Diaspirin cross-linked Hb and norepinephrine prevent the sepsis-induced increase in critical O(2) delivery

We hypothesized that support of arterial perfusion pressure with diaspirin cross-linked Hb (DCLHb) would prevent the sepsis-induced attenuation in the systemic O(2) delivery-O(2) uptake relationship. Awake septic rats were treated with a chronic infusion of DCLHb or a reference treatment [norepinephrine (NE)] to increase mean arterial pressure by 10-20% over 18 h. Septic and sham control groups received normal saline. Isovolemic hemodilution to create anemic hypoxia was then performed in a metabolic box during continuous measurement of systemic O(2) uptake. O(2) delivery was calculated from hemodynamic variables, and the critical point of O(2) delivery (DO(2 crit)) was determined using piecewise regression analysis of the O(2) delivery-O(2) uptake relationship. Sepsis increased DO(2 crit) from 4.99 +/- 0.17 to 6.69 +/- 0.42 ml x min(-1) x 100 g(-1) (P < 0.01), while O(2) extraction capacity was decreased (P < 0.05). DCLHb and NE infusion prevented the sepsis-induced increase in DO(2 crit) [4.56 +/- 0.42 ml x min(-1) x 100 g(-1) (P < 0.01) and 5.04 +/- 0.56 ml x min(-1) x 100 g(-1) (P < 0.05), respectively]. This was explained by a 59% increase in O(2) extraction capacity in the DCLHb group compared with septic controls (P < 0.05), whereas NE treatment decreased systemic O(2) uptake in anemic hypoxia (1.51 +/- 0.08 vs. 1.87 +/- 0.1 ml x min(-1) x 100 g(-1) in septic controls, P < 0.05). We conclude that DCLHb ameliorated O(2) extraction capacity in the septic microcirculation, whereas NE decreased the metabolic demands of the tissues.     

Subcutaneous PO2 as an index of the physiological limits for hemodilution in the rat.

This study was designed to test the hypothesis that changes in subcutaneous PO2 (PscO2) during progressive hemodilution will reliably predict a "critical point" at which tissue O2 consumption (VO2) becomes dependent on O2 delivery (QO2). Twelve pentobarbital-anesthetized male Sprague-Dawley rats (315-375 g) underwent stepwise exchange of plasma for blood (1.5 ml of plasma for each 1 ml of blood lost). The initial exchange was equal to 25% of the estimated circulatory blood volume, and each subsequent exchange was equal to 10% of the estimated circulatory blood volume. After nine exchanges, the hematocrit (Hct) fell from 42 +/- 1 to 6 +/- 1%. Cardiac output and O2 extraction rose significantly. PscO2 became significantly reduced (P < 0.05) after exchange of 45% of the blood volume (Hct = 16 +/- 1%). VO2 became delivery dependent when QO2 fell below 21 ml x min(-1) x kg body wt(-1) (mean Hct = 13 +/- 1%). Eight control rats undergoing 1:1 blood-blood exchange showed no change in PscO2, pH, HCO3(-), or hemodynamics. Measurement of PscO2 may be a useful guide to monitor the adequacy of QO2 during hemodilution.     

Hepatic dysoxia commences during O2 supply dependence.

Hepatic O2 consumption (VO2) remains relatively constant (O2 supply independent) as O2 delivery (DO2) progressively decreases, until a critical DO2 (DO2c) is reached below which hepatic VO2 also decreases (O2 supply dependence). Whether this decrease in VO2 represents an adaptive reduction in O2 demand or a manifestation of tissue dysoxia, i.e., O2 supply that is inadequate to support O2 demand, is unknown. We tested the hypothesis that the decrease in hepatic VO2 during O2 supply dependence represents dysoxia by evaluating hepatic mitochondrial NAD redox state during O2 supply independence and dependence induced by progressive hemorrhage in six pentobarbital-anesthetized dogs. Hepatic mitochondrial NAD redox state was estimated by measuring hepatic venous beta-hydroxybutyrate-to-acetoacetate ratio (beta OHB/AcAc). The value of DO2c was 5.02 +/- 1.64 (SD) ml.100 g-1.min-1. The beta-hydroxybutyrate-to-acetoacetate ratio was constant until a DO2 value (3.03 +/- 1.08 ml.100 g-1.min-1) was reached (P = 0.05 vs. DO2c) and then increased linearly. Peak liver lactate extraction ratio was 15.2 +/- 14.1%, occurring at a DO2 of 5.48 +/- 2.54 ml.100 g-1.min-1 (P = NS vs. DO2c). Our data support the hypothesis that the decrease in VO2 during O2 supply dependence represents tissue dysoxia.     

Effects of training on muscle O2 transport at VO2max.

To quantify the relative contributions of convective and peripheral diffusive components of O2 transport to the increase in leg O2 uptake (VO2leg) at maximum O2 uptake (VO2max) after 9 wk of endurance training, 12 sedentary subjects (age 21.8 +/- 3.4 yr, VO2max 36.9 +/- 5.9 ml.min-1.kg-1) were studied. VO2max, leg blood flow (Qleg), and arterial and femoral venous PO2, and thus VO2leg, were measured while the subjects breathed room air, 15% O2, and 12% O2. The sequence of the three inspirates was balanced. After training, VO2max and VO2leg increased at each inspired O2 concentration [FIO2; mean over the 3 FIO2 values 25.2 +/- 17.8 and 36.5 +/- 33% (SD), respectively]. Before training, VO2leg and mean capillary PO2 were linearly related through the origin during hypoxia but not during room air breathing, suggesting that, at 21% O2, VO2max was not limited by O2 supply. After training, VO2leg and mean capillary PO2 at each FIO2 fell along a straight line with zero intercept, just as in athletes (Roca et al. J. Appl. Physiol. 67: 291-299, 1989). Calculated muscle O2 diffusing capacity (DO2) rose 34% while Qleg increased 19%. The relatively greater rise in DO2 increased the DO2/Qleg, which led to 9.9% greater O2 extraction. By numerical analysis, the increase in Qleg alone (constant DO2) would have raised VO2leg by 35 ml/min (mean), but that of DO2 (constant Qleg) would have increased VO2leg by 85 ml/min, more than twice as much. The sum of these individual effects (120 ml/min) was less (P = 0.013) than the observed rise of 164 ml/min (mean). This synergism (explained by the increase in DO2/Qleg) seems to be an important contribution to increases in VO2max with training.     

Increased plasma O2 solubility improves O2 uptake of in situ dog muscle working maximally.

A perfluorocarbon emulsion [formulation containing 90% wt/vol perflubron (perfluorooctylbromide); Alliance Pharmaceutical] was used to increase O2 solubility in the plasma compartment during hyperoxic low hemoglobin concentration ([Hb]) perfusion of a maximally working dog muscle in situ. Our hypothesis was that the increased plasma O2 solubility would increase the muscle O2 diffusing capacity (DO2) by augmenting the capillary surface area in contact with high [O2]. Oxygen uptake (VO2) was measured in isolated in situ canine gastrocnemius (n = 4) while working for 6 min at a maximal stimulation rate of 1 Hz (isometric tetanic contractions) on three to four separate occasions for each muscle. On each occasion, the last 4 min of the 6-min work period was split into 2 min of a control treatment (only emulsifying agent mixed into blood) and 2 min of perflubron treatment (6 g/kg body wt), reversing the order for each subsequent work bout. Before contractions, the [Hb] of the dog was decreased to 8-9 g/100 ml and arterial PO2 was increased to 500-600 Torr by having the dog breathe 100% O2 to maximize the effect of the perflubron. Muscle blood flow was held constant between the two experimental conditions. Plasma O2 solubility was almost doubled to 0.005 ml O2 x 100 ml blood-1 x Torr-1 by the addition of the perflubron. Muscle O2 delivery and maximal VO2 were significantly improved (at the same blood flow and [Hb]) by 11 and 12.6%, respectively (P < 0.05), during the perflubron treatment compared with the control. O2 extraction by the muscle remained the same between the two treatments, as did the estimate of DO2.(ABSTRACT TRUNCATED AT 250 WORDS)     

Flow redistribution during progressive hemorrhage is a determinant of critical O2 delivery

O2 consumption (VO2) of anesthetized whole mammals is independent of O2 delivery (DO2) until DO2 declines to a critical value (DO2c). Below this value, VO2 becomes O2 supply dependent. We assessed the influence of whole body DO2 redistribution among organs with respect to the commencement of O2 supply dependency. We measured DO2, VO2, and DO2c of whole body, liver, intestine, kidney, and remaining carcass in eight mongrel dogs during graded progressive hemorrhage. Whole body DO2 was redistributed such that the organ-to-whole body DO2 ratio declined for liver and kidney and increased for carcass. We then created a mathematical model wherein each organ-to-whole body DO2 ratio remained approximately constant at all values of whole body DO2 and assigned organ VO2 to predicted organ DO2 by interpolation and extrapolation of observed VO2-DO2 plots. The model predicted that O2 supply dependency without redistribution would have commenced at a higher value of whole body DO2 for whole body (8.11 +/- 0.89 vs. 6.98 +/- 1.16 ml.kg-1.min-1, P less than 0.05) and carcass (6.83 +/- 1.16 vs. 5.06 +/- 1.15 ml.kg-1.min-1, P less than 0.01) and at a lower value of whole body DO2 for liver (6.33 +/- 1.86 vs. 7.59 +/- 1.95, ml.kg-1.min-1, P less than 0.02) and kidney (1.25 +/- 0.64 vs. 4.54 +/- 1.29 ml.kg-1.min-1, P less than 0.01). We conclude that redistribution of whole body DO2 among organs facilitates whole body O2 regulation.     

Skeletal muscle metabolism is unaffected by DCA infusion and hyperoxia after onset of intense aerobic exercise

This study investigated whether hyperoxic breathing (100% O(2)) or increasing oxidative substrate supply [dichloroacetate (DCA) infusion] would increase oxidative phosphorylation and reduce the reliance on substrate phosphorylation at the onset of high-intensity aerobic exercise. Eight male subjects cycled at 90% maximal O(2) uptake (VO(2 max)) for 90 s in three randomized conditions: 1) normoxic breathing and saline infusion over 1 h immediately before exercise (CON), 2) normoxic breathing and saline infusion with DCA (100 mg/kg body wt), and 3) hyperoxic breathing for 20 min at rest and during exercise and saline infusion (HYP). Muscle biopsies from the vastus lateralis were sampled at rest and after 30 and 90 s of exercise. DCA infusion increased pyruvate dehydrogenase (PDH) activation above CON and HYP (3.10 +/- 0.23, 0.56 +/- 0.08, 0.69 +/- 0.05 mmol x kg wet muscle(-1) x min(-1), respectively) and significantly increased both acetyl-CoA and acetylcarnitine (11.0 +/- 0.7, 2.0 +/- 0.5, 2.2 +/- 0.5 mmol/kg dry muscle, respectively) at rest. However, DCA and HYP did not alter phosphocreatine degradation and lactate accumulation and, therefore, the reliance on substrate phosphorylation during 30 s (CON, 51.2 +/- 5.4; DCA, 56.5 +/- 7.1; HYP, 69.5 +/- 6.3 mmol ATP/kg dry muscle) and 90 s of exercise (CON, 90.6 +/- 9.5; DCA, 107.2 +/- 13.0; HYP, 101.2 +/- 15.2 mmol ATP/kg dry muscle). These data suggest that the rate of oxidative phosphorylation at the onset of exercise at 90% VO(2 max) is not limited by oxygen availability to the active muscle or by substrate availability (metabolic inertia) at the level of PDH in aerobically trained subjects.     

Living and training in moderate hypoxia does not improve VO2 max more than living and training in normoxia.

The objective of these experiments was to determine whether living and training in moderate hypoxia (MHx) confers an advantage on maximal normoxic exercise capacity compared with living and training in normoxia. Rats were acclimatized to and trained in MHx [inspired PO2 (PI(O2)) = 110 Torr] for 10 wk (HTH). Rats living in normoxia trained under normoxic conditions (NTN) at the same absolute work rate: 30 m/min on a 10 degrees incline, 1 h/day, 5 days/wk. At the end of training, rats exercised maximally in normoxia. Training increased maximal O2 consumption (VO2 max) in NTN and HTH above normoxic (NS) and hypoxic (HS) sedentary controls. However, VO2 max and O2 transport variables were not significantly different between NTN and HTH: VO2 max 86.6 +/- 1.5 vs. 86.8 +/- 1.1 ml x min(-1) x kg(-1); maximal cardiac output 456 +/- 7 vs. 443 +/- 12 ml x min(-1) x kg(-1); tissue blood O2 delivery (cardiac output x arterial O2 content) 95 +/- 2 vs. 96 +/- 2 ml x min(-1) x kg(-1); and O2 extraction ratio (arteriovenous O2 content difference/arterial O2 content) 0.91 +/- 0.01 vs. 0.90 +/- 0.01. Mean pulmonary arterial pressure (Ppa, mmHg) was significantly higher in HS vs. NS (P < 0.05) at rest (24.5 +/- 0.8 vs. 18.1 +/- 0.8) and during maximal exercise (32.0 +/- 0.9 vs. 23.8 +/- 0.6). Training in MHx significantly attenuated the degree of pulmonary hypertension, with Ppa being significantly lower at rest (19.3 +/- 0.8) and during maximal exercise (29.2 +/- 0.5) in HTH vs. HS. These data indicate that, despite maintaining equal absolute training intensity levels, acclimatization to and training in MHx does not confer significant advantages over normoxic training. On the other hand, the pulmonary hypertension associated with acclimatization to hypoxia is reduced with hypoxic exercise training.     

Epinephrine infusion during moderate intensity exercise increases glucose production and uptake

The glucoregulatory response to intense exercise [IE, >80% maximum O(2) uptake (VO(2 max))] comprises a marked increment in glucose production (R(a)) and a lesser increment in glucose uptake (R(d)), resulting in hyperglycemia. The R(a) correlates with plasma catecholamines but not with the glucagon-to-insulin (IRG/IRI) ratio. If epinephrine (Epi) infusion during moderate exercise were able to markedly stimulate R(a), this would support an important role for the catecholamines' response in IE. Seven fit male subjects (26 +/- 2 yr, body mass index 23 +/- 0.5 kg/m(2), VO(2 max) 65 +/- 5 ml x kg(-1) x min(-1)) underwent 40 min of postabsorptive cycle ergometer exercise (145 +/- 14 W) once without [control (CON)] and once with Epi infusion [EPI (0.1 microg x kg(-1) x min(-1))] from 30 to 40 min. Epi levels reached 9.4 +/- 0.8 nM (20x rest, 10x CON). R(a) increased approximately 70% to 3.75 +/- 0.53 in CON but to 8.57 +/- 0.58 mg x kg(-1) x min(-1) in EPI (P < 0.001). Increments in R(a) and Epi correlated (r(2) = 0.923, P 相似文献   

Venoarterial CO(2) difference during regional ischemic or hypoxic hypoxia.

To test the role of blood flow in tissue hypoxia-related increased veno-arterial PCO(2) difference (DeltaPCO(2)), we decreased O(2) delivery (&Ddot;O(2)) by either decreasing flow [ischemic hypoxia (IH)] or arterial PO(2) [hypoxic hypoxia (HH)] in an in situ, vascularly isolated, innervated dog hindlimb perfused with a pump-membrane oxygenator system. Twelve anesthetized and ventilated dogs were studied, with systemic hemodynamics maintained within normal range. In the IH group (n = 6), hindlimb DO(2) was progressively lowered every 15 min by decreasing pump-controlled flow from 60 to 10 ml. kg(-1). min(-1), with arterial PO(2) constant at 100 Torr. In the HH group (n = 6), hindlimb DO(2) was progressively lowered every 15 min by decreasing PO(2) from 100 to 15 Torr, when flow was constant at 60 ml. kg(-1). min(-1). Limb DO(2), O(2) uptake (VO(2)), and DeltaPCO(2) were obtained every 15 min. Below the critical DO(2), VO(2) decreased, indicating dysoxia, and O(2) extraction ratio (VO(2)/DO(2)) rose continuously and similarly in both groups, reaching a maximal value of approximately 90%. DeltaPCO(2) significantly increased in IH but never differed from baseline in HH. We conclude that absence of increased DeltaPCO(2) does not preclude the presence of tissue dysoxia and that decreased flow is a major determinant in increased DeltaPCO(2).     

Increases in myocardial cyclic GMP attenuate contractile delay in myocardial stunning

We tested the hypothesis that the effects of myocardial stunning would be reduced by cyclic GMP in rabbit hearts. In three groups of anesthetized open-chest New Zealand white rabbits, myocardial stunning was produced by 15 min of occlusion of the left anterior descending coronary artery followed by 15 min of reperfusion repeated twice. Either control vehicle (saline plus 1% dimethyl sulfoxide) or 8-bromo-cyclic GMP (8-Br-cGMP (10(-4) and 10(-3) M)) was topically applied to the left ventricular surface. Hemodynamic (left ventricular and aortic pressures) and functional parameters (wall thickening, delay in onset of wall thickening, and rate of wall thickening) were determined. Coronary blood flow (microspheres) and O2 extraction (microspectrophotometry) were used to determine myocardial O2 consumption (VO2). Myocardial stunning was observed in the control group through an increased delay in onset of myocardial wall thickening (29 +/- 7 versus 55 +/- 16 ms) and decreased maximal rate of wall thickening (20 +/- 8 versus 11 +/- 3 mm x s(-1)). After treatment with 8-Br-cGMP 10(-4) and 10(-3) M, stunning did not increase the delay (37 +/- 5 versus 39 +/- 7 and 39 +/- 7 versus 28 +/- 8 ms). Myocardial stunning did not significantly alter VO2. 8-Br-cGMP 10(-3) M significantly decreased subepicardial VO2 (6.2 +/- 0.8 versus 3.7 +/- 0.6 mL O2 x min(-1) 100 g(-1)) and insignificantly decreased subendocardial VO2 (8.6 +/- 0.9 versus 6.3 +/- 1.2 mL O2 x min(-1) x 100 g(-1)) when compared with the vehicle-treated rabbits. We conclude that increasing cyclic GMP reduced the effects of myocardial stunning in the rabbit heart by ameliorating the delay in onset of wall thickening and decreasing the local O2 costs in the stunned region.     

Mechanism of action of exenatide to reduce postprandial hyperglycemia in type 2 diabetes

We examined the contributions of insulin secretion, glucagon suppression, splanchnic and peripheral glucose metabolism, and delayed gastric emptying to the attenuation of postprandial hyperglycemia during intravenous exenatide administration. Twelve subjects with type 2 diabetes (3 F/9 M, 44 +/- 2 yr, BMI 34 +/- 4 kg/m2, Hb A(1c) 7.5 +/- 1.5%) participated in three meal-tolerance tests performed with double tracer technique (iv [3-3H]glucose and oral [1-14C]glucose): 1) iv saline (CON), 2) iv exenatide (EXE), and 3) iv exenatide plus glucagon (E+G). Acetaminophen was given with the mixed meal (75 g glucose, 25 g fat, 20 g protein) to monitor gastric emptying. Plasma glucose, insulin, glucagon, acetaminophen concentrations and glucose specific activities were measured for 6 h post meal. Post-meal hyperglycemia was markedly reduced (P < 0.01) in EXE (138 +/- 16 mg/dl) and in E+G (165 +/- 12) compared with CON (206 +/- 15). Baseline plasma glucagon ( approximately 90 pg/ml) decreased by approximately 20% to 73 +/- 4 pg/ml in EXE (P < 0.01) and was not different from CON in E+G (81 +/- 2). EGP was suppressed by exenatide [231 +/- 9 to 108 +/- 8 mg/min (54%) vs. 254 +/- 29 to189 +/- 27 mg/min (26%, P < 0.001, EXE vs. CON] and partially reversed by glucagon replacement [247 +/- 15 to 173 +/- 18 mg/min (31%)]. Oral glucose appearance was 39 +/- 4 g in CON vs. 23 +/- 6 g in EXE (P < 0.001) and 15 +/- 5 g in E+G, (P < 0.01 vs. CON). The glucose retained within the splanchnic bed increased from approximately 36g in CON to approximately 52g in EXE and to approximately 60g in E+G (P < 0.001 vs. CON). Acetaminophen((AUC)) was reduced by approximately 80% in EXE vs. CON (P < 0.01). We conclude that exenatide infusion attenuates postprandial hyperglycemia by decreasing EGP (by approximately 50%) and by slowing gastric emptying.     

Determinants of maximal O(2) uptake in rats selectively bred for endurance running capacity.

O(2) transport during maximal exercise was studied in rats bred for extremes of exercise endurance, to determine whether maximal O(2) uptake (VO(2 max)) was different in high- (HCR) and low-capacity runners (LCR) and, if so, which were the phenotypes responsible for the difference. VO(2 max) was determined in five HCR and six LCR female rats by use of a progressive treadmill exercise protocol at inspired PO(2) of approximately 145 (normoxia) and approximately 70 Torr (hypoxia). Normoxic VO(2 max) (in ml. min(-1). kg(-1)) was 64.4 +/- 0.4 and 57.6 +/- 1.5 (P < 0.05), whereas VO(2 max) in hypoxia was 42.7 +/- 0.8 and 35.3 +/- 1.5 (P < 0.05) in HCR and LCR, respectively. Lack of significant differences between HCR and LCR in alveolar ventilation, alveolar-to-arterial PO(2) difference, or lung O(2) diffusing capacity indicated that neither ventilation nor efficacy of gas exchange contributed to the difference in VO(2 max) between groups. Maximal rate of blood O(2) convection (cardiac output times arterial blood O(2) content) was also similar in both groups. The major difference observed was in capillary-to-tissue O(2) transfer: both the O(2) extraction ratio (0.81 +/- 0.002 in HCR, 0.74 +/- 0.009 in LCR, P < 0.001) and the tissue diffusion capacity (1.18 +/- 0.09 in HCR and 0.92 +/- 0.05 ml. min(-1). kg(-1). Torr(-1) in LCR, P < 0.01) were significantly higher in HCR. The data indicate that selective breeding for exercise endurance resulted in higher VO(2 max) mostly associated with a higher transfer of O(2) at the tissue level.     

Pulmonary clearance of 99mTc-DTPA: influence of background activity

To study the effects of circulatory occlusion on the time course and magnitude of postexercise O2 consumption (VO2) and blood lactate responses, nine male subjects were studied twice for 50 min on a cycle ergometer. On one occasion, leg blood flow was occluded with surgical thigh cuffs placed below the buttocks and inflated to 200 mmHg. The protocol consisted of a 10-min rest, 12 min of exercise at 40% peak O2 consumption (VO2 peak), and a 28-min resting recovery while respiratory gas exchange was determined breath by breath. Occlusion (OCC) spanned min 6-8 during the 12-min work bout and elicited mean blood lactate of 5.2 +/- 0.8 mM, which was 380% greater than control (CON). During 18 min of recovery, blood lactate after OCC remained significantly above CON values. VO2 was significantly lower during exercise with OCC compared with CON but was significantly higher during the 4 min of exercise after cuff release. VO2 was higher after OCC during the first 4 min of recovery but was not significantly different thereafter. Neither total recovery VO2 (gross recovery VO2 with no base-line subtraction) nor excess postexercise VO2 (net recovery VO2 above an asymptotic base line) was significantly different for OCC and CON conditions (13.71 +/- 0.45 vs. 13.44 +/- 0.61 liters and 4.93 +/- 0.26 vs. 4.17 +/- 0.35 liters, respectively). Manipulation of exercise blood lactate levels had no significant effect on the slow ("lactacid") component of the recovery VO2.     

Cellular PO2 as a determinant of maximal mitochondrial O(2) consumption in trained human skeletal muscle.

Previously, by measuring myoglobin-associated PO(2) (P(Mb)O(2)) during maximal exercise, we have demonstrated that 1) intracellular PO(2) is 10-fold less than calculated mean capillary PO(2) and 2) intracellular PO(2) and maximum O(2) uptake (VO(2 max)) fall proportionately in hypoxia. To further elucidate this relationship, five trained subjects performed maximum knee-extensor exercise under conditions of normoxia (21% O(2)), hypoxia (12% O(2)), and hyperoxia (100% O(2)) in balanced order. Quadriceps O(2) uptake (VO(2)) was calculated from arterial and venous blood O(2) concentrations and thermodilution blood flow measurements. Magnetic resonance spectroscopy was used to determine myoglobin desaturation, and an O(2) half-saturation pressure of 3.2 Torr was used to calculate P(Mb)O(2) from saturation. Skeletal muscle VO(2 max) at 12, 21, and 100% O(2) was 0.86 +/- 0.1, 1.08 +/- 0.2, and 1.28 +/- 0.2 ml. min(-1). ml(-1), respectively. The 100% O(2) values approached twice that previously reported in human skeletal muscle. P(Mb)O(2) values were 2.3 +/- 0.5, 3.0 +/- 0.7, and 4.1 +/- 0.7 Torr while the subjects breathed 12, 21, and 100% O(2), respectively. From 12 to 21% O(2), VO(2) and P(Mb)O(2) were again proportionately related. However, 100% O(2) increased VO(2 max) relatively less than P(Mb)O(2), suggesting an approach to maximal mitochondrial capacity with 100% O(2). These data 1) again demonstrate very low cytoplasmic PO(2) at VO(2 max), 2) are consistent with supply limitation of VO(2 max) of trained skeletal muscle, even in hyperoxia, and 3) reveal a disproportionate increase in intracellular PO(2) in hyperoxia, which may be interpreted as evidence that, in trained skeletal muscle, very high mitochondrial metabolic limits to muscle VO(2) are being approached.     

Effect of hemoglobin concentration on maximal O2 uptake in canine gastrocnemius muscle in situ

O2 delivery to maximally working muscle was decreased by altering hemoglobin (Hb) concentration and arterial PO2 (PaO2) to investigate whether the reductions in maximal O2 uptake (VO2max) that occur with lowered [Hb] are in part related to changes in the effective muscle O2 diffusing capacity (DmO2). Two sets of experiments were conducted. In the initial set (n = 8), three levels of Hb [5.8 +/- 0.3, 9.4 +/- 0.1, and 14.4 +/- 0.6 (SE) g/100 ml] in the blood were used in random order to pump perfuse, at equal muscle blood flows and PaO2, maximally working isolated dog gastrocnemius muscle. VO2max declined with decreasing [Hb], but the relationship between VO2max and both the effluent venous PO2 (PvO2) and the calculated mean capillary PO2 (PcO2) was not linear through the origin and, therefore, not compatible with a single value of DmO2 (as calculated by Bohr integration using a model based on Fick's law of diffusion). To clarify these results, a second set of experiments (n = 6) was conducted in which two levels of Hb (14.0 +/- 0.6 and 6.9 +/- 0.6 g/100 ml) were each combined with two levels of oxygenation (PaO2 79 +/- 8 and 29 +/- 2 Torr) and applied in random sequence to again pump perfuse maximally working dog gastrocnemius muscle at constant blood flow. In these experiments, the relationship between VO2max and both PvO2 and calculated PcO2 for each [Hb] was consistent with a constant estimate of DmO2 as PaO2 was reduced, but the calculated DmO2 for the lower [Hb] was 33% less than that at the higher [Hb] (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Iloprost for the attenuation of ischaemia/reperfusion injury in a distant organ

The objective of this study was to investigate antioxidant and cytoprotective properties of iloprost in a distant organ after ischaemia reperfusion injury. Male Wistar rats were divided into two groups. After application of anesthaesia both hindlimbs were occluded. A 2-h reperfusion procedure was carried out after 60 min of ischemia. Study group (STU) rats (n=10) received 10 microg kg(-1) iloprost in 1 ml of saline from the tail vein 10 min before reperfusion. Control (CON) group rats (n=10) received an equal amount of saline. The rats were sacrificed by injection of a high dose of thiopentone sodium. Blood and tissue samples (right kidneys) were taken for analysis. Differences in malondialdehyde (MDA), myeloperoxidase (MPO), Na+-K+ ATPase and total antioxidant capacity (TAC) between the groups were analysed. MPO, MDA and TAC levels in the sera of CON and STU groups were 1.60+/-0.26 U l(-1), 11.42+/-5.23 nmol ml(-1), 8.30 x 10(-2)+/- 3.93 x 10(-2) nmol ml(-1) h(-1) and 1.07+/-0.11 U l(-1), 7.60+/-1.81 nmol ml(-1) and 0.15+/-3.23 x 10(-2) nmol ml(-1) h(-1) (p=0.0001, p=0.043 and p=0.0001 respectively). MPO, ATPase and MDA levels in kidneys for CON and STU groups were 1.24+/-0.58 U g(-1), 85.70+/-52.05 nmol mg(-1), 17.90+/-7.40 nmol ml(-1) and 0.78+/-0.31 U g(-1), 195.90+/-56.13 nmol mg(-1) and 10.10+/-0.99 nmol ml(-1) (p=0.046, p=0.0001 and p=0.009 respectively). When given prior to reperfusion, the positive effect of iloprost in the attenuation of distant organ reperfusion injury has been demonstrated.     

Catecholamine response is attenuated during moderate-intensity exercise in response to the "lactate clamp"

Catecholamine release is known to be regulated by feedforward and feedback mechanisms. Norepinephrine (NE) and epinephrine (Epi) concentrations rise in response to stresses, such as exercise, that challenge blood glucose homeostasis. The purpose of this study was to assess the hypothesis that the lactate anion is involved in feedback control of catecholamine concentration. Six healthy active men (26 +/- 2 yr, 82 +/- 2 kg, 50.7 +/- 2.1 ml.kg(-1).min(-1)) were studied on five occasions after an overnight fast. Plasma concentrations of NE and Epi were determined during 90 min of rest and 90 min of exercise at 55% of peak O2 consumption (VO2 peak) two times with exogenous lactate infusion (lactate clamp, LC) and two times without LC (CON). The blood lactate profile ( approximately 4 mM) of a preliminary trial at 65% VO2 peak (65%) was matched during the subsequent LC trials. In resting men, plasma NE concentration was not different between trials, but during exercise all conditions were different with 65% > CON > LC (65%: 2,115 +/- 166 pg/ml, CON: 1,573 +/- 153 pg/ml, LC: 930 +/- 174 pg/ml, P < 0.05). Plasma Epi concentrations at rest were different between conditions, with LC less than 65% and CON (65%: 68 +/- 9 pg/ml, CON: 59 +/- 7 pg/ml, LC: 38 +/- 10 pg/ml, P < 0.05). During exercise, Epi concentration showed the same trend (65%: 262 +/- 37 pg/ml, CON: 190 +/- 34 pg/ml, LC: 113.2 +/- 23 pg/ml, P < 0.05). In conclusion, lactate attenuates the catecholamine response during moderate-intensity exercise, likely by feedback inhibition.     

Evidence of O2 supply-dependent VO2 max in the exercise-trained human quadriceps.

Maximal O2 delivery and O2 uptake (VO2) per 100 g of active muscle mass are far greater during knee extensor (KE) than during cycle exercise: 73 and 60 ml. min-1. 100 g-1 (2.4 kg of muscle) (R. S. Richardson, D. R. Knight, D. C. Poole, S. S. Kurdak, M. C. Hogan, B. Grassi, and P. D. Wagner. Am. J. Physiol. 268 (Heart Circ. Physiol. 37): H1453-H1461, 1995) and 28 and 25 ml. min-1. 100 g-1 (7.5 kg of muscle) (D. R. Knight, W. Schaffartzik, H. J. Guy, R. Predilleto, M. C. Hogan, and P. D. Wagner. J. Appl. Physiol. 75: 2586-2593, 1993), respectively. Although this is evidence of muscle O2 supply dependence in itself, it raises the following question: With such high O2 delivery in KE, are the quadriceps still O2 supply dependent at maximal exercise? To answer this question, seven trained subjects performed maximum KE exercise in hypoxia [0.12 inspired O2 fraction (FIO2)], normoxia (0.21 FIO2), and hyperoxia (1.0 FIO2) in a balanced order. The protocol (after warm-up) was a square wave to a previously determined maximum work rate followed by incremental stages to ensure that a true maximum was achieved under each condition. Direct measures of arterial and venous blood O2 concentration in combination with a thermodilution blood flow technique allowed the determination of O2 delivery and muscle VO2. Maximal O2 delivery increased with inspired O2: 1.3 +/- 0.1, 1.6 +/- 0.2, and 1.9 +/- 0.2 l/min at 0.12, 0.21, and 1.0 FIO2, respectively (P < 0.05). Maximal work rate was affected by variations in inspired O2 (-25 and +14% at 0.12 and 1.0 FIO2, respectively, compared with normoxia, P < 0.05) as was maximal VO2 (VO2 max): 1.04 +/- 0.13, 1. 24 +/- 0.16, and 1.45 +/- 0.19 l/min at 0.12, 0.21, and 1.0 FIO2, respectively (P < 0.05). Calculated mean capillary PO2 also varied with FIO2 (28.3 +/- 1.0, 34.8 +/- 2.0, and 40.7 +/- 1.9 Torr at 0.12, 0.21, and 1.0 FIO2, respectively, P < 0.05) and was proportionally related to changes in VO2 max, supporting our previous finding that a decrease in O2 supply will proportionately decrease muscle VO2 max. As even in the isolated quadriceps (where normoxic O2 delivery is the highest recorded in humans) an increase in O2 supply by hyperoxia allows the achievement of a greater VO2 max, we conclude that, in normoxic conditions of isolated KE exercise, KE VO2 max in trained subjects is not limited by mitochondrial metabolic rate but, rather, by O2 supply.     

Intrapulmonary oxygen consumption in experimental pneumococcal pneumonia

To test the hypothesis that lung affected by acute bacterial pneumonia consumes significant amounts of O2, whole-body O2 consumption (VO2) was measured simultaneously by collection of expired gas (VO2exp) and by the Fick principle (VO2Fick) in five dogs with acute experimental pneumococcal pneumonia and in five uninfected controls. This approach is based on the premise that VO2Fick will not detect lung VO2, whereas the expired gas measurement represents the true whole-body VO2, including the lung. In controls VO2 exp averaged 110 +/- 20 ml/min (4.78 +/- 0.78 ml.min-1.kg-1), and VO2Fick was nearly identical at 114 +/- 21 ml/min (4.96 +/- 0.79 ml.min-1.kg-1). The VO2Fick in the pneumonia group was 127 ml/min, similar to both control group values when indexed for body weight (4.91 +/- 1.17 ml.min-1.kg-1). VO2exp, however, was 146 +/- 46 ml/min (5.74 +/- 1.57 ml.min-1.kg-1), exceeding VO2Fick by an average of 20 +/- 9 ml/min (P less than 0.01). This between-method difference of 20 +/- 9 ml/min (or 24 ml/min if the difference in the control group is assumed to apply to the pneumonia group) amounted to 13-15% of whole-body VO2 and can be attributed to VO2 in the lung, presumably by cells involved in the acute inflammatory response. Implications include the potential for significant underestimate of whole-body VO2 by the Fick method when used in the presence of lung inflammation and overestimate of blood flow to shunting or low ventilation-perfusion ratio lung units by the O2 method of measuring venous admixture-like perfusion. This observation may also explain the disproportionate hypoxemia sometimes seen in patients with severe pneumonia.