonically induced lung hemorrhage in humans. Multiple experimental laboratories have shown that diagnostic ultrasound exposure can cause hemorrhage in the lungs of laboratory animals. The left lung of 50 patients (6 women, 44 men, mean age 61 years) was observed directly by the surgeon after routine intraoperative transesophageal echocardiography was performed. From manufacturer specifications the maximum derated intensity in the sound field of the system used was 186 W/cm2, the maximum derated rarefactional acoustic pressure was 2.4 MPa, and the maximum mechanical index was 1.3. The lowest frequency used was 3.5 MHz. This exposure exceeds the threshold found for surface lung hemorrhage seen on gross observation of laboratory animals. No hemorrhage was noted on any lung surface by the surgeon on gross observation. We conclude that clinical transesophageal echocardiography, even at field levels a little greater than the reported thresholds for lung hemorrhage in laboratory animals, did not cause surface lung hemorrhage apparent on gross observation. These negative results support the conclusion that the human lung is not markedly more sensitive to ultrasound exposure than that of other mammals.

Comparison of Intracellular PO2 and Conditions for Blood-Tissue O2 Transport in Heart and Working Red Skeletal Muscle

1. Neither anoxic nor hypoxic cells were found in epicardium of anaesthetized dogs, cats, rabbits and rats despite heterogeneity of flow (Wieringa et al., 1982) and haematocrit (Honig et al., in press) in the coronary capillary network. 2. Median PO2 in unstressed dog heart and cat heart are 4.8 and 5.2 torr, respectively. These values are close to the P50 of the oxymyoglobin dissociation curve, and well above PcritO2. 3. A dense, interconnected capillary network and high capillary haematocrit appear essential to achieve high O2 extraction at flows characteristic of maximally working myocardium. 4. Mb promotes O2 transport in myocardium by: a) maximizing the driving force for transcapillary diffusion, b) minimizing spatial variability in PmbO2, c) facilitating O2 diffusion in myocytes and, d) permitting close capillary packing without a diffusion shunt for O2. 5. The O2 conductance of the red cell-capillary system is a major determinant of O2 mass transfer in red muscle.

Precapillary O2 Loss and Arteriovenous O2 Diffusion Shunt are Below Limit of Detection in Myocardium

1. Mean intracellular PO2 is much lower than mean venous PO2 in subepicardium. 2. The drop in Hb saturation between aorta and terminal arterioles is within the 5% error of our method. 3. Arteriolar O2 has no effect on saturation in paired countercurrent venules in myocardium. 4. Saturation in coronary venules is independent of venule diameter and indistinguishable from saturation in macroscopic epicardial veins. 5. Since diffusive O2 shunting is negligible and PO2 is approximately linearly related to saturations over the observed range, mean coronary venous PO2 should closely approximate mean-end capillary PO2. 6. O2 mass transport from blood to tissue requires a steep PO2 gradient between the capillary and the surface of a tissue cell.

Myoglobin Saturation and Calculated PO2 in Single Cells of Resting Gracilis Muscles

Use of myoglobin (Mb) as an indicator of intracellular PO2 has been dormant for half a century, chiefly because of difficulty in differentiating Mb from hemoglobin (Hb) when both are illuminated. We recently devised a microspectrophotometer with which light can be collected exclusively from either Hb or Mb. Spatial resolution is 2–5 μ. Since freezing arrests chemical reaction, saturation measurements on a large cell population can be interpreted as though all the measurements had been made simultaneously. In this way the purely spatial uniformity of O2 delivery can be evaluated. Measurements can be made at several loci within one cell, at various loci in a cell cluster, or in cells selected at random from grossly different regions of the muscle. The method offers the further advantage that the contribution of local capillary recruitment to O2 delivery can be evaluated.

Direct Measurement of Intracellular O2 Gradients; Role of Convection and Myoglobin

During steady phasic exercise in a red muscle the entire O2 gradient between capillary and mitochondria occurs as a step over less than 5 m. The magnitude of this step is determined by VO2 and capillary PO2, and is independent of distance from a capillary, or local capillary density. The above cannot be explained by ordinary and/or facilitated diffusion, according to a classical Krogh model. A step gradient can be produced by intracellular convection and Mb, acting in concert. A uniformly low cell PO2 maximizes the trans-capillary O2 gradient, and hence the O2 flux. Since the O2 affinity of Mb is about 50 times less than that cytochrome a, a3, mitochondria can respire maximally at tensions well below the Mb P50. It seems likely that the principal function of Mb during steady, phasic exercise is to compensate for short capillary transit times by accelerating O2 release from Hb.

A Graphical Analysis of the Influence of Red Cell Transit Time, Carrier-Free Layer Thickness, and Intracellular PO2 on Blood-Tissue O2 Transport

This paper relates spectroscopic determinations of myoglobin (Mb) saturation and PO2 in individual myocytes (Gayeski and Honig, 1986) to a mathematical model of O2 transport (Federspiel, 1983). A graphical analysis of model results is used to illustrate interactions among the main determinants of O2 transport between hemoglobin (Hb) and cytochrome. The results of the analysis are summarized in a plot called the O2 release curve. The results are qualitatively applicable to normal and pathophysiology, and to Mb-free tissues.

Lactate Production in a Pure Red Muscle in Absence of Anoxia: Mechanisms and Significance

Neither lactate accumulation in nor lactate release from muscle tissue can be used as evidence of anoxic tissue. We propose that the principal function of the lactate accumulation in tissue is to buffer cytosolic NADH levels and promote AEROBIC ATP production. This aerobic function of lactate metabolism should increase efficiency and extend the range of muscle performance.

Shallow Intracellular O2 Gradients and Absence of Perimitochondrial O2 “Wells” in Heavily Working Red Muscle

It is generally believed that the principal site of resistance to O2 mass transport resides within the tissue cells.1,2 In this view the ΔPO2 from sarcolemma to cell interior greatly exceeds the ΔPO2 from red cell to interstitium. Precisely the reverse is suggested by recent mathematical models of O2 release from capillaries,3,4,5,6 and by measurements on suspensions of cardiac myocytes in vitro.7 This paper reports the first measurements with sufficient spatial resolution to map intracellular O2 gradients in vivo. We find that the large-scale O2 gradient from sarcolemma to cell interior is indeed shallow, and is not significantly perturbed by small-scale gradients around individual mitochondria.

An Upper Bound on the Minimum PO2 for O2 Consumption in Red Muscle

At a certain PO2 the rate of O2 consumption (VO2) becomes limited by O2 availability rather than energy demand. This PO2 may be defined as the critical PO2 (PcritO2) for the corresponding rate of cytochrome turnover. PcritO2 sets the minimum PO2 which convective and diffusive transport must defend. To date there have been no estimates of PcritO2 for VO2 in vivo, though the influence of O2 on redox ratios has been studied extensively in heart, liver and brain. Some contend that cytochrome a,a3 is highly reduced in tissue over the entire physiologic range of O2 tensions.1,2 Such reduction implies that tissue respiration should be strongly O2 dependent and that there should be no PcritO2 for VO2 in vivo. Chance and associates studied O2 binding to cytochrome a, a3 in brain in the presence and absence of CO.3 They interpret their data to mean that cytochrome a, a3 is almost fully oxidized in vivo and in vitro. Lubbers and associates found cytochrome a, a3 more than 95% oxidized in rat heart (personal communication). Highly oxidized a, a3 suggests that VO2 depends solely on redox and phosphorylation potentials above a PO2 negligible for O2 transport.