AJP - Heart Ad Instruments
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Am J Physiol Heart Circ Physiol 293: H467-H473, 2007. First published March 16, 2007; doi:10.1152/ajpheart.00045.2007
0363-6135/07 $8.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
293/1/H467    most recent
00045.2007v1
Right arrow Alert me when this article is cited
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 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 Web of Science (3)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Kim, Y.-S.
Right arrow Articles by van Lieshout, J. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Kim, Y.-S.
Right arrow Articles by van Lieshout, J. J.

Effects of hyperglycemia on the cerebrovascular response to rhythmic handgrip exercise

Yu-Sok Kim,1 Rikke Krogh-Madsen,3,4 Peter Rasmussen,2,4 Peter Plomgaard,3,4 Shigehiko Ogoh,5 Niels H. Secher,2,4 and Johannes J. van Lieshout1

1Department of Internal Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; 2Departments of Anesthesiology and Infectious Diseases, 3The Center of Inflammation and Metabolism, and 4The Copenhagen Muscle Research Center, Rigshospitalet, University of Copenhagen, Denmark; and 5Department of Integrative Physiology, University of North Texas Health Science Center, Fort Worth, Texas

Submitted 12 January 2007 ; accepted in final form 14 March 2007


   ABSTRACT
TOP
 ABSTRACT
EXPERIMENTAL PROCEDURES
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Dynamic cerebral autoregulation (CA) is challenged by exercise and may become less effective when exercise is exhaustive. Exercise may increase arterial glucose concentration, and we evaluated whether the cerebrovascular response to exercise is affected by hyperglycemia. The effects of a hyperinsulinemic euglycemic clamp (EU) and hyperglycemic clamp (HY) on the cerebrovascular (CVRI) and systemic vascular resistance index (SVRI) responses were evaluated in seven healthy subjects at rest and during rhythmic handgrip exercise. Transfer function analysis of the dynamic relationship between beat-to-beat changes in mean arterial pressure and middle cerebral artery (MCA) mean blood flow velocity (Vmean) was used to assess dynamic CA. At rest, SVRI decreased with HY and EU (P < 0.01). CVRI was maintained with EU but became reduced with HY [11% (SD 3); P < 0.01], and MCA Vmean increased (P < 0.05), whereas brain catecholamine uptake and arterial PCO2 did not change significantly. HY did not affect the normalized low-frequency gain between mean arterial pressure and MCA Vmean or the phase shift, indicating maintained dynamic CA. With HY, the increase in CVRI associated with exercise was enhanced (19 ± 7% vs. 9 ± 7%; P < 0.05), concomitant with a larger increase in heart rate and cardiac output and a larger reduction in SVRI (22 ± 4% vs. 14 ± 2%; P < 0.05). Thus hyperglycemia lowered cerebral vascular tone independently of CA capacity at rest, whereas dynamic CA remained able to modulate cerebral blood flow around the exercise-induced increase in MCA Vmean. These findings suggest that elevated blood glucose does not explain that dynamic CA is affected during intense exercise.

cerebral autoregulation; cardiac output; human; vascular tone

CEREBRAL BLOOD FLOW (CBF) is under autoregulatory control and is also influenced by regional changes in neural activity (33, 46). Cerebral autoregulation (CA) spans the range of prevailing demands on CBF in everyday life and comprises both fast- and slow-acting regulatory components (1, 41). Static CA reflects the overall efficiency of the system, whereas dynamic CA refers to the ability to restore CBF in the face of a sudden change in arterial pressure, reflecting the latency of the cerebral vasoregulatory system (2, 19, 32). Brain activation by exercise provokes an increase in cerebral perfusion, and regional and global CBF increases 20–30% with the transition from rest to moderate exercise (11, 16–18, 22). During exercise, middle cerebral artery (MCA) blood flow velocity varies in response to pulse pressure, and dynamic CA allows for maintenance of cerebral circulation during the exercise-induced increase in blood pressure (30). The effectiveness of dynamic CA may, however, become reduced by exhaustive exercise (29), and the effects of metabolites and arterial PCO2 (PaCO2) on the brain vasculature are proposed as possible causative factors (29). Although plasma glucose concentration usually remains relatively constant during exercise, hyperglycemia may occur (9); whether hyperglycemia affects CA and modifies the cerebrovascular response to exercise has not been evaluated. Dynamic CA may also be affected in patients with small vessel disease (20), e.g., diabetes, where loss of autoregulation of tissue perfusion is attributed to persistent hyperglycemia (5, 7). Early Type 1 diabetes mellitus is associated with vasodilatation and hyperperfusion of vascular beds (27, 47). In healthy subjects, sustained hyperglycemia induces moderate vasodilatation in resting skeletal muscle and increases blood flow in the absence of changes in sympathetically mediated vasomotor tone (45). Blunted responses of cerebral arterioles have been reported in an animal model of diabetes mellitus and in diabetic patients with impairment of CA (5, 8, 24–26). However, results from animal studies with regard to the possible effects of glucose on CBF are inconclusive with both a reduced (13) and maintained CBF (39) in response to acute hyperglycemia.

The primary purpose of this study was to examine whether hyperglycemia affects the CBF response to exercise. We hypothesized that sustained hyperglycemia induces cerebrovascular vasodilatation interfering with CA. We further hypothesized that hyperglycemia would enhance the increase in cerebral perfusion induced by rhythmic exercise. Accordingly, we set out to determine the cerebral and systemic vascular responses and the arterial-internal jugular venous differences for catecholamines as a marker of their net brain uptake in healthy subjects during euglycemia and hyperglycemia at rest and during rhythmic handgrip exercise.


   EXPERIMENTAL PROCEDURES
TOP
 ABSTRACT
 EXPERIMENTAL PROCEDURES
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Seven healthy, recreationally active nonsmoking male subjects participated in the study. Their mean characteristics were as follows: age 25 (range 22–29) yr, height 185 (range 175–205) cm, and weight 81 (range 71–105) kg. Oral and written informed consent were obtained, and the study was approved by the Ethics Committee of Copenhagen and Frederiksberg (KF 01-257245). Before the study was initiated, the subjects underwent an examination, which included blood samples for renal, hepatic, and thyroid function, hemoglobin, white blood cell counts, electrolytes, and plasma glucose; all tests proved to be normal. The subjects abstained from caffeinated beverages for at least 6 h, and none of the subjects used any medication.

Central hemodynamic and cerebrovascular measurements were obtained during a steady-state hyperglycemic clamp (HY) and a hyperinsulinemic euglycemic clamp (EU) with blood glucose maintained at the fasting concentration. In a random order crossover design, the subjects were studied on 2 days separated by at least 1 wk in a room at 22°C. The subjects reported to the laboratory at 8:00 AM after an overnight fast. The order of the studies was EU-HY in four subjects and HY-EU in three subjects. Subjects were placed in the supine position and instrumented with arterial, internal jugular, and peripheral venous catheters. A standard lead II electrocardiogram was used for monitoring purposes. Cannulas were introduced percutaneously into the brachial artery of the nondominant arm (19 gauge) and under local anesthesia (2% lidocaine) retrograde into the internal jugular vein (14 gauge) and advanced to its bulb. A catheter was placed in an antecubital vein for infusion of insulin and glucose. The arterial catheter was connected to a pressure-monitoring system (Dialogue 2000, Copenhagen, Denmark), which was used to obtain blood for measurement of glucose, insulin, potassium, blood-gas variables, and catecholamines. The catheter lumens were flushed with 3 ml/h isotonic saline. Arterial pressure was measured with a transducer (Edwards Life Sciences, Irving, CA) that was calibrated and zeroed at the level of the right atrium in the midaxillary line. The transcranial Doppler-derived blood velocity was measured in the proximal segment of the right MCA and insonated (DWL Multidop X4, Sipplingen, Germany) through the posterior temporal "window." Once the optimal signal-to-noise ratio was obtained, the probe was secured with a headband. Both at rest and during exercise, determination of flow velocity in the MCA has a coefficient of variation of ~5% (35). Stroke volume (SV) was calculated from the blood pressure waveform using the model flow method incorporating age, sex, height, and weight (BeatScope 1.0 software; BMEye, Amsterdam, The Netherlands) (21). This technique tracks fast changes in SV during static and dynamic exercise (18, 29, 40, 44). The signals of arterial pressure, spectral envelope of MCA blood flow velocity, and ECG were analog-to-digital converted at 200 Hz and stored on a hard disk for off-line analysis.

Hyperinsulinemic HY. Glucose (1,000 mM) was infused intravenously to maintain a blood level of 15 mM, with the rate of infusion adjusted by a computer-controlled pump according to the arterial blood glucose concentrations analyzed at intervals of 5 min during the first hour and then every 10th min (34). Steady-state blood glucose concentrations were achieved after ~1 h. To maintain potassium at the baseline level, isotonic saline containing potassium (51 mmol/l) was infused continuously. To flush lines after blood sampling, a total of ~1,000 ml of isotonic saline was needed during the study and compensated for the blood withdrawn. Arterial blood samples for measurements of insulin and plasma catecholamines were drawn before glucose infusion and after steady-state hyperglycemia was achieved.

Hyperinsulinemic EU. Insulin was infused at 0.08 IU·min–1·m–2. Glucose was provided via a computer-controlled infusion pump adjusted to maintain blood glucose at baseline (fasting) concentration in a manner similar to that described for HY clamping with other infusions. Arterial blood for measurement of insulin and catecholamines was drawn as mentioned for HY clamping.

Exercise. For rhythmic handgrip exercise, a strain-gauge dynamometer was used, and force was measured by bridge (CN801, K&N Hellerup, Denmark). At the start of each study, maximal voluntary contraction was determined. Exercise included 10 min of intermittent handgrip contractions at 65% of maximal voluntary contraction with 2 s of contraction alternated with 4 s of relaxation.

Blood samples. Blood samples obtained at baseline and during EU and HY were analyzed [potassium, glucose concentrations, and blood-gas variables (ABL 625 & 700, Radiometer, Copenhagen, Denmark), as well as lactate (Yellow Springs Instruments, Yellow Springs, OH)]. Plasma catecholamines were determined with a 2 CATecho-lamine Elisa ImmunoAssay (BA 10–1500; Labor Dianostika Nord, Nordhorn, Germany). Net brain catecholamine uptake was expressed as the arterial-to-internal jugular venous epinephrine and norepinephrine difference for the brain (15).

Data analysis. Beat-to-beat values for MCA mean blood flow velocity (Vmean) and mean arterial pressure (MAP) were derived as the integral over one beat divided by the corresponding beat interval. Heart rate (HR) was the inverse of the interbeat pressure interval, and cardiac output (CO) was the product of SV and HR. Systemic vascular resistance index (SVRI) was calculated as MAP/CO, and an effect of hyperglycemia on the cerebral vascular resistance was expressed as an index (CVRI) calculated from MAP and MCA Vmean (19). Cerebral and systemic hemodynamic values were expressed as the averages of 6-min manifestations of MAP, HR, SV, CO, pulse pressure, SVRI, MCA Vmean, and CVRI. Dynamic CA is frequency dependent, and frequency-domain analysis of autoregulation allows for quantification of the counterregulatory capacity to maintain MCA Vmean during induced or spontaneous changes in blood pressure (32, 52). In healthy subjects, MCA Vmean leads MAP by ~60° in the frequency domain around the 0.1-Hz spontaneous blood pressure variability (12). Dynamic CA was determined in the frequency domain from 6-min episodes of beat-to-beat data of MAP and MCA Vmean before and during HY and EU. To quantify the variability of pressure and velocity, power spectra were computed for MAP and MCA Vmean with discrete Fourier transform after spline interpolation and resampling at 4 Hz of the beat-to-beat data sets. The data were averaged over 6 min during baseline and EU and HY at rest and over 2 min during exercise. Results are expressed as the integrated area in the low-frequency (LF; 0.07–0.15 Hz) range. To examine the strength of the relation between the LF power of the MAP and MCA Vmean, the coherence function was calculated to estimate the fraction of output power (MCA Vmean) that can be linearly related to the input power (MAP) at each frequency (28). Similarly to a correlation coefficient, it varies between 0 and 1. From the MAP-to-MCA Vmean cross-spectrum, the transfer function gain (cm·s–1·mmHg–1) and the MCA Vmean-to-MAP phase lead (degrees) were obtained in the LF area. The transfer function gain was normalized for MAP and MCA Vmean to account for the intersubject variability and expressed as percent change (in cm/s per percent change in mmHg) (19, 20, 32). Phase was defined as positive where MCA Vmean leads MAP. Baroreflex sensitivity was derived from frequency analysis of systolic blood pressure and interbeat interval time series. Power spectral density and cross-spectra of systolic blood pressure and interbeat interval were computed with the use of discrete Fourier transform (14, 50).

Statistical analysis. Data are presented as means and SD. Two-way ANOVA for repeated measures was used to identify differences across glycemic condition (EU vs. HY) and time. Post hoc pair-wise multiple comparisons vs. rest were performed with the Holm-Sidak method, and correlation strength was assessed with Pearson's test on the average values across subjects. When data fitted a normal distribution, as indicated by Kolmogorov-Smirnov analysis, a t-test was used; a Mann-Whitney rank sum test was applied when data were not normally distributed, with P < 0.05 considered to indicate a statistically significant difference.


   RESULTS
TOP
 ABSTRACT
 EXPERIMENTAL PROCEDURES
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
At rest before glucose clamping, baseline cerebro- and cardiovascular variables and plasma concentrations for insulin [EU vs. HY: 10.4 pmol/l (SD 7.7) vs. 8.0 pmol/l (SD 6.9)], glucose [4.9 mmol/l (SD 0.1) vs. 4.9 mmol/l (SD 0.1)], PaCO2, and epinephrine and norepinephrine did not differ between experiments (Table 1).


View this table:
[in this window]
[in a new window]

  		Table 1. Systemic and cerebrovascular hemodynamic variables

 
EU and HY clamping. The plasma glucose concentration was maintained at 4.9 mmol/l (SD 0.1) for EU and 14.8 mmol/l (SD 0.2) for HY (Fig. 1). Plasma insulin concentrations during exercise were not different between conditions [906 pmol/l (SD 46) for EU vs. 688 pmol/l (SD 100) for HY; P = 0.07]. During EU and HY clamping, MAP and arterial catecholamine concentrations did not change significantly. At the same time, SVRI decreased with both HY and EU (P < 0.01). The CVRI was maintained with EU but became reduced with HY [11% (SD 3); P < 0.01], and MCA Vmean increased (P < 0.05; Table 1), whereas brain catecholamine uptake and PaCO2 did not change significantly. Arterial lactate concentrations increased with both HY and EU (P < 0.01).


Figure 1
View larger version (6K):
[in this window]
[in a new window]

  		Fig. 1. Plasma glucose during euglycemic ({circ}) and hyperglycemic (bullet) clamp for 7 subjects. Bars: rhythmic handgrip exercise.

 
Spectral and transfer function analysis. Baroreflex sensitivity was within normal limits and did not change with EU [17 ms/mmHg (SD 3) vs. 16 ms/mmHg (SD 2)] vs. HY [19 ms/mmHg (SD 3) vs. 18 ms/mmHg (SD 3)]. Transfer function analysis of the dynamic relationship between beat-to-beat changes in MCA Vmean and MAP assessed dynamic CA across changes in plasma glucose. The phase and normalized transfer function gain between MCA Vmean and MAP in the LF range were not altered across changes in the plasma glucose concentration (Table 2).


View this table:
[in this window]
[in a new window]

  		Table 2. Transfer function gain, phase, and coherence function

 
Rhythmic handgrip exercise. During exercise, MAP, HR, pulse pressure, CO, and MCA Vmean increased (P < 0.05), whereas SV, PaCO2, arterial catecholamine concentrations, and arteriovenous lactate difference did not change significantly (Table 1). Also, the increase in MAP was similar for both glycemic conditions, whereas the increase in HR and CO during HY vs. EU was larger (P < 0.05; Fig. 2), concomitant to a larger reduction in SVRI (22 ± 4% vs. 14 ± 2%; P < 0.05; Fig. 3). During HY vs. control, the increase in CVRI was larger (19 ± 7% vs. 9 ± 7%; P < 0.05), whereas net brain catecholamine uptake and PaCO2 did not change.


Figure 2
View larger version (17K):
[in this window]
[in a new window]

  		Fig. 2. Mean arterial pressure (MAP), middle cerebral artery mean blood flow velocity (MCA Vmean), heart rate (HR), and cardiac output (CO) responses to rhythmic handgrip during euglycemic clamp (EU; {circ}) and hyperglycemic clamp (HY; bullet) vs. at control conditions (CTRL; {blacksquare}). Values are means ± SE for 7 subjects. Bars: rhythmic handgrip exercise. {dagger}P < 0.05 vs. rest (time = –3 min); {ddagger}P < 0.01 vs. rest; *P < 0.05 vs. control.

 

Figure 3
View larger version (16K):
[in this window]
[in a new window]

  		Fig. 3. Responses of cerebral and systemic vascular resistance indexes to exercise during EU ({circ}) and HY (bullet) vs. at control conditions ({blacksquare}). Values are mean ± SE for 7 subjects. Bars: rhythmic handgrip exercise. CVRI, cerebrovascular resistance index; SVRI, systemic vascular resistance index. {dagger}P < 0.05 vs. rest (time = –3 min); {ddagger}P < 0.01 vs. rest; *P < 0.05 vs. control.

 

   DISCUSSION
TOP
 ABSTRACT
 EXPERIMENTAL PROCEDURES
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
The present study provides novel information regarding the influence of hyperglycemia on the vascular responses of the cerebral and systemic circulations in humans from rest to exercise. At rest, SVRI decreased both with HY and EU. At the same time, CVRI was maintained with EU but declined in response to HY independently of CA, suggesting an important role for glucose. Second, HY enhanced the decline in SVRI and the increase in CO associated with exercise. Thus HY lowered cerebral vascular tone independently of autoregulatory capacity at rest, whereas dynamic CA retained the ability to modulate CBF around the exercise-induced increase in MCA Vmean. Collectively, these findings suggest that elevated blood glucose does not explain that dynamic CA may become affected during intense exercise.

Hyperglycemia and hyperinsulinemia each elicit systemic vasodilatation, but controversies exist as to the vascular effects of insulin (3, 38, 45) because both systemic vasoconstrictive and vasodilatory effects of insulin have been reported (6, 38, 45, 49, 51). Endothelium-dependent vasodilatation is impaired in Type 1 (42) and in Type 2 diabetes (4, 43); however, in healthy humans, acute hyperglycemia does not impair endothelial function (37). The vascular effects of insulin may reflect the balance between sympathetic and local nitric oxide effects with vasodilatation at elevated plasma concentrations vs. vasoconstriction at lower concentrations (51). In addition, the effects of hyperinsulinemic hyperglycemia are different for healthy subjects vs. patients with insulin-dependent diabetes mellitus, with regional vasodilatation shown in healthy subjects but not in patients (23, 31). Possible differences in dose-response vascular effects of elevated insulin levels need to be established, and we cannot, therefore, exclude some vascular contribution of a slightly higher insulin concentration during EU vs. HY.

In healthy subjects, euinsulinemic hyperglycemia induces moderate vasodilatation in skeletal muscle in the absence of changes in sympathetic tone or blood pressure (45). A new observation from the present study is that, during exercise, the decline in SVRI is enhanced by hyperglycemia. This systemic vasodilatation developed in the absence of significant changes in baroreflex sensitivity, plasma norepinephrine concentration, or LF spectral power of arterial pressure and interbeat interval oscillations, suggesting that sympathetic activity did not change (10, 50).

In an isolated cerebral artery model, acute glucose exposure dilates cerebral arteries (8), whereas, after chronic exposure to hyperglycemia, vascular responses diminish (26). We hypothesized that the cerebral vasculature would respond in a similar way and evaluated the CVRI during HY as an indicator for cerebral artery vasomotor tone. A reduction in CVRI was demonstrated with HY during rest in parallel to the systemic vasodilatation that took place without a change in PaCO2 or brain catecholamine uptake. However, the findings that the MAP-to-MCA Vmean transfer function gain and phase were not affected by EU and HY support that dynamic CA was preserved during both acute hyperinsulinemia and hyperglycemia. Sympathetic nerve stimulation increases MAP and MCA Vmean (48), and brain activation by rhythmic exercise results in an increase in MAP, CVRI, and MCA Vmean (17, 22). During exercise with HY, the increase in MAP was comparable to that with EU, but the increase in CO was larger and accompanied by an enhanced CVRI response.

The MCA Vmean was chosen for evaluation of exercise-induced changes in CBF with the assumption that changes in MCA Vmean are representative of those in CBF. Transcranial Doppler monitors blood velocity rather than blood flow, and changes in the diameter of the insonated vessel by enhanced sympathetic activity could modulate velocity independently of flow. However, the large cerebral arteries are conductance rather than resistance vessels, and moderate sympathetic activation does not modify the luminar diameter of a systemic conduit artery (36). With exercise, MCA Vmean demonstrates a graded increase to work rate and reflects the increase in regional CBF (11, 17, 22). When large muscle groups are exercised, the increase in plasma norepinephrine is up to 16-fold higher than during moderate exercise such as with rhythmic handgrip. In the present study, the systemic to cerebral norepinephrine difference did not change significantly during exercise, and we consider an adrenergic vasoconstrictive effect on the MCA unlikely (35).

This study did not address the mechanism involved in the differential cerebral and systemic circulatory responses to hyperglycemia, but the data suggest that, during exercise, maintained dynamic CA counterbalanced the vasodilatatory effect of hyperglycemia manifest in other vascular beds. Thus hyperglycemia lowered cerebral vascular tone independently of CA capacity at rest, whereas dynamic CA remained able to modulate CBF around the exercise-induced increase in MCA Vmean. These findings suggest that an elevated blood glucose does not explain that dynamic CA may become affected during intense exercise.


   GRANTS
TOP
 ABSTRACT
 EXPERIMENTAL PROCEDURES
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
Y. S. Kim is supported by the Dutch Diabetes Foundation (Grant 04-00-00), and P. Rasmussen is supported by the Lundbeck Foundation. The Centre of Inflammation and Metabolism is supported by a grant from the Danish National Research Foundation (Grant 02-512-55).


   FOOTNOTES
 

Address for reprint requests and other correspondence: J. J. van Lieshout, Medium Care Unit, Dept. of Internal Medicine, F7-205, Academic Medical Center, Univ. of Amsterdam, PO Box 22700, 1100 DE Amsterdam, The Netherlands (e-mail: j.j.vanlieshout{at}amc.uva.nl)

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
 EXPERIMENTAL PROCEDURES
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 

  1. Aaslid R. Cerebral hemodynamics. In: Transcranial Doppler, edited by Newell DW and Aaslid R. New York: Raven, 1992, p. 49–55.
  2. Aaslid R, Lindegaard KF, Sorteberg W, Nornes H. Cerebral autoregulation dynamics in humans. Stroke 20: 45–52, 1989.[Abstract/Free Full Text]
  3. Anderson EA, Hoffman RP, Balon TW, Sinkey CA, Mark AL. Hyperinsulinemia produces both sympathetic neural activation and vasodilation in normal humans. J Clin Invest 87: 2246–2252, 1991.[Web of Science][Medline]
  4. Beckman JA, Goldfine AB, Gordon MB, Creager MA. Ascorbate restores endothelium-dependent vasodilation impaired by acute hyperglycemia in humans. Circulation 103: 1618–1623, 2001.[Abstract/Free Full Text]
  5. Bentsen N, Larsen B, Lassen NA. Chronically impaired autoregulation of cerebral blood flow in long-term diabetics. Stroke 6: 497–502, 1975.[Abstract/Free Full Text]
  6. Berne C, Fagius J, Pollare T, Hjemdahl P. The sympathetic response to euglycaemic hyperinsulinaemia. Evidence from microelectrode nerve recordings in healthy subjects. Diabetologia 35: 873–879, 1992.[CrossRef][Web of Science][Medline]
  7. Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature 414: 813–820, 2001.[CrossRef][Medline]
  8. Cipolla MJ, Porter JM, Osol G. High glucose concentrations dilate cerebral arteries and diminish myogenic tone through an endothelial mechanism. Stroke 28: 405–410, 1997.[Abstract/Free Full Text]
  9. Coggan AR. Plasma glucose metabolism during exercise in humans. Sports Med 11: 102–124, 1991.[Web of Science][Medline]
  10. Cooke WH, Hoag JB, Crossman AA, Kuusela TA, Tahvanainen KU, Eckberg DL. Human responses to upright tilt: a window on central autonomic integration. J Physiol 517: 617–628, 1999.[Abstract/Free Full Text]
  11. Delp MD, Armstrong RB, Godfrey DA, Laughlin MH, Ross CD, Wilkerson MK. Exercise increases blood flow to locomotor, vestibular, cardiorespiratory and visual regions of the brain in miniature swine. J Physiol 533: 849–859, 2001.[Abstract/Free Full Text]
  12. Diehl RR, Linden D, Lucke D, Berlit P. Phase relationship between cerebral blood flow velocity and blood pressure. A clinical test of autoregulation. Stroke 26: 1801–1804, 1995.[Abstract/Free Full Text]
  13. Duckrow RB, Beard DC, Brennan RW. Regional cerebral blood flow decreases during hyperglycemia. Ann Neurol 17: 267–272, 1985.[CrossRef][Web of Science][Medline]
  14. Gisolf J, Immink RV, Van Lieshout JJ, Stok WJ, Karemaker JM. Orthostatic blood pressure control before and after space flight, determined by time-domain baroreflex method. J Appl Physiol 98: 1682–1690, 2005.[Abstract/Free Full Text]
  15. Gonzalez-Alonso J, Dalsgaard MK, Osada T, Volianitis S, Dawson EA, Yoshiga CC, Secher NH. Brain and central hemodynamics and oxygenation during maximal exercise in humans. J Physiol 557: 331–342, 2004.[Abstract/Free Full Text]
  16. Hedlund S, Nyling G, Regnstrom O. The behaviour of the cerebral circulation during muscular exercise. Acta Physiol Scand 54: 316–324, 1962.[Web of Science][Medline]
  17. Hellstrøm G, Fischer-Colbrie W, Wahlgren NG, Jøgestrand T. Carotid artery blood flow and middle cerebral artery blood flow velocity during physical exercise. J Appl Physiol 81: 413–418, 1996.[Abstract/Free Full Text]
  18. Ide K, Pott F, Van Lieshout JJ, 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][Web of Science][Medline]
  19. Immink RV, van den Born BJ, Van Montfrans GA, Koopmans RP, Karemaker JM, Van Lieshout JJ. Impaired cerebral autoregulation in patients with malignant hypertension. Circulation 110: 2241–2245, 2004.[Abstract/Free Full Text]
  20. Immink RV, Van Montfrans GA, Stam J, Karemaker JM, Diamant M, Van Lieshout JJ. Dynamic cerebral autoregulation in acute lacunar and middle cerebral artery territory ischemic stroke. Stroke 36: 2595–2600, 2005.[Abstract/Free Full Text]
  21. Jellema WT, Wesseling KH, Groeneveld AB, Stoutenbeek CP, Thijs LG, Van Lieshout JJ. Continuous cardiac output in septic shock by simulating a model of the aortic input impedance: a comparison with bolus injection thermodilution. Anesthesiology 90: 1317–1328, 1999.[CrossRef][Web of Science][Medline]
  22. Jørgensen LG, Perko G, Secher NH. Regional cerebral artery mean flow velocity and blood flow during dynamic exercise in humans. J Appl Physiol 73: 1825–1830, 1992.[Abstract/Free Full Text]
  23. Makimattila S, Virkamaki A, Malmstrom R, Utriainen T, Yki-Jarvinen H. Insulin resistance in type I diabetes mellitus: a major role for reduced glucose extraction. J Clin Endocrinol Metab 81: 707–712, 1996.[Abstract]
  24. Mankovsky BN, Piolot R, Mankovsky OL, Ziegler D. Impairment of cerebral autoregulation in diabetic patients with cardiovascular autonomic neuropathy and orthostatic hypotension. Diabet Med 20: 119–126, 2003.[CrossRef][Web of Science][Medline]
  25. Marthol H, Brown CM, Zikeli U, Ziegler D, Dimitrov N, Baltadzhieva R, Hilz MJ. Altered cerebral regulation in type 2 diabetic patients with cardiac autonomic neuropathy. Diabetologia 49: 2481–2487, 2006.[CrossRef][Web of Science][Medline]
  26. Mayhan WG, Simmons LK, Sharpe GM. Mechanism of impaired responses of cerebral arterioles during diabetes mellitus. Am J Physiol Heart Circ Physiol 260: H319–H326, 1991.[Abstract/Free Full Text]
  27. Miller JA, Floras JS, Zinman B, Skorecki KL, Logan AG. Abnormalities in the renal and vascular responses to LBNP in humans with early diabetes. Am J Physiol Regul Integr Comp Physiol 266: R442–R450, 1994.[Abstract/Free Full Text]
  28. Ogoh S, Brothers RM, Barnes Q, Eubank WL, Hawkins MN, Purkayastha S, Yurvati A, Raven PB. The effect of changes in cardiac output on middle cerebral artery mean blood velocity at rest and during exercise. J Physiol 569: 697–704, 2005.[Abstract/Free Full Text]
  29. Ogoh S, Dalsgaard MK, Yoshiga CC, Dawson EA, Keller DM, Raven PB, Secher NH. Dynamic cerebral autoregulation during exhaustive exercise in humans. Am J Physiol Heart Circ Physiol 288: H1461–H1467, 2005.[Abstract/Free Full Text]
  30. Ogoh S, Fadel PJ, Zhang R, Selmer C, Jans O, Secher NH, Raven PB. Middle cerebral artery flow velocity and pulse pressure during dynamic exercise in humans. Am J Physiol Heart Circ Physiol 288: H1526–H1531, 2005.[Abstract/Free Full Text]
  31. Oomen PH, Kant GD, Dullaart RP, Reitsma WD, Smit AJ. Acute hyperglycemia and hyperinsulinemia enhance vasodilatation in Type 1 diabetes mellitus without increasing capillary permeability and inducing endothelial dysfunction. Microvasc Res 63: 1–9, 2002.[CrossRef][Web of Science][Medline]
  32. Panerai RB, Dawson SL, Potter JF. Linear and nonlinear analysis of human dynamic cerebral autoregulation. Am J Physiol Heart Circ Physiol 277: H1089–H1099, 1999.[Abstract/Free Full Text]
  33. Paulson OB, Strandgaard S, Edvinsson L. Cerebral autoregulation. Cerebrovasc Brain Metab Rev 2: 161–192, 1990.[Web of Science][Medline]
  34. Plomgaard P, Bouzakri K, Krogh-Madsen R, Mittendorfer B, Zierath JR, Pedersen BK. Tumor necrosis factor-{alpha} induces skeletal muscle insulin resistance in healthy human subjects via inhibition of Akt substrate 160 phosphorylation. Diabetes 54: 2939–2945, 2005.[Abstract/Free Full Text]
  35. Pott F, Jensen K, Hansen H, Christensen NJ, Lassen NA, Secher NH. Middle cerebral artery blood velocity and plasma catecholamines during exercise. Acta Physiol Scand 158: 349–356, 1996.[CrossRef][Web of Science][Medline]
  36. Pott F, Ray CA, Olesen HL, Ide K, Secher NH. Middle cerebral artery blood velocity, arterial diameter and muscle sympathetic nerve activity during post-exercise muscle ischaemia. Acta Physiol Scand 160: 43–47, 1997.[CrossRef][Web of Science][Medline]
  37. Reed AS, Charkoudian N, Vella A, Shah P, Rizza RA, Joyner MJ. Forearm vascular control during acute hyperglycemia in healthy humans. Am J Physiol Endocrinol Metab 286: E472–E480, 2004.[Abstract/Free Full Text]
  38. Scherrer U, Sartori C. Insulin as a vascular and sympathoexcitatory hormone: implications for blood pressure regulation, insulin sensitivity, and cardiovascular morbidity. Circulation 96: 4104–4113, 1997.[Abstract/Free Full Text]
  39. Simpson RE III, Phillis JW, Buchannan J. A comparison of cerebral blood flow during basal, hypotensive, hypoxic and hypercapnic conditions between normal and streptozotocin diabetic rats. Brain Res 531: 136–142, 1990.[CrossRef][Web of Science][Medline]
  40. Sugawara J, Tanabe T, Miyachi M, Yamamoto K, Takahashi K, Iemitsu M, Otsuki T, Homma S, Maeda S, Ajisaka R, Matsuda M. Non-invasive assessment of cardiac output during exercise in healthy young humans: comparison between Modelflow method and Doppler echocardiography method. Acta Physiol Scand 179: 361–366, 2003.[CrossRef][Web of Science][Medline]
  41. Tiecks FP, Lam AM, Aaslid R, Newell DW. Comparison of static and dynamic cerebral autoregulation measurements. Stroke 26: 1014–1019, 1995.[Abstract/Free Full Text]
  42. Timimi FK, Ting HH, Haley EA, Roddy MA, Ganz P, Creager MA. Vitamin C improves endothelium-dependent vasodilation in patients with insulin-dependent diabetes mellitus. J Am Coll Cardiol 31: 552–557, 1998.[Abstract/Free Full Text]
  43. Ting HH, Timimi FK, Boles KS, Creager SJ, Ganz P, Creager MA. Vitamin C improves endothelium-dependent vasodilation in patients with non-insulin-dependent diabetes mellitus. J Clin Invest 97: 22–28, 1996.[Web of Science][Medline]
  44. Van Dijk N, de Bruin IG, Gisolf J, Bruin-Bon HA, Linzer M, van Lieshout JJ, Wieling W. Hemodynamic effects of legcrossing and skeletal muscle tensing during free standing in patients with vasovagal syncope. J Appl Physiol 98: 584–590, 2005.[Abstract/Free Full Text]
  45. Van Gurp PJ, Rongen GA, Lenders JW, Al Nabawy AK, Timmers HJ, 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][Web of Science][Medline]
  46. Van Lieshout JJ, Wieling W, Karemaker JM, Secher NH. Syncope cerebral perfusion, oxygenation. J Appl Physiol 94: 833–848, 2003.[Abstract/Free Full Text]
  47. Vervoort G, Wetzels JF, Lutterman JA, van Doorn LG, Berden JH, Smits P. Elevated skeletal muscle blood flow in noncomplicated type 1 diabetes mellitus: role of nitric oxide and sympathetic tone. Hypertension 34: 1080–1085, 1999.[Abstract/Free Full Text]
  48. Wahlgren NG, Hellstrom G, Lindquist C, Rudehill A. Sympathetic nerve stimulation in humans increases middle cerebral artery blood flow velocity. Cerebrovasc Dis 2: 359–364, 1992.[CrossRef][Web of Science]
  49. Westerbacka J, Bergholm R, Tiikkainen M, Yki-Jarvinen H. Glargine and regular human insulin similarly acutely enhance endothelium-dependent vasodilatation in normal subjects. Arterioscler Thromb Vasc Biol 24: 320–324, 2004.[Abstract/Free Full Text]
  50. Westerhof BE, Gisolf J, Karemaker JM, Wesseling KH, Secher NH, van Lieshout JJ. Time course analysis of baroreflex sensitivity during postural stress. Am J Physiol Heart Circ Physiol 291: H2864–H2874, 2006.[Abstract/Free Full Text]
  51. Yki-Jarvinen H, Utriainen T. Insulin-induced vasodilatation: physiology or pharmacology? Diabetologia 41: 369–379, 1998.[CrossRef][Web of Science][Medline]
  52. Zhang R, Zuckerman JH, Giller CA, Levine BD. Transfer function analysis of dynamic cerebral autoregulation in humans. Am J Physiol Heart Circ Physiol 274: H233–H241, 1998.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 Nephrol Dial TransplantHome page
K. J. Schjoedt, P. K. Christensen, A. Jorsal, F. Boomsma, P. Rossing, and H.-H. Parving
Autoregulation of glomerular filtration rate during spironolactone treatment in hypertensive patients with type 1 diabetes: a randomized crossover trial
Nephrol. Dial. Transplant., November 1, 2009; 24(11): 3343 - 3349.
[Abstract] [Full Text] [PDF]

Home page
 J. Appl. Physiol.Home page
S. Ogoh and P. N. Ainslie
Cerebral blood flow during exercise: mechanisms of regulation
J Appl Physiol, November 1, 2009; 107(5): 1370 - 1380.
[Abstract] [Full Text] [PDF]

Home page
 StrokeHome page
Y.-S. Kim, E. Nur, E. J. van Beers, J. Truijen, S. C.A.T. Davis, B. J. Biemond, and J. J. van Lieshout
Dynamic Cerebral Autoregulation in Homozygous Sickle Cell Disease
Stroke, March 1, 2009; 40(3): 808 - 814.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
293/1/H467    most recent
00045.2007v1
Right arrow Alert me when this article is cited
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 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 Web of Science (3)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Kim, Y.-S.
Right arrow Articles by van Lieshout, J. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Kim, Y.-S.
Right arrow Articles by van Lieshout, J. J.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online
Copyright © 2007 by the American Physiological Society.