Cerebral lactate uptake during exercise is driven by the increased arterial lactate concentration.

Exercise facilitates cerebral lactate uptake, likely by increasing arterial lactate concentration and hence the diffusion gradient across the blood-brain barrier. However, nonspecific ß-adrenergic blockade by propranolol has previously reduced the arterio-jugular venous lactate difference (AVLac) during exercise, suggesting ß-adrenergic control of cerebral lactate uptake. Alternatively, we hypothesized that propranolol reduces cerebral lactate uptake by decreasing arterial lactate concentration. To test that hypothesis, we evaluated cerebral lactate uptake taking changes in arterial concentration into account. Nine healthy males performed incremental cycling exercises to exhaustion with and without intravenous propranolol (18.7 ± 1.9 mg). Lactate concentration was determined in arterial and internal jugular venous blood at the end of each workload. To take changes in arterial lactate into account, we calculated the fractional extraction (FELac) defined as AVLac divided by the arterial lactate concentration. Arterial lactate concentration was reduced by propranolol at any workload (P < 0.05), reaching 14 ± 3 and 11 ± 3 mmol·l-1 during maximal exercise without and with propranolol, respectively. Although AVLac and FELac increased during exercise (both P < 0.05), they were both unaffected by propranolol at any workload (P = 0.68 and P = 0.26) or for any given arterial lactate concentration (P = 0.78 and P = 0.22). These findings support that while propranolol may reduce cerebral lactate uptake, this effect reflects the propranolol-induced reduction in arterial lactate concentration and not inhibition of a ß-adrenergic mechanism within the brain. We hence conclude that cerebral lactate uptake during exercise is directly driven by the increasing arterial concentration with work rate.NEW & NOTEWORTHY During exercise the brain consumes lactate as a substitute for glucose. Propranolol has previously attenuated this cerebral lactate uptake, suggesting a ß-adrenergic transport mechanism. However, in the present study, we demonstrate that the fractional extraction of arterial lactate by the brain is unaffected by propranolol throughout incremental exercise to exhaustion. We conclude that cerebral lactate uptake during exercise is passively driven by the increasing arterial concentration, rather than by a ß-adrenergic mechanism within the brain.

Similar hemostatic responses to hypovolemia induced by hemorrhage and lower body negative pressure reveal a hyperfibrinolytic subset of non-human primates.

BACKGROUND: To study central hypovolemia in humans, lower body negative pressure (LBNP) is a recognized alternative to blood removal (HEM). While LBNP mimics the cardiovascular responses of HEM in baboons, similarities in hemostatic responses to LBNP and HEM remain unknown in this species. METHODS: Thirteen anesthetized baboons were exposed to progressive hypovolemia by HEM and, four weeks later, by LBNP. Hemostatic activity was evaluated by plasma markers, thromboelastography (TEG), flow cytometry, and platelet aggregometry at baseline (BL), during and after hypovolemia. RESULTS: BL values were indistinguishable for most parameters although platelet count, maximal clot strength (MA), protein C, thrombin anti-thrombin complex (TAT), thrombin activatable fibrinolysis inhibitor (TAFI) activity significantly differed between HEM and LBNP. Central hypovolemia induced by either method activated coagulation; TEG R-time decreased and MA increased during and after hypovolemia compared to BL. Platelets displayed activation by flow cytometry; platelet count and functional aggregometry were unchanged. TAFI activity and protein, Factors V and VIII, vWF, Proteins C and S all demonstrated hemodilution during HEM and hemoconcentration during LBNP, whereas tissue plasminogen activator (tPA), plasmin/anti-plasmin complex, and plasminogen activator inhibitor-1 did not. Fibrinolysis (TEG LY30) was unchanged by either method; however, at BL, fibrinolysis varied greatly. Post-hoc analysis separated baboons into low-lysis (LY30 <2%) or high-lysis (LY30 >2%) whose fibrinolytic state matched at both HEM and LBNP BL. In high-lysis, BL tPA and LY30 correlated strongly (r = 0.95; P<0.001), but this was absent in low-lysis. In low-lysis, BL TAFI activity and tPA correlated (r = 0.88; P<0.050), but this was absent in high-lysis. CONCLUSIONS: Central hypovolemia induced by either LBNP or HEM resulted in activation of coagulation; thus, LBNP is an adjunct to study hemorrhage-induced pro-coagulation in baboons. Furthermore, this study revealed a subset of baboons with baseline hyperfibrinolysis, which was strongly coupled to tPA and uncoupled from TAFI activity.

Role of spleen and liver for enhanced hemostatic competence following administration of adrenaline to humans.

This study evaluated by thrombelastography® (TEG) and Multiplate® analyses the role of the spleen and the liver for adrenaline-induced enhanced hemostatic competence. Eight splenectomized subjects and eight matched healthy control subjects were exposed to one-hour infusion of adrenaline (6 µg/kg/h). Administration of adrenaline to the healthy subjects reduced time to TEG-detected initial fibrin formation (by 22%) and increased rate of clot development (by 10%), maximal amplitude (by 8%), platelet count (by 30%), and Multiplate evaluated Ristocetin-induced platelet aggregation (by 21%) (all p ≤ 0.05), but infusion of adrenaline did not result in significant arterial to liver vein differences for plasma markers of coagulation. In the splenectomized subjects, adrenaline reduced the TEG-determined time to initial fibrin formation (by 17%; p = 0.005) whereas rate of clot development and maximum amplitude were unaffected. Also, 6 patients undergoing liver transplantation were exposed to infusion of adrenaline (4.8 µg/kg/h) during the anhepatic phase of the operation and that increased TEG-determined rate of clot formation (by 10%; p < 0.05), maximal amplitude (by 9%; p = 0.002) and tended to reduce time to initial fibrin formation (p = 0.1). In conclusion, adrenaline enhances hemostasis as evaluated by TEG in both healthy subjects and in anhepatic patients during liver transplantation and Ristocetin-induced aggregation in control subjects. In contrast, infusion of adrenaline reduces only time to initial fibrin formation in splenectomized subjects. These findings suggest that mobilization of platelets from the spleen dominates the adrenaline-induced enhanced hemostatic competence.

Hemostatic responses to exercise, dehydration, and simulated bleeding in heat-stressed humans.

Heat stress followed by an accompanying hemorrhagic challenge may influence hemostasis. We tested the hypothesis that hemostatic responses would be increased by passive heat stress, as well as exercise-induced heat stress, each with accompanying central hypovolemia to simulate a hemorrhagic insult. In aim 1, subjects were exposed to passive heating or normothermic time control, each followed by progressive lower-body negative pressure (LBNP) to presyncope. In aim 2 subjects exercised in hyperthermic environmental conditions, with and without accompanying dehydration, each also followed by progressive LBNP to presyncope. At baseline, pre-LBNP, and post-LBNP (<1, 30, and 60 min), hemostatic activity of venous blood was evaluated by plasma markers of hemostasis and thrombelastography. For aim 1, both hyperthermic and normothermic LBNP (H-LBNP and N-LBNP, respectively) resulted in higher levels of factor V, factor VIII, and von Willebrand factor antigen compared with the time control trial (all P < 0.05), but these responses were temperature independent. Hyperthermia increased fibrinolysis [clot lysis 30 min after the maximal amplitude reflecting clot strength (LY30)] to 5.1% post-LBNP compared with 1.5% (time control) and 2.7% in N-LBNP ( P = 0.05 for main effect). Hyperthermia also potentiated increased platelet counts post-LBNP as follows: 274 K/µl for H-LBNP, 246 K/µl for N-LBNP, and 196 K/µl for time control ( P < 0.05 for the interaction). For aim 2, hydration status associated with exercise in the heat did not affect the hemostatic activity, but fibrinolysis (LY30) was increased to 6-10% when subjects were dehydrated compared with an increase to 2-4% when hydrated ( P = 0.05 for treatment). Central hypovolemia via LBNP is a primary driver of hemostasis compared with hyperthermia and dehydration effects. However, hyperthermia does induce significant thrombocytosis and by itself causes an increase in clot lysis. Dehydration associated with exercise-induced heat stress increases clot lysis but does not affect exercise-activated or subsequent hypovolemia-activated hemostasis in hyperthermic humans. Clinical implications of these findings are that quickly restoring a hemorrhaging hypovolemic trauma patient with cold noncoagulant fluids (crystalloids) can have serious deleterious effects on the body's innate ability to form essential clots, and several factors can increase clot lysis, which should therefore be closely monitored.

Hypoxia compounds exercise-induced free radical formation in humans; partitioning contributions from the cerebral and femoral circulation.

This study examined to what extent the human cerebral and femoral circulation contribute to free radical formation during basal and exercise-induced responses to hypoxia. Healthy participants (5♂, 5♀) were randomly assigned single-blinded to normoxic (21% O2) and hypoxic (10% O2) trials with measurements taken at rest and 30 min after cycling at 70% of maximal power output in hypoxia and equivalent relative and absolute intensities in normoxia. Blood was sampled from the brachial artery (a), internal jugular and femoral veins (v) for non-enzymatic antioxidants (HPLC), ascorbate radical (A•-, electron paramagnetic resonance spectroscopy), lipid hydroperoxides (LOOH) and low density lipoprotein (LDL) oxidation (spectrophotometry). Cerebral and femoral venous blood flow was evaluated by transcranial Doppler ultrasound (CBF) and constant infusion thermodilution (FBF). With 3 participants lost to follow up (final n = 4♂, 3♀), hypoxia increased CBF and FBF (P = 0.041 vs. normoxia) with further elevations in FBF during exercise (P = 0.002 vs. rest). Cerebral and femoral ascorbate and α-tocopherol consumption (v < a) was accompanied by A•-/LOOH formation (v > a) and increased LDL oxidation during hypoxia (P < 0.043-0.049 vs. normoxia) implying free radical-mediated lipid peroxidation subsequent to inadequate antioxidant defense. This was pronounced during exercise across the femoral circulation in proportion to the increase in local O2 uptake (r = -0.397 to -0.459, P = 0.037-0.045) but unrelated to any reduction in PO2. These findings highlight considerable regional heterogeneity in the oxidative stress response to hypoxia that may be more attributable to local differences in O2 flux than to O2 tension.

The Gly16 Allele of the G16R Single Nucleotide Polymorphism in the ß 2 -Adrenergic Receptor Gene Augments the Glycemic Response to Adrenaline in Humans.

Cerebral non-oxidative carbohydrate consumption may be driven by a ß2-adrenergic mechanism. This study tested whether the 46G > A (G16R) single nucleotide polymorphism of the ß2-adrenergic receptor gene (ADRB2) influences the metabolic and cerebrovascular responses to administration of adrenaline. Forty healthy Caucasian men were included from a group of genotyped individuals. Cardio- and cerebrovascular variables at baseline and during a 60-min adrenaline infusion (0.06 µg kg-1 min-1) were measured by Model flow, near-infrared spectroscopy and transcranial Doppler sonography. Blood samples were obtained from an artery and a retrograde catheter in the right internal jugular vein. The ADRB2 G16R variation had no effect on baseline arterial glucose, but during adrenaline infusion plasma glucose was up to 1.2 mM (CI95: 0.36-2.1, P < 0.026) higher in the Gly16 homozygotes compared with Arg16 homozygotes. The extrapolated steady-state levels of plasma glucose was 1.9 mM (CI95: 1.0 -2.9, PNLME < 0.0026) higher in the Gly16 homozygotes compared with Arg16 homozygotes. There was no change in the cerebral oxygen glucose index and the oxygen carbohydrate index during adrenaline infusion and the two indexes were not affected by G16R polymorphism. No difference between genotype groups was found in cardiac output at baseline or during adrenaline infusion. The metabolic response of glucose during adrenergic stimulation with adrenaline is associated to the G16R polymorphism of ADRB2, although without effect on cerebral metabolism. The differences in adrenaline-induced blood glucose increase between genotypes suggest an elevated ß2-adrenergic response in the Gly16 homozygotes with increased adrenaline-induced glycolysis compared to Arg16 homozygotes.

Nitrite and S-Nitrosohemoglobin Exchange Across the Human Cerebral and Femoral Circulation: Relationship to Basal and Exercise Blood Flow Responses to Hypoxia.

BACKGROUND: The mechanisms underlying red blood cell (RBC)-mediated hypoxic vasodilation remain controversial, with separate roles for nitrite () and S-nitrosohemoglobin (SNO-Hb) widely contested given their ability to transduce nitric oxide bioactivity within the microcirculation. To establish their relative contribution in vivo, we quantified arterial-venous concentration gradients across the human cerebral and femoral circulation at rest and during exercise, an ideal model system characterized by physiological extremes of O2 tension and blood flow. METHODS: Ten healthy participants (5 men, 5 women) aged 24±4 (mean±SD) years old were randomly assigned to a normoxic (21% O2) and hypoxic (10% O2) trial with measurements performed at rest and after 30 minutes of cycling at 70% of maximal power output in hypoxia and equivalent relative and absolute intensities in normoxia. Blood was sampled simultaneously from the brachial artery and internal jugular and femoral veins with plasma and RBC nitric oxide metabolites measured by tri-iodide reductive chemiluminescence. Blood flow was determined by transcranial Doppler ultrasound (cerebral blood flow) and constant infusion thermodilution (femoral blood flow) with net exchange calculated via the Fick principle. RESULTS: Hypoxia was associated with a mild increase in both cerebral blood flow and femoral blood flow (P<0.05 versus normoxia) with further, more pronounced increases observed in femoral blood flow during exercise (P<0.05 versus rest) in proportion to the reduction in RBC oxygenation (r=0.680-0.769, P<0.001). Plasma gradients reflecting consumption (arterial>venous; P<0.05) were accompanied by RBC iron nitrosylhemoglobin formation (venous>arterial; P<0.05) at rest in normoxia, during hypoxia (P<0.05 versus normoxia), and especially during exercise (P<0.05 versus rest), with the most pronounced gradients observed across the bioenergetically more active, hypoxemic, and acidotic femoral circulation (P<0.05 versus cerebral). In contrast, we failed to observe any gradients consistent with RBC SNO-Hb consumption and corresponding delivery of plasma S-nitrosothiols (P>0.05). CONCLUSIONS: These findings suggest that hypoxia and, to a far greater extent, exercise independently promote arterial-venous delivery gradients of intravascular nitric oxide, with deoxyhemoglobin-mediated reduction identified as the dominant mechanism underlying hypoxic vasodilation.

Sympathetic Vasoconstrictor Responsiveness of the Leg Vasculature During Experimental Endotoxemia and Hypoxia in Humans.

OBJECTIVE: Sympathetic vasoconstriction regulates peripheral circulation and controls blood pressure, but sepsis is associated with hypotension. We evaluated whether apparent loss of sympathetic vasoconstrictor responsiveness relates to distended smooth muscles or to endotoxemia and/or hypoxia. DESIGN: Prospective descriptive study. SETTING: Hospital research laboratory. SUBJECTS: Ten healthy young men (age [mean ± SD], 31 ± 8 yr; body weight, 83 ± 10 kg) participated in the study. INTERVENTIONS: Leg blood flow and mean arterial pressure were determined, whereas leg vascular conductance was calculated during 1) adenosine infusion (vasodilator control), 2) hypoxia (FIO2 = 10%), 3) endotoxemia, and 4) endotoxemia + hypoxia. Leg sympathetic vasoconstrictor responsiveness (reduction in leg vascular conductance) was evaluated by femoral artery tyramine infusion. MEASUREMENTS AND MAIN RESULTS: Endotoxemia increased body temperature from 36.9 ± 0.4°C to 38.6 ± 0.5°C (p < 0.01) and plasma tumor necrosis factor-α from 6 pg/mL (3-8 pg/mL) to 391 pg/mL (128-2258 pg/mL) (p < 0.01; median [range]). Mean arterial pressure decreased similarly during endotoxemia (-11% ± 16%) and endotoxemia + hypoxia (-10% ± 15%; both p < 0.05). Leg blood flow and leg vascular conductance were not affected by endotoxemia, whereas both were elevated by adenosine infusion (leg blood flow, +94% ± 61%; leg vascular conductance, +97% ± 57%), hypoxia (leg blood flow: +93% ± 58%; leg vascular conductance, +100% ± 115%), and endotoxemia + hypoxia (leg blood flow, +67% ± 120%; leg vascular conductance, +65% ± 57%; p < 0.05). Endotoxemia lessened the tyramine-induced reduction in leg vascular conductance (-28% ± 13%) compared with the reduction during adenosine infusion (-47% ± 5%; p < 0.05). Also, endotoxemia + hypoxia (-17% ± 21%) attenuated the tyramine-induced reduction in leg vascular conductance compared with both adenosine infusion and hypoxia (-45% ± 13%; p < 0.05). CONCLUSIONS: Both endotoxemia and combined hypoxia and endotoxemia blunted sympathetic vasoconstrictor responsiveness. Furthermore, tyramine normalized the doubled leg vascular conductance during administration of adenosine, suggesting that distension of vascular smooth muscles does not explain blunted sympathetic vasoconstrictor responsiveness during endotoxemia.

Extra-cerebral oxygenation influence on near-infrared-spectroscopy-determined frontal lobe oxygenation in healthy volunteers: a comparison between INVOS-4100 and NIRO-200NX.

INTRODUCTION: Frontal lobe oxygenation (Sc O2 ) is assessed by spatially resolved near-infrared spectroscopy (SR-NIRS) although it seems influenced by extra-cerebral oxygenation. We aimed to quantify the impact of extra-cerebral oxygenation on two SR-NIRS derived Sc O2 . METHODS: Multiple regression analysis estimated the influence of extra-cerebral oxygenation as exemplified by skin oxygenation (Sskin O2 ) on Sc O2 in 21 healthy subjects exposed to whole-body exercise in hypoxia (Fi O2  = 12%; n = 10) and normoxia (n = 12), whole-body heating, hyperventilation (n = 21), administration of norepinephrine with and without petCO2 -correction (n = 15), phenylephrine and head-up tilt (n = 7). Sc O2 was assessed simultaneously by NIRO-200NX (Sniro O2 ) and INVOS-4100 (Sinvos O2 ). Arterial (Sa O2 ) and jugular bulb oxygen saturations (Sj O2 ) were obtained. RESULTS: The regression analysis indicated that Sinvos O2 reflects 46% arterial, 14% jugular, 35% skin and 4% oxygenation of tissues not interrogated. Sinvos O2 follows a calculated estimate of cerebral capillary oxygenation (r = 0·67; P<0·0001). In contrast, the NIRO-200NX-determined Sc O2 did not correlate with the estimate of cerebral oxygenation (r = 0·026; P = 0·71). CONCLUSION: For all interventions, 35% of the INVOS-4100 signal reflected extra-cerebral oxygenation while, on the other hand, NIRO-200NX did not follow changes in a calculated estimate of cerebral capillary oxygenation. Thus, the NIRO-200NX and INVOS-4100 do not provide for unbiased evaluation of the cerebral signal.

Platelet activation after presyncope by lower body negative pressure in humans.

Central hypovolemia elevates hemostatic activity which is essential for preventing exsanguination after trauma, but platelet activation to central hypovolemia has not been described. We hypothesized that central hypovolemia induced by lower body negative pressure (LBNP) activates platelets. Eight healthy subjects were exposed to progressive central hypovolemia by LBNP until presyncope. At baseline and 5 min after presyncope, hemostatic activity of venous blood was evaluated by flow cytometry, thrombelastography, and plasma markers of coagulation and fibrinolysis. Cell counts were also determined. Flow cytometry revealed that LBNP increased mean fluorescence intensity of PAC-1 by 1959±455 units (P<0.001) and percent of fluorescence-positive platelets by 27±18%-points (P = 0.013). Thrombelastography demonstrated that coagulation was accelerated (R-time decreased by 0.8±0.4 min (P = 0.001)) and that clot lysis increased (LY60 by 6.0±5.8%-points (P = 0.034)). Plasma coagulation factor VIII and von Willebrand factor ristocetin cofactor activity increased (P = 0.011 and P = 0.024, respectively), demonstrating increased coagulation activity, while von Willebrand factor antigen was unchanged. Plasma protein C activity and tissue-type plasminogen activator increased (P = 0.007 and P = 0.017, respectively), and D-dimer increased by 0.03±0.02 mg l(-1) (P = 0.031), demonstrating increased fibrinolytic activity. Plasma prothrombin time and activated partial thromboplastin time were unchanged. Platelet count increased by 15±13% (P = 0.014) and red blood cells by 9±4% (P = 0.002). In humans, LBNP-induced presyncope activates platelets, as evidenced by increased exposure of active glycoprotein IIb/IIIa, accelerates coagulation. LBNP activates fibrinolysis, similar to hemorrhage, but does not alter coagulation screening tests, such as prothrombin time and activated partial thromboplastin time. LBNP results in increased platelet counts, but also in hemoconcentration.

[Identification of mesenteric traction syndrome using laser speckle contrast imaging].

A mesenteric traction syndrome manifests in some patients undergoing major abdominal surgery and is identified by flushing, accompanied by hypotension and tachycardia. We used laser speckle contrast imaging to quantify blood flow in forehead skin of patients undergoing Whipple's operation. In two patients with similar blood pressure (-50 mmHg) and profound drop in systemic vascular resistance (-40%), forehead skin perfusion increased three-fold in one patient, while it was unchanged in a patient for whom flushing was not evident.

[Mesenteric traction syndrome]. / Mesenterielt traktionssyndrom.

Mesenteric traction syndrome (MTS) manifests in 58-87% of patients undergoing upper abdominal surgery and is characterised by a triad of hypotension, tachycardia, and flushing. Prostacyclin is released from the gut mucosa following intestinal eventration and cyclooxygenase antagonists prevent the development of MTS. Also the use of remifentanil appears to increase the incidence of MTS and hypotension is aggravated by epidural analgesia. Yet, prostacyclin may be important for maintaining microcirculation within the splanchnic area and preserve its mucosal barrier.

Coagulation competence and fluid recruitment after moderate blood loss in young men.

The coagulation system is activated by a reduction of the central blood volume during orthostatic stress and lower body negative pressure suggesting that also a blood loss enhances coagulation. During bleeding, however, the central blood volume is supported by fluid recruitment to the circulation and redistribution of the blood volume. In eight supine male volunteers (24 ± 3 years, blood volume of 6.9 ± 0.7 l; mean ± SD), 2 × 450 ml blood was withdrawn over ∼ 30 min while cardiovascular variables were monitored. Coagulation was evaluated by thrombelastography, and fluid recruitment was estimated by red blood cell count. Withdrawing 900 ml blood increased heart rate (62 ± 7 to 69 ± 13 bpm, P < 0.05; mean ± SD) and reduced stroke volume (113 ± 12 to 96 ± 14 ml, P < 0.05) leaving cardiac output, mean arterial pressure, and total peripheral resistance unchanged and, furthermore, reduced red blood cell count (4.80 ± 0.33 to 4.64 ± 0.37 × 10(12) cells l(-1), P < 0.05) indicating that 218 ± 173 ml fluid was recruited to the circulation. Withdrawing 450 ml blood reduced the time until initial fibrin formation (R: 6.5 ± 0.9 to 5.1 ± 1.0 min, P < 0.01), whereas the rate of clot formation increased after withdrawal of 900 ml blood (α-Angle: 66 ± 4 to 70 ± 3 deg, P < 0.01). Clot strength (maximal amplitude: 57 ± 4 mm), clot lysis 30 min after maximal amplitude (LY30: 0.8% [0-3.5%] (median [range])), and platelet count (218 ± 25 × 10(9) l(-1)) were unaffected. For supine males, ∼ 25% of a moderate blood loss is compensated by fluid recruitment to the circulation, which may explain the minor cardiovascular response. Yet, a blood loss of 450 ml accelerates coagulation, and this is further accentuated when blood loss is 900 ml.

Hypoxia and exercise provoke both lactate release and lactate oxidation by the human brain.

Lactate is shuttled between organs, as demonstrated in the Cori cycle. Although the brain releases lactate at rest, during physical exercise there is a cerebral uptake of lactate. Here, we evaluated the cerebral lactate uptake and release in hypoxia, during exercise and when the two interventions were combined. We measured cerebral lactate turnover via a tracer dilution method ([1-(13)C]lactate), using arterial to right internal jugular venous differences in 9 healthy individuals (5 males and 4 females), at rest and during 30 min of submaximal exercise in normoxia and hypoxia (F(i)o(2) 10%, arterial oxygen saturation 72 ± 10%, mean ± sd). Whole-body lactate turnover increased 3.5-fold and 9-fold at two workloads in normoxia and 18-fold during exercise in hypoxia. Although middle cerebral artery mean flow velocity increased during exercise in hypoxia, calculated cerebral mitochondrial oxygen tension decreased by 13 mmHg (P<0.001). At the same time, cerebral lactate release increased from 0.15 ± 0.1 to 0.8 ± 0.6 mmol min(-1) (P<0.05), corresponding to ∼10% of cerebral energy consumption. Concurrently, cerebral lactate uptake was 1.0 ± 0.9 mmol min(-1) (P<0.05), of which 57 ± 9% was oxidized, demonstrating that lactate oxidation may account for up to ∼33% of the energy substrate used by the brain. These results support the existence of a cell-cell lactate shuttle that may involve neurons and astrocytes.

Functional sympatholysis during exercise in patients with type 2 diabetes with intact response to acetylcholine.

OBJECTIVE: Sympathetic vasoconstriction is blunted in contracting human skeletal muscles (functional sympatholysis). In young subjects, infusion of adenosine and ATP increases blood flow, and the latter compound also attenuates α-adrenergic vasoconstriction. In patients with type 2 diabetes and age-matched healthy subjects, we tested 1) the sympatholytic capacity during one-legged exercise, 2) the vasodilatory capacity of adenosine and ATP, and 3) the ability to blunt α-adrenergic vasoconstriction during ATP infusion. RESEARCH DESIGN AND METHODS: In 10 control subjects and 10 patients with diabetes and normal endothelial function, determined by leg blood flow (LBF) response to acetylcholine infusion, we measured LBF and venous NA, with and without tyramine-induced sympathetic vasoconstriction, during adenosine-, ATP-, and exercise-induced hyperemia. RESULTS: LBF during acetylcholine did not differ significantly. LBF increased ninefold during exercise and during adenosine- and ATP-induced hyperemia. Infusion of tyramine during exercise did not reduce LBF in either the control or the patient group. During combined ATP and tyramine infusions, LBF decreased by 30% in both groups. Adenosine had no sympatholytic effect. CONCLUSIONS: In patients with type 2 diabetes and normal endothelial function, functional sympatholysis was intact during moderate exercise. The vasodilatory response for adenosine and ATP did not differ between the patients with diabetes and the control subjects; however, the vasodilatory effect of adenosine and ATP and the sympatholytic effect of ATP seem to decline with age.

Interindividual variation in platelets and the cardiovascular response to haemorrhage in the pig.

The platelet count varies two-fold among healthy individuals. Considering the haemostatic role of platelets, this study evaluated the relation between cardiovascular and metabolic responses to uncontrolled haemorrhage and the pretrauma platelet count in pigs. A laceration liver injury was inflicted in 19 pigs (34 ± 3 kg; mean ± SD). To simulate a prehospital setting, fluid administration was delayed 7 min and was then by lactated Ringer. After 30 min, the fluid administered was by hydroxyethyl starch 130/0.4 to stabilize the blood volume. The platelet count for the pigs was 385 (193-507) × 109/l (median (range)). The injury was similar for all pigs and caused a similar blood loss (1.4 ± 0.4 and 2.4 ± 0.4 l after administration of lactated Ringer and hydroxyethyl starch, respectively) and survival time (79 ± 17 min). At baseline, none of the cardiovascular variables were related to the pretrauma platelet count. After administration of lactated Ringer and hydroxyethyl starch, however, mean arterial pressure (R² = 0.60, P < 0.001 and R² = 0.52, P < 0.01), cardiac output (R² = 0.36, P < 0.05 and R² = 0.84, P < 0.0001), and thus oxygen delivery (R² = 0.38, P < 0.05 and R² = 0.92, P < 0.0001) related to the pretrauma platelet count and at 60 min, that was also the case for standard base excess (R² = 0.37, P < 0.01), bicarbonate (R² = 0.44, P < 0.01), and oxygen uptake (R² = 0.51, P < 0.01). Following a liver trauma in pigs, the immediate cardiovascular and metabolic responses were related to the pretrauma platelet count although it did not affect the blood loss. These results support that platelets exert functions during bleeding beyond their importance for clot formation.

Coupling between the blood lactate-to-pyruvate ratio and MCA Vmean at the onset of exercise in humans.

Activation-induced increase in cerebral blood flow is coupled to enhanced metabolic activity, maybe with brain tissue redox state and oxygen tension as key modulators. To evaluate this hypothesis at the onset of exercise in humans, blood was sampled at 0.1 to 0.2 Hz from the radial artery and right internal jugular vein, while middle cerebral artery mean flow velocity (MCA V(mean)) was recorded. Both the arterial and venous lactate-to-pyruvate ratio increased after 10 s (P < 0.05), and the arterial ratio remained slightly higher than the venous (P < 0.05). The calculated average cerebral capillary oxygen tension decreased by 2.7 mmHg after 5 s (P < 0.05), while MCA V(mean) increased only after 30 s. Furthermore, there was an unaccounted cerebral carbohydrate uptake relative to the uptake of oxygen that became significant 50 s after the onset of exercise. These findings support brain tissue redox state and oxygenation as potential modulators of an increase in cerebral blood flow at the onset of exercise.

Blood lactate is an important energy source for the human brain.

Lactate is a potential energy source for the brain. The aim of this study was to establish whether systemic lactate is a brain energy source. We measured in vivo cerebral lactate kinetics and oxidation rates in 6 healthy individuals at rest with and without 90 mins of intravenous lactate infusion (36 mumol per kg bw per min), and during 30 mins of cycling exercise at 75% of maximal oxygen uptake while the lactate infusion continued to establish arterial lactate concentrations of 0.89+/-0.08, 3.9+/-0.3, and 6.9+/-1.3 mmol/L, respectively. At rest, cerebral lactate utilization changed from a net lactate release of 0.06+/-0.01 to an uptake of 0.16+/-0.07 mmol/min during lactate infusion, with a concomitant decrease in the net glucose uptake. During exercise, the net cerebral lactate uptake was further increased to 0.28+/-0.16 mmol/min. Most (13)C-label from cerebral [1-(13)C]lactate uptake was released as (13)CO(2) with 100%+/-24%, 86%+/-15%, and 87%+/-30% at rest with and without lactate infusion and during exercise, respectively. The contribution of systemic lactate to cerebral energy expenditure was 8%+/-2%, 19%+/-4%, and 27%+/-4% for the respective conditions. In conclusion, systemic lactate is taken up and oxidized by the human brain and is an important substrate for the brain both under basal and hyperlactatemic conditions.

Contractile properties of the functionally divided python heart: two sides of the same matter.

The heart of Python regius is functionally divided so that systemic blood pressure is much higher than pulmonary pressure (6.6+/-1.0 and 0.7+/-0.1 kPa, respectively). The present study shows that force production of cardiac strips from the cavum arteriosum and cavum pulmonale exhibits similar force production when stimulated in vitro. The high systemic blood pressure is caused, therefore, by a thicker ventricular wall surrounding the cavum arteriosum rather than differences in the intrinsic properties of the cardiac tissues. Similarly, there were no differences between the contractile properties of right and left atria. Force production was similar in atria and ventricle but the atria contracted and relaxed much faster than the ventricle. Graded hypoxia markedly reduced twitch force of all four cardiac tissues, and this was most pronounced when PO(2) was below 40 kPa. In contrast, the four cardiac tissues were insensitive to acidosis during normoxia although acidosis increased the sensitivity to hypoxia. Adrenergic stimulation increased twitch force of all cardiac tissues, while cholinergic stimulation only affected the atria and reduced twitch force markedly. In spite of the different oxygen availability of the two sides of the heart, the biochemical and functional properties are alike and the differences may instead be overcome by the coronary blood supply.

Arterial acid-base status during digestion and following vascular infusion of NaHCO(3) and HCl in the South American rattlesnake, Crotalus durissus.

Digestion is associated with gastric secretion that leads to an alkalinisation of the blood, termed the "alkaline tide". Numerous studies on different reptiles and amphibians show that while plasma bicarbonate concentration ([HCO(3)(-)](pl)) increases substantially during digestion, arterial pH (pHa) remains virtually unchanged, due to a concurrent rise in arterial PCO(2) (PaCO(2)) caused by a relative hypoventilation. This has led to the suggestion that postprandial amphibians and reptiles regulate pHa rather than PaCO(2). Here we characterize blood gases in the South American rattlesnake (Crotalus durissus) during digestion and following systemic infusions of NaHCO(3) and HCl in fasting animals to induce a metabolic alkalosis or acidosis in fasting animals. The magnitude of these acid-base disturbances were similar in magnitude to that mediated by digestion and exercise. Plasma [HCO(3)(-)] increased from 18.4+/-1.5 to 23.7+/-1.0 mmol L(-1) during digestion and was accompanied by a respiratory compensation where PaCO(2) increased from 13.0+/-0.7 to 19.1+/-1.4 mm Hg at 24 h. As a result, pHa decreased slightly, but were significantly below fasting levels 36 h into digestion. Infusion of NaHCO(3) (7 mmol kg(-1)) resulted in a 10 mmol L(-1) increase in plasma [HCO(3)(-)] within 1 h and was accompanied by a rapid elevation of pHa (from 7.58+/-0.01 to 7.78+/-0.02). PaCO(2), however, did not change following HCO(3)(-) infusion, which indicates a lack of respiratory compensation. Following infusion of HCl (4 mmol kg(-1)), plasma pHa decreased by 0.07 units and [HCO(3)(-)](pl) was reduced by 4.6 mmol L(-1) within the first 3 h. PaCO(2), however, was not affected and there was no evidence for respiratory compensation. Our data show that digesting rattlesnakes exhibit respiratory compensations to the alkaline tide, whereas artificially induced metabolic acid-base disturbances of same magnitude remain uncompensated. It seems difficult to envision that the central and peripheral chemoreceptors would experience different stimuli during these conditions. One explanation for the different ventilatory responses could be that digestion induces a more relaxed state with low responsiveness to ventilatory stimuli.