Journal of Applied Physiology Fuel your research with LabChart
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

J Appl Physiol 101: 1406-1411, 2006. First published June 22, 2006; doi:10.1152/japplphysiol.00423.2006
8750-7587/06 $8.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow All Versions of this Article:
101/5/1406    most recent
00423.2006v1
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (3)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Rasmussen, P.
Right arrow Articles by Quistorff, B.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Rasmussen, P.
Right arrow Articles by Quistorff, B.

MCA Vmean and the arterial lactate-to-pyruvate ratio correlate during rhythmic handgrip

Peter Rasmussen,1 Peter Plomgaard,2 Rikke Krogh-Madsen,2 Yu-Sok Kim,4 Johannes J. van Lieshout,4 Niels H. Secher,1 and Bjørn Quistorff3

1Department of Anesthesia, Copenhagen Muscle Research Center; 2Department of Infectious Diseases, Center of Inflammation and Metabolism, Rigshospitalet; 3Department of Medical Biochemistry and Genetics, University of Copenhagen, Copenhagen, Denmark; and 4Cardiovascular Research Institute Amsterdam, Department of Internal Medicine, Academic Medical Center, Amsterdam, the Netherlands

Submitted 11 April 2006 ; accepted in final form 16 June 2006


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Regulation of cerebral blood flow during physiological activation including exercise remains unknown but may be related to the arterial lactate-to-pyruvate (L/P) ratio. We evaluated whether an exercise-induced increase in middle cerebral artery mean velocity (MCA Vmean) relates to the arterial L/P ratio at two plasma lactate levels. MCA Vmean was determined by ultrasound Doppler sonography at rest, during 10 min of rhythmic handgrip exercise at ~65% of maximal voluntary contraction force, and during 20 min of recovery in seven healthy male volunteers during control and a ~15 mmol/l hyperglycemic clamp. Cerebral arteriovenous differences for metabolites were obtained by brachial artery and retrograde jugular venous catheterization. Control resting arterial lactate was 0.78 ± 0.09 mmol/l (mean ± SE) and pyruvate 55.7 ± 12.0 µmol/l (L/P ratio 16.4 ± 1.0) with a corresponding MCA Vmean of 46.7 ± 4.5 cm/s. During rhythmic handgrip the increase in MCA Vmean to 51.2 ± 4.6 cm/s was related to the increased L/P ratio (23.8 ± 2.5; r2 = 0.79; P < 0.01). Hyperglycemia increased arterial lactate and pyruvate to 1.9 ± 0.2 mmol/l and 115 ± 4 µmol/l, respectively, but it did not significantly influence the L/P ratio or MCA Vmean at rest or during exercise. Conversely, MCA Vmean did not correlate significantly, neither to the arterial lactate nor to the pyruvate concentrations. These results support that the arterial plasma L/P ratio modulates cerebral blood flow during cerebral activation independently from the plasma glucose concentration.

cerebral blood flow; cerebral activation; exercise; hyperglycemia; transcranial ultrasound Doppler

GENERALLY PHYSIOLOGICAL ACTIVATION increases tissue energy metabolism and blood flow (11, 12, 19). Although global cerebral blood flow (CBF) is maintained relatively stable, the regional flow increases during exercise in activated areas of the brain, e.g., as accessed by the transcranial ultrasound Doppler (TCD) sonography determined mean blood flow velocity in basal arteries (Vmean) (21), by functional magnetic resonance imaging or by positron emission tomography (25). A variety of factors contribute to flow regulation such as mean arterial pressure (MAP), cardiac output (CO) (17), local vasodilator compounds including ATP and adenosine (15), the arterial carbon dioxide (PaCO2) (23, 29) and oxygen (PaO2) (23) tensions, the arterial glucose (31) and lactate content (18), and the arterial plasma lactate-to-pyruvate ratio (L/P ratio) (18, 27, 32). The separate contribution of each of these mechanisms to blood flow control during physiological activation of the brain, however, is uncertain. Thus increased regional blood flow appears uncoupled from metabolic rate because oxygen and glucose provision increase more than consumption (6, 11, 12).

In an upright position MAP is important for cerebral perfusion pressure because the cerebral circulation is not supported by a siphon (7, 13, 14). However, during exercise alterations in MAP do not seem to play a significant role because, although MAP does increase during static exercise, middle cerebral artery (MCA) Vmean is elevated only for some 3 s (28) and then decreases to the resting level for the remaining exercise bout. MCA Vmean also remains unchanged during postexercise muscle ischemia, despite MAP remaining elevated by ~40% (20). Furthermore, the increase in MCA Vmean is confined to the contralateral hemisphere of the exercising arm (20). The increase in MCA Vmean upon exercise depends on the concomitant increase in CO, as illustrated by the inability of patients with atrial fibrillation to increase MCA Vmean unless CO increases as well (16). The cerebral circulation is reactive to changes in PaCO2 at rest (23) and during exercise (29) and PaCO2 increases during light to moderate dynamic exercise along with MCA Vmean whereas both variables decrease during intense exercise (21, 26). However, during rhythmic handgrip there is a similar increase in MCA Vmean although PaCO2 does not change significantly, indicating that the MCA Vmean response to exercise does not depend on PaCO2 (20).

Increased blood flow and reduced cerebral autoregulatory capacity develop in response to elevated plasma glucose (22). For example, hyperglycemia increases forearm blood flow independently of sympathetic activity (31). Also, the L/P ratio takes part in regulation of blood flow in activated tissue such as brain and muscle (18, 19, 27, 32). To the extent allowed by the respective monocarboxylate carriers, plasma lactate and pyruvate equilibrate with the cytosolic concentrations of the two metabolites. These are, in turn, believed to be in near equilibrium with the cytosolic free NADH and NAD+ concentrations via the reaction catalyzed by lactate dehydrogenase. During activation of the brain an increased rate of glycolysis may lead to increased L/P ratio of the cytosol, which could provide a signal for flow increase, either locally or transmitted downstream via the blood or lymph to other tissues. Similarly, increased lactate production in activated muscle may contribute to an increase in brain blood flow through an increased L/P ratio of venous blood draining from the muscle and transmitted to the brain (27). It has been suggested that the mechanistic coupling between the L/P ratio and flow is via changes in ratio of cytosolic free NAD+ and NADH concentrations affecting the nitric oxide synthase system in the endothelial cells (18, 19, 27, 32).

We manipulated arterial L/P ratio with rhythmic handgrip exercise and evaluated its relationship to MCA Vmean. The relationship between MCA Vmean and the L/P ratio was furthermore studied at different levels of arterial lactate. This was obtained by clamping arterial glucose at euglycemic (~5 mmol/l) and hyperglycemic (15 mmol/l) levels, while choosing an exercise protocol in which changes in PaCO2 are limited (2).


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Seven healthy men at an age of 22–29 yr participated in this study [body weight 80.9 (12.2 SD) kg, height 185.2 (10.8 SD) cm]. The subjects underwent a clinical examination and it was verified that renal, hepatic, and thyroid function, hemoglobin, white blood cells counts, plasma electrolytes, and resting plasma glucose and insulin were normal. The subjects provided informed consent to the study as approved by the Ethical Committee of Copenhagen and Frederiksberg (KF 01-257245).

Experimental design.   Before the experiment the subjects were familiarized with the protocol and individual maximal voluntary handgrip contraction was determined. On the following day the subjects reported to the laboratory after an overnight fast. Under local anesthesia (2%, lidocaine), a catheter was placed retrograde with Seldinger technique in the right internal jugular vein (1.6 mm, 14 gauge; ES-04706, Arrow International). Placement of the catheter was guided by an ultrasound image, and the catheter was subsequently advanced to the bulb of the vein. Arterial blood was drawn from a catheter in the brachial artery (1.1 mm, 20 gauge) of the nondominant arm. Cerebral perfusion was evaluated by TCD (Transcan, EME, Überlingen, Germany) in the contralateral MCA. Depending on the position with the best signal-to-noise ratio, the proximal part of the MCA was insonated at a depth of 40–60 mm from the temporal bone and the probe was secured with a headband. Using TCD for evaluation of cerebral perfusion has several advantages compared with image-diagnostic methods such as positron emission tomography or infusion of tracer substances. Being noninvasive and robust against movement artifacts, TCD is used to gauge brain activation paradigms such as whole body exercise that cannot be evaluated inside a scanner. MAP was measured with a transducer (Edwards Life Sciences, Irving, CA) placed at the level of the heart. Blood pressure data were interfaced with a Dialogue-2000 (IBC-Danica), sampled at 200 Hz (DI-720, Dataq) and stored. Offline the arterial pressure waveform was analyzed for changes in left ventricular stroke volume (SV) and heart rate (HR) by using Modelflow (Beatscope software, BMI-TNO, The Netherlands). The SV was computed by simulation of a nonlinear, time-varying model of the aortic input impedance (3). The CO was the product of SV and HR, and the modeled flow tracks changes in SV and CO with a ~2% accuracy (34).

After this preparation the subjects rested in a semisupine position with the back and head supported at an angle of ~45° for 1 h. Following sampling of blood and cerebral and systemic circulatory variables, the subjects performed 10 min of rhythmic handgrip exercise at 65% of the maximal voluntary contraction in that 2 s of contraction was followed by 4 s of recovery. During handgrip exercise rating of perceived exertion (RPE; Borg 6–20 scale) (4) was noted every minute. Blood and circulatory variables were sampled after 5 and 9 min of handgrip exercise and after 1, 3, 7, and 20 min of recovery. After 30 min of recovery, the arterial plasma glucose was clamped at ~15 mmol/l, and after 3 h of hyperglycemic clamp the handgrip exercise protocol was repeated.

Hyperglycemic clamp.   The hyperglycemic clamp was established according to DeFronzo et al. (8). Glucose (1.0 mol/l) was infused intravenously to maintain a blood glucose level of 15 mmol/l with the rate of infusion adjusted by a computer-controlled infusion pump according to the arterial blood glucose level. To maintain potassium at the baseline value, isotonic saline with potassium (51 mmol/l) was infused continuously. In addition, the catheters were kept open by flushing a total of ~1,000 ml of isotonic saline during the study.

Blood samples.   Samples for measurement of glucose and potassium concentrations were taken every 10 min, and steady-state hyperglycemia were reached after ~1 h. Blood was sampled in preheparinized syringes and arterial and venous hemoglobin saturation and O2 content as well as pH and PaCO2 were obtained immediately on an ABL 725 apparatus (Radiometer, Copenhagen, Denmark). CO2 content was calculated according to Douglas et al. (9). EDTA plasma was analyzed enzymatically for glucose, lactate, and pyruvate on an automatic analyzer (Cobas Fara, Roche, Basel, Switzerland).

Statistical analysis.   A statistical package was used for the analysis (SigmaStat, Build 3.0, SPSS, Chicago, IL) and a P value < 0.05 was considered statistically significant. Two-way ANOVA for repeated measures was used to identify differences across glucose levels and time. Post hoc pairwise multiple comparisons vs. rest were performed with the Holm-Sidak method. Correlation strength was assessed with Pearson's test, and data are presented as means ± SE except RPE scores, presented as median and range.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
Cardiovascular variables.   HR was 66 ± 2 beats/min, CO 5.5 ± 0.3 l/min, and MAP 95 ± 3 mmHg and increased during exercise (P < 0.001; Table 1) associated with no significant changes in PaCO2 or arterial pH. During hyperglycemia PaCO2 (P < 0.001) and pH (P < 0.01) were lower, and HR (P < 0.01) and CO (P < 0.001) were higher, while MAP remained unaffected. Both during exercise and in the recovery all variables showed similar responses as established during and after normoglycemic exercise.


View this table:
[in this window]
[in a new window]
  		Table 1. Arterial blood plasma and hemodynamic variables

 
Perceived exertion.   During control exercise, RPE increased from 11 (7–13) after 1 min of exercise and to 17 (14–18) after 9 min (P < 0.001). Hyperglycemia had no effect on the RPE score.

Cerebral oxygen, glucose, lactate, and pyruvate extraction.   The cerebral arteriovenous (a-v) difference for oxygen tended to declined (but not significantly) during exercise but increased in the early recovery (P < 0.01; Table 2). Conversely, the cerebral a-v difference for both lactate (–0.06 ± 0.01 to 0.01 ± 0.02 mmol/l; P < 0.01) and pyruvate (–9.9 ± 2.2 to 5.8 ± 2.5 µmol/l; P < 0.001) increased with handgrip exercise and returned to baseline 20 min after exercise. There was no significant change in the glucose a-v difference.


View this table:
[in this window]
[in a new window]
  		Table 2. Cerebral arterio venous differences and metabolic ratios

 
Throughout hyperglycemia the cerebral a-v difference for oxygen was lower (P < 0.01), whereas the a-v differences for lactate (P < 0.01) and pyruvate (P < 0.05) were higher but displayed the same response to handgrip as during control exercise. Hyperglycemia had no significant effect on the cerebral a-v difference for glucose (Table 2).

Cerebral metabolic ratios.   No significant changes in the cerebral metabolic ratios of oxygen-to-carbohydrate or carbon dioxide-to-carbohydrate were observed during the handgrip exercise (Table 2). Hyperglycemia had no significant effect on the cerebral metabolic ratios.

MCA Vmean in relation to arterial and venous L/P ratio.   Resting arterial lactate was 0.8 ± 0.1 mmol/l, pyruvate was 56 ± 12 µmol/l, and the L/P ratio 16.4 ± 1.0 with a corresponding MCA Vmean of 46.7 ± 4.5 cm/s. During rhythmic handgrip arterial plasma lactate increased and reached a zenith at 1.5 ± 0.2 mmol/l after 9 min (P < 0.001 vs. preexercise) and decreased during the recovery to the baseline value (0.8 ± 0.1 mmol/l) after 20 min (Fig. 1). Conversely, the arterial pyruvate concentration did not increase during the first 5 min of exercise, but it did increase after exercise with a peak after 3 min of recovery (84 ± 15 µmol/l; P < 0.001 vs. preexercise). The arterial pyruvate concentration returned to baseline (58 ± 11 µmol/l) after 20 min of recovery.


Figure 1
View larger version (21K):
[in this window]
[in a new window]
  		Fig. 1. Plasma lactate (A), pyruvate (B), their ratio (C), and middle cerebral mean velocity (D; MCA Vmean) at rest, during 10 min of handgrip activation, and in recovery. Circles and solid lines, arterial; triangles and dashed lines, jugular venous. Solid symbols, normoglycemic arterial glucose concentration (~5 mmol); open symbols, hyperglycemic clamp (~15 mmol). *, **, and *** P < 0.05, 0.01, and 0.001, respectively, vs. normoglycemia or rest. Data are means ± SE for N = 7 subjects.

 
The L/P ratio increased with handgrip exercise to 23.8 ± 2.5 (P < 0.001) after 5 min together with MCA Vmean (to 51.2 ± 4.6 cm/s; P < 0.01) and the L/P ratio remained elevated until 3 min of recovery. Thus MCA Vmean and the L/P ratio correlated (r = 0.89; P < 0.01; Fig. 2). The L/P ratio did not change between the arterial and the venous blood coming from the brain.


Figure 2
View larger version (10K):
[in this window]
[in a new window]
  		Fig. 2. Relationship between MCA Vmean and lactate-to-pyruvate ratio at rest, during handgrip activation, and during recovery. Circles, arterial; triangles, jugular venous. Solid symbols, normoglycemic arterial glucose concentration (~5 mmol); open symbols, hyperglycemic clamp (~15 mmol). Data are for N = 7 subjects with linear regression and 95% prediction intervals based on both normo- and hyperglycemic values. No differences in regression slopes between normo- and hyperglycemia were observed (P = 0.89).

 
During hyperglycemia arterial lactate (1.9 ± 0.2 mmol/l; P < 0.01) and pyruvate (115 ± 4 µmol/l; P < 0.01) were higher compared with control exercise, but the response to exercise was similar to that established during control exercise. Neither the L/P ratio nor MCA Vmean were, however, significantly elevated at baseline compared with control exercise nor was the response to exercise different from that observed during control exercise (Fig. 1). Although there was no significant correlation between MCA Vmean and the L/P ratio during hyperglycemia (r = 0.70; P = 0.06; Fig. 2), the combined normo- and hyperglycemic data did correlate (r = 0.70; P < 0.01).


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
CBF is under influence of numerous factors during exercise, e.g., MAP, CO, and PaCO2, but no single variable accounts for the increase in regional CBF in response to cerebral activation. The arterial L/P ratio has been proposed as a regulating parameter (18, 27) that could account for the increased regional flow to activated regions of the brain. The present study extends this literature by showing that, in response to exercise, blood flow in the territory of a large cerebral artery changes together with plasma L/P changes. An additional finding is that this relationship is unaffected by the changes in lactate and pyruvate levels induced by hyperglycemia.

Exchange of lactate and pyruvate between plasma and the intracellular compartment represents a means of organ-organ interaction on the metabolic level. A well-known example of such interorgan metabolic coupling is the Cori cycle, in which the plasma-carried substrates lactate, pyruvate, and alanine institute a close metabolic coupling between the energy metabolism of the muscle and the pathways of gluconeogenesis, lipogenesis, and ureagenesis in the liver. Similarly, major organ-organ interactions via lactate are demonstrated between muscle and brain (6). It is less clear how organ-organ coupling at the level of the cytosolic redox state plays a regulatory role, albeit almost all major pathways of the cell may be affected by changes in the redox state. It is, therefore, an attractive idea, first suggested by Ido et al. (19), that the increase in plasma L/P ratio occurring in working skeletal muscle may induce appropriate flow regulation in other organs. NADH is a candidate as a sensor of cellular energy need and also a possible mediator of tissue blood flow (19). In all major tissues, including muscle, liver, heart, erythrocytes, and brain, the cytosolic enzyme lactate dehydrogenase is abundantly expressed and is believed to be in a near equilibrium state (18). Thus the L/P ratio of the cytosol of a given cell can be expected to reflect the cytosolic NADH-to-NAD+ ratio multiplied by the LDH equilibrium constant, assuming one single cytosolic compartment of the individual cell.

To what extent the extracellular (plasma) L/P ratio is a reflection of the intracellular L/P ratio is unknown but would be expected to depend on the activity and kinetics of the relevant monocarboxylate carriers (33). Conversely, for the plasma L/P ratio to elicit a flow regulatory effect, lactate and pyruvate have to enter the intracellular compartment of the endothelium, the glia cells, and/or the neurons to modulate the cytosolic NADH-to-NAD+ ratio and thereby affect the vasoconstriction systems. Table 2 demonstrates a positive arteriovenous difference for both pyruvate and lactate, indicating their uptake in the brain, and these events were correlated with increased MCA Vmean. Figure 1 further demonstrates how the arterial L/P ratio increases during handgrip and Fig. 2 how the change correlates with MCA Vmean.

However, CO is coupled to the exercise, as is the rise of lactate and the L/P ratio, and the blood flow to motor cortex. The coupling between regional CBF and exercise has not been elucidated, and it might be the NADH-to-NAD+ ratio or the NADH concentration, or both, as related to the L/P ratio, that determine the magnitude of blood flow. The present data only present a correlation and a role of systemic L/P changes in localized effect in the brain is speculative. On the other hand, this study expands the findings of previous reports by observing that increased lactate with unchanged L/P ratio does not cause a flow increase in the brain. This finding is significant because it indicates that an increase in lactate alone does not qualify as signal for increased CBF.

In order for the plasma L/P ratio to qualify as a signal for flow increase of the brain, the CBF and the L/P ratio must not only correlate. The plasma L/P ratio change must also precede the flow changes. During intense activation of the brain, the flow increases within seconds (10), but the temporal resolution of the measurements of the present study was insufficient to verify that notion. With the exercise protocol of the present study arterial lactate and pyruvate are not expected to change until 20–30 s after initiation of handgrip (1). Thus, during the first part of the activation, the observed increase in cerebral perfusion is not likely to be driven by muscle-derived L/P ratio changes but rather by regional cerebral metabolism. Thereafter it could be modulated by the arterial L/P ratio. The time resolution of the measurements does not allow conclusions as to whether the increase in CBF occurred before the L/P ratio increase, and our findings therefore do not provide direct evidence of a causal relationship between increased plasma L/P ratio and MCA Vmean. It should be noted that the jugular venous L/P ratio does not differ from the arterial L/P ratio, indicating that the brain does not contribute to L/P changes in the blood in the present experiment.

Diabetes mellitus is associated with increased blood plasma glucose and is connected with increased blood flow and reduced cerebral autoregulatory capacity (22). These perturbations of blood flow could be due to a permanent change in the L/P ratio. In humans and animals hyperglycemia increases arterial lactate concentration (2), L/P ratio (24), and blood flow (31). The present study is compatible with the idea that the flow perturbations associated with diabetes mellitus are related to a permanently increased L/P ratio. However, hyperglycemia failed to mimic this aspect of diabetes mellitus as the L/P ratio was not elevated.

MCA is robust to changes in PaCO2 (5, 30), and PaCO2 did not change with exercise; we regard MCA Vmean as a valid measure of CBF. We consider it therefore unlikely that the changes in flow were due to a CO2-elicited vasodilatation or constriction. The present study supports the notion of a correlation between cerebral perfusion and arterial L/P ratio.


   GRANTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
The study received support from The Centre of Inflammation and Metabolism (supported by a grant from the Danish National Research Foundation, DG 02-512-555); The Copenhagen Muscle Research Centre (supported by grants from The University of Copenhagen, Faculties of Science and of Health Sciences); The Copenhagen Hospital Corporation, The Danish National Research Foundation (Grant 504-14), the Commission of the European Communities (contract no. LSHM-CT-2004-005272 EXGENESIS). The study was also supported by grants from The Danish Research Agency (22-01-0019), Anti Doping Danmark, the Novo Nordisk Foundation, the Lundbeck Foundation, and the A. P. Møller Foundation.


   FOOTNOTES
 

Address for reprint requests and other correspondence: P. Rasmussen, Rigshospitalet, AN2041, Blegdamsvej 9, DK-2100 Copenhagen, Denmark (e-mail: peter{at}prec.dk)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 

  1. Bangsbo J, Gibala MJ, Krustrup P, Gonzalez-Alonso J, and Saltin B. Enhanced pyruvate dehydrogenase activity does not affect muscle O2 uptake at onset of intense exercise in humans. Am J Physiol Regul Integr Comp Physiol 282: R273–R280, 2002.[Abstract/Free Full Text]
  2. Bjorkman O and Eriksson LS. Influence of a 60-hour fast on insulin-mediated splanchnic and peripheral glucose metabolism in humans. J Clin Invest 76: 87–92, 1985.[ISI][Medline]
  3. Bogert LW and van Lieshout JJ. Non-invasive pulsatile arterial pressure and stroke volume changes from the human finger. Exp Physiol 90: 437–446, 2005.[Abstract/Free Full Text]
  4. Borg G. Simple rating for estimation of perceived exertion. In: Physical Work and Effort, edited by Borg G. New York: Pergamon, 1975, p. 39–46.
  5. Bradac GB, Simon RS, and Heidsieck CH. Angiographically verified transient alteration of intercranial arteries and veins in dependence of different CO2 tension. Neuroradiology 10: 257–262, 1976.[CrossRef][ISI][Medline]
  6. Dalsgaard MK. Fuelling cerebral activity in exercising man. J Cereb Blood Flow Metab 26: 731–750, 2006.[CrossRef][ISI][Medline]
  7. Dawson EA, Secher NH, Dalsgaard MK, Ogoh S, Yoshiga CC, Gonzalez-Alonso J, Steensberg A, and Raven PB. Standing up to the challenge of standing: a siphon does not support cerebral blood flow in humans. Am J Physiol Regul Integr Comp Physiol 287: R911–R914, 2004.[Abstract/Free Full Text]
  8. DeFronzo RA, Tobin JD, and Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol Endocrinol Metab Gastrointest Physiol 237: E214–E223, 1979.[Abstract/Free Full Text]
  9. Douglas AR, Jones NL, and Reed JW. Calculation of whole blood CO2 content. J Appl Physiol 65: 473–477, 1988.[Abstract/Free Full Text]
  10. Durduran T, Burnett MG, Yu G, Zhou C, Furuya D, Yodh AG, Detre JA, and Greenberg JH. Spatiotemporal quantification of cerebral blood flow during functional activation in rat somatosensory cortex using laser-speckle flowmetry. J Cereb Blood Flow Metab 24: 518–525, 2004.[CrossRef][ISI][Medline]
  11. Fox PT and Raichle ME. Focal physiological uncoupling of cerebral blood flow and oxidative metabolism during somatosensory stimulation in human subjects. Proc Natl Acad Sci USA 83: 1140–1144, 1986.[Abstract/Free Full Text]
  12. Fox PT, Raichle ME, Mintun MA, and Dence C. Nonoxidative glucose consumption during focal physiologic neural activity. Science 241: 462–464, 1988.[Abstract/Free Full Text]
  13. Gisolf J, Gisolf A, van Lieshout JJ, and Karemaker JM. The siphon controversy: an integration of concepts and the brain as baffle. Am J Physiol Regul Integr Comp Physiol 289: R627–R629, 2005.[Free Full Text]
  14. Gisolf J, van Lieshout JJ, van Heusden K, Pott F, Stok WJ, and Karemaker JM. Human cerebral venous outflow pathway depends on posture and central venous pressure. J Physiol 560: 317–327, 2004.[Abstract/Free Full Text]
  15. Gonzalez-Alonso J, Olsen DB, and Saltin B. Erythrocyte and the regulation of human skeletal muscle blood flow and oxygen delivery: role of circulating ATP. Circ Res 91: 1046–1055, 2002.[Abstract/Free Full Text]
  16. Ide K, Gulløv AL, Pott F, Van Lieshout JJ, Koefoed BG, Petersen P, and Secher NH. Middle cerebral artery blood velocity during exercise in patients with atrial fibrillation. Clin Physiol 19: 284–289, 1999.[CrossRef][ISI][Medline]
  17. Ide K, Pott F, Van Lieshout JJ, and Secher NH. Middle cerebral artery blood velocity depends on cardiac output during exercise with a large muscle mass. Acta Physiol Scand 162: 13–20, 1998.[CrossRef][ISI][Medline]
  18. Ido Y, Chang K, and Williamson JR. NADH augments blood flow in physiologically activated retina and visual cortex. Proc Natl Acad Sci USA 101: 653–658, 2004.[Abstract/Free Full Text]
  19. Ido Y, Chang K, Woolsey TA, and Williamson JR. NADH: sensor of blood flow need in brain, muscle, and other tissues. FASEB J 15: 1419–1421, 2001.[Free Full Text]
  20. Jørgensen LG. Transcranial Doppler ultrasound for cerebral perfusion. Acta Physiol Scand Suppl 625: 1–44, 1995.[Medline]
  21. Jørgensen LG, Perko M, Hanel B, Schroeder TV, and Secher NH. Middle cerebral artery flow velocity and blood flow during exercise and muscle ischemia in humans. J Appl Physiol 72: 1123–1132, 1992.[Abstract/Free Full Text]
  22. Kastrup J, Rørsgaard S, Parving HH, and Lassen NA. Impaired autoregulation of cerebral blood flow in long-term type I (insulin-dependent) diabetic patients with nephropathy and retinopathy. Clin Physiol 6: 549–559, 1986.[ISI][Medline]
  23. Kety SS and Schmidt CF. The effects of altered arterial tensions of carbon dioxide and oxygen on cerebral blood flow and cerebral oxygen consumption of normal young men. J Clin Invest 27: 484–492, 1948.[ISI][Medline]
  24. Kraupp O, Adler-Kastner L, Kolassa N, Nell G, Plank B, and Chirikdjian JJ. Arterial levels, cardiac and hepatic arteriovenous differences, extraction coefficients and oxygen extraction ratios of various substrates in normal, and in acute and chronic alloxan-diabetic dogs. Eur J Biochem 6: 114–125, 1968.[ISI][Medline]
  25. Langfitt TW, Obrist WD, Alavi A, Grossman RI, Zimmerman R, Jaggi J, Uzzell B, Reivich M, and Patton DR. Computerized tomography, magnetic resonance imaging, and positron emission tomography in the study of brain trauma. Preliminary observations. J Neurosurg 64: 760–767, 1986.[ISI][Medline]
  26. Linkis P, Jørgensen L, Olesen HL, Madsen PL, Lassen NA, and Secher NH. Dynamic exercise enhances regional cerebral artery mean flow velocity. J Appl Physiol 78: 12–16, 1995.[Abstract/Free Full Text]
  27. Mintun MA, Vlassenko AG, Rundle MM, and Raichle ME. Increased lactate/pyruvate ratio augments blood flow in physiologically activated human brain. Proc Natl Acad Sci USA 101: 659–664, 2004.[Abstract/Free Full Text]
  28. Pott F, van Lieshout JJ, Ide K, Madsen P, and Secher NH. Middle cerebral artery blood velocity during a Valsalva maneuver in the standing position. J Appl Physiol 88: 1545–1550, 2000.[Abstract/Free Full Text]
  29. Rasmussen P, Stie H, Nielsen B, and Nybo L. Enhanced cerebral CO2 reactivity during strenuous exercise in man. Eur J Appl Physiol 96: 299–304, 2006.[CrossRef][ISI][Medline]
  30. Valdueza JM, Draganski B, Hoffmann O, Dirnagl U, and Einhaupl KM. Analysis of CO2 vasomotor reactivity and vessel diameter changes by simultaneous venous and arterial Doppler recordings. Stroke 30: 81–86, 1999.[Abstract/Free Full Text]
  31. Van Gurp PJ, Rongen GA, Lenders JW, Al Nabawy AK, Timmers HJ, and Tack CJ. Sustained hyperglycaemia increases muscle blood flow but does not affect sympathetic activity in resting humans. Eur J Appl Physiol 93: 648–654, 2005.[CrossRef][ISI][Medline]
  32. Vlassenko AG, Rundle MM, Raichle ME, and Mintun MA. Regulation of blood flow in activated human brain by cytosolic NADH/NAD+ ratio. Proc Natl Acad Sci USA 103: 1964–1969, 2006.[Abstract/Free Full Text]
  33. Von Grumbckow L, Elsner P, Hellsten Y, Quistorff B, and Juel C. Kinetics of lactate and pyruvate transport in cultured rat myotubes. Biochim Biophys Acta 1417: 267–275, 1999.[Medline]
  34. Wesseling KH, Jansen JR, Settels JJ, and Schreuder JJ. Computation of aortic flow from pressure in humans using a nonlinear, three-element model. J Appl Physiol 74: 2566–2573, 1993.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 J. Physiol.Home page
T. S. Larsen, P. Rasmussen, M. Overgaard, N. H. Secher, and H. B. Nielsen
Non-selective {beta}-adrenergic blockade prevents reduction of the cerebral metabolic ratio during exhaustive exercise in humans
J. Physiol., June 1, 2008; 586(11): 2807 - 2815.
[Abstract] [Full Text] [PDF]

Home page
 J. Appl. Physiol.Home page
N. H. Secher, T. Seifert, and J. J. Van Lieshout
Cerebral blood flow and metabolism during exercise: implications for fatigue
J Appl Physiol, January 1, 2008; 104(1): 306 - 314.
[Abstract] [Full Text] [PDF]

Home page
 JNMHome page
P. Herrero, C. S. Dence, A. R. Coggan, Z. Kisrieva-Ware, P. Eisenbeis, and R. J. Gropler
L-3-11C-Lactate as a PET Tracer of Myocardial Lactate Metabolism: A Feasibility Study
J. Nucl. Med., December 1, 2007; 48(12): 2046 - 2055.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow All Versions of this Article:
101/5/1406    most recent
00423.2006v1
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (3)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Rasmussen, P.
Right arrow Articles by Quistorff, B.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Rasmussen, P.
Right arrow Articles by Quistorff, B.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online
Copyright © 2006 by the American Physiological Society.