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Am J Physiol Heart Circ Physiol 292: H432-H438, 2007. First published September 8, 2006; doi:10.1152/ajpheart.00794.2006
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Frequency response characteristics of cerebral blood flow autoregulation in rats

Brittany Kolb, Diane L. Rotella, and Harald M. Stauss

The University of Iowa, Department of Integrative Physiology, Iowa City, Iowa

Submitted 24 July 2006 ; accepted in final form 1 September 2006


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Transfer function analysis of blood pressure and cerebral blood flow in humans demonstrated that cerebrovascular autoregulation operates most effectively for slow fluctuations in perfusion pressure, not exceeding a frequency of ~0.15 Hz. No information on the dynamic properties of cerebrovascular autoregulation is available in rats. Therefore, we tested the hypothesis that cerebrovascular autoregulation in rats is also most effective for slow fluctuations in perfusion pressure below 0.15 Hz. Normotensive Wistar-Kyoto rats (n = 10) were instrumented with catheters in the left common carotid artery and jugular vein and flow probes around the right internal carotid artery. During isoflurane anesthesia, fluctuations in cerebral perfusion pressure were elicited by periodically occluding the abdominal aorta at eight frequencies ranging from 0.008 Hz to 0.5 Hz. The protocol was repeated during inhibition of myogenic vascular function (nifedipine, 0.25 mg/kg body wt iv). Increases in cerebral perfusion pressure elicited initial increases in cerebrovascular conductance and decreases in resistance. At low occlusion frequencies (<0.1 Hz), these initial responses were followed by decreases in conductance and increases in resistance that were abolished by nifedipine. At occlusion frequencies of 0.1 Hz and above, the gains of the transfer functions between pressure and blood flow and between pressure and resistance were equally high in the control and nifedipine trial. At occlusion frequencies below 0.1 Hz, the gains of the transfer functions decreased twice as much under control conditions than during nifedipine application. We conclude that dynamic autoregulation of cerebral blood flow is restricted to very low frequencies (<0.1 Hz) in rats.

myogenic vascular function; blood pressure variability; hemorrhagic stroke; nifedipine; transfer function analysis

MAINTENANCE OF CEREBRAL PERFUSION during physiological challenges, such as postprandial hypotension (23) and orthostasis (26), is of utmost importance to maintain brain function and to avoid cerebral hypoxia, loss of consciousness, and irreversible brain damage. Autoregulation of cerebral blood flow is one of the most important mechanisms securing sufficient brain perfusion under varying physiological conditions. This mechanism causes cerebral blood flow to remain relatively constant even if perfusion pressures fluctuate in a wide range of ~60–150 mmHg in healthy subjects (25). The myogenic vascular response is a major mechanism contributing to autoregulation of cerebral blood flow. The myogenic vascular response, first described by Sir William Bayliss (2), is characterized by a vasoconstriction if perfusion pressure increases and a vasodilatation if perfusion pressure decreases. Other mechanisms, such as metabolic effects, perivascular nerves, and endothelial factors, have also been shown to contribute to autoregulation of cerebral blood flow (25).

Whereas autoregulation of cerebral blood flow operates reasonably well for slow fluctuations in perfusion pressure, more rapid changes in perfusion pressure may not be buffered as well and may elicit pressure-dependent changes in cerebral blood flow. This concept of the time dependency of autoregulation of cerebral blood flow is often referred to as "dynamic properties of cerebral autoregulation." In humans, these dynamic properties of cerebral autoregulation have been studied intensively during physiological (12, 17, 22, 24, 38, 39) and pathophysiological conditions (14, 20, 26, 27). With the use of transfer function analysis between blood pressure and cerebral blood flow velocity, recorded by transcranial Doppler, these studies revealed that dynamic autoregulation of cerebral blood flow is most effective at frequencies below 0.07 Hz. However, some studies (22, 27) suggested that autoregulation of cerebral blood flow can operate at frequencies as high as 0.15 Hz. With the assumption of a highest operating frequency for dynamic autoregulation of cerebral blood flow of 0.1 Hz in humans, blood flow would return to baseline levels within ~10 s after a sudden change in perfusion pressure. Thus the time course of autoregulation of cerebral blood flow is just fast enough to prevent fainting after a sudden drop in perfusion pressure, such as during the transition from the supine to the upright posture.

To the best of our knowledge, no information on dynamic properties of autoregulation of cerebral blood flow is available for rats. Impaired autoregulation of cerebral blood flow has been suggested to contribute to hemorrhagic stroke in stroke-prone spontaneously hypertensive rats (29, 31) and in salt-sensitive Dahl rats (30). Furthermore, dynamic, but not static, cerebrovascular autoregulation was found to be impaired in acute ischemic stroke (8). Thus information on the dynamic properties of cerebral autoregulation in rats is important to better understand the pathophysiological mechanisms involved in hemorrhage stroke development in stroke-prone or salt-sensitive rats.

Therefore, we employed an experimental protocol that allowed for periodic changes in cerebral perfusion pressure at different frequencies and to simultaneously record internal carotid artery blood flow as a surrogate measure of cerebral blood flow in rats. Transfer functions between cerebral perfusion pressure and internal carotid artery blood flow and between perfusion pressure and internal carotid artery resistance were calculated to characterize the dynamic properties of autoregulation of cerebral blood flow in rats. These are the same analytical techniques that have been used to characterize dynamic cerebrovascular autoregulation in humans (12, 14, 20, 22, 24, 27, 38, 39). The gain of the transfer function between cerebral perfusion pressure and cerebral blood flow is a measure of how much blood flow changes for a given change in pressure and can be seen as a measure of the potency of cerebrovascular autoregulation. A passive vascular response to changes in pressure would elicit large changes in flow (high gain of the transfer function), whereas no changes in flow (0 gain of the transfer function) would be expected in the case of perfect autoregulation. Similarly, the gain of the transfer function between perfusion pressure and vascular resistance, a measure of how much vascular resistance changes in response to a given change in pressure, largely depends on myogenic vascular function. On the basis of the findings in humans (12, 14, 20, 22, 24, 27, 38, 39), we tested the hypothesis that dynamic autoregulation of cerebral blood flow in rats only operates at frequencies below a certain corner frequency. This corner frequency may not necessarily be the same in humans and rats.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Animals. Experiments were performed in 10 male normotensive Wistar-Kyoto rats (WKY/NCrl, Charles River, Wilmington, MA) at an age of 63 ± 4 days (217 ± 19 g body wt). Experiments were performed in accordance with the "Guiding Principles in the Care and Use of Animals" of the American Physiological Society (37) and have been approved by the Institutional Animal Care and Use Review Committee of The University of Iowa (Animal Care and Use Review Form no. 0307140).

Instrumentation. Initially, anesthesia was achieved by a combination of ketamine (91 mg/kg) and acepromazine (0.91 mg/kg) administered intraperitoneally. Rats were placed on a temperature-controlled heating pad to maintain body core temperature during instrumentation and experimental protocols. Through a midline neck incision, catheters were inserted in the left common carotid artery and left external jugular vein for recording of cerebral perfusion pressure and drug administration, respectively. An ultrasound Doppler flow probe (model 1PRB, Transonic Systems, Ithaca, NY) was placed around the right internal carotid artery for recording of cerebrovascular blood flow. The Doppler device (model TS420, Transonic Systems) is a transit time flowmeter and provides absolute blood flow values, calibrated in milliliters per minute. The abdominal cavity was opened, and a string was placed around the abdominal aorta caudal from the branches of the renal arteries. With the use of this string, blood flow in the abdominal aorta could be interrupted periodically to elicit oscillations in total peripheral resistance and, hence, cerebral perfusion pressure.

Experimental protocol. After instrumentation, anesthesia was switched to isoflurane (1% in O2), which has been demonstrated to have fewer detrimental effects on cerebral blood flow autoregulation than ketamine (4). Cerebral perfusion pressure was measured via the left carotid artery catheter, and right internal carotid artery blood flow was monitored as a surrogate measure of cerebral blood flow. Pressure and flow were recorded at a sampling rate of 500 Hz using the freely available HemoLab software (http://www.intergate.com/~harald/HemoLab/HemoLab.html). Once stable baseline conditions were established, a 10-min baseline recording (without aortic occlusion) was obtained. Blood flow through the abdominal aorta was then periodically interrupted caudally from the branches of the renal arteries using the string wound around the abdominal aorta. These periodic occlusions were performed at eight different occlusion frequencies applied in a randomized order. The specific parameters for the periodic aortic occlusion protocol are provided in Table 1. The periodic aortic occlusion protocol was repeated during blockade of myogenic vascular function that was achieved by an intravenous bolus injection of the L-type Ca2+ channel blocker nifedipine (0.25 mg/kg body wt) (36). Effectiveness of Ca2+ channel blockade was confirmed by an immediate decrease in arterial blood pressure of roughly 20 mmHg. Ca2+ channel blockade was maintained by repeated intravenous bolus applications of 0.10 mg/kg body wt nifedipine every 20 min given between periodic occlusion sequences. At the end of the protocol, placement of the ultrasound Doppler flow probe on the right internal (versus external) carotid artery was confirmed by injection of blue ink into the artery and identification of stained cerebral arteries.


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  		Table 1. Periodic aortic occlusion protocol

 
Data analysis. From the original data files, the baseline recordings and the individual periodic aortic occlusion sequences were extracted, resulting in nine files under control conditions and nine files during inhibition of myogenic vascular function for each of the 10 animals. From the carotid artery pressure and internal carotid artery blood flow signals (sampled at 500 Hz), systolic, mean, and diastolic blood pressure, heart rate, internal carotid artery conductance (mean flow divided by mean blood pressure), and internal carotid artery resistance (mean blood pressure divided by mean flow) were derived on a beat-by-beat basis. These nonequidistant time series were interpolated (cubic spline) and resampled at an equidistant sampling rate of 12 Hz. The mean blood pressure time series were used to determine the amplitudes of the blood pressure oscillations elicited by the periodic aortic occlusions. This was done for each of the 10 occlusion cycles at each occlusion frequency. Mean values from all 12-Hz time series and from the amplitudes of the mean blood pressure oscillations elicited by the periodic aortic occlusions were used for statistical analysis.

Transfer function analyses between mean blood pressure (input function) and internal carotid artery blood flow (output function) and between mean blood pressure (input function) and internal carotid artery resistance (output function) were performed using an algorithm based on the fast Fourier transform and as described previously (10, 33, 34). Mean blood pressure was used for transfer function analysis, because myogenic vascular responses are slow. Because of the integrating properties of the cardiovascular system, we assume that changes in mean blood pressure are the driving forces that elicit myogenic responses. The squared coherence function {gamma}2(q) and the phase {phi}(q) and gain |H(q)| of the transfer functions were calculated on the basis of the autospectral density functions and the cross-spectrum of the input (mean blood pressure) and output (flow or resistance) functions. The unit of the gain |H(q)| of the transfer function is ml/(min·mmHg) for flow as the output function and min/ml for resistance as the output function. These units result from the definition of the gain, i.e., a change in flow (unit = ml/min) or resistance (unit = mmHg·min·ml–1) for a given change in mean blood pressure (unit = mmHg). For normalization, the gain of the transfer function was multiplied with internal carotid artery resistance for flow as the output function and with internal carotid artery blood flow for resistance as output function. The resulting normalized gains are without units and more easily allow comparison between experimental conditions with different baseline levels of arterial blood pressure or blood flow (control versus Ca2+ channel blockade). Passive vascular responses to pressure would result in large gains of the transfer function between mean blood pressure and flow (large change in flow for a given change in pressure), whereas autoregulation of blood flow would reduce the gain of this transfer function (less change in flow for a given change in pressure). For interpretation of the gain of the transfer function between mean blood pressure and resistance, the phase of the transfer function needs to be considered. This phase is expected to be in the range from 0 rad to –{pi} rad, because phases are defined to be negative if the input parameter (mean blood pressure) leads to output parameter (vascular resistance). In the case of perfect autoregulation, a change in pressure would elicit an immediate (no time delay) change in resistance in the same direction, indicated by a phase of 0 rad. For example, a pressure-induced increase in flow would be antagonized by a concomitant increase in vascular resistance. In the case of pure passive vascular responses, a change in pressure would elicit an immediate (no time delay) inverse change in resistance, indicated by a phase of –{pi} rad. For example, an increase in perfusion pressure would cause a decrease in resistance (and further increase in flow) due to passive distension of the blood vessels. Thus a large gain of the transfer function between pressure and resistance indicates proper autoregulation if the phase is close to 0 rad and passive vascular responses if the phase is close to –{pi} rad. For statistical comparisons, values for the squared coherence, the phase, and the normalized gains of the transfer functions were averaged in frequency bands (0.004–0.012, 0.010–0.024, 0.017–0.033, 0.020–0.046, 0.035–0.065, 0.08–0.12, 0.2–0.3, and 0.4–0.6 Hz) centered around each periodic occlusion frequency (listed in Table 1).

Statistics. All data are presented as means ± SE. Statistical comparisons were done by two-way analysis of variance (2-way ANOVA) for repeated measures with post hoc Fisher tests for individual comparisons. The two factors were the experimental condition (control vs. Ca2+ channel blockade) and the aortic occlusion frequency. Statistical significance was assumed for P < 0.05.


   RESULTS
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 METHODS
 RESULTS
DISCUSSION
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Figure 1 shows original recordings during control conditions and during inhibition of myogenic vascular function by Ca2+ channel blockade. In this recording, the abdominal aorta was periodically clamped and opened for 30 s each (cycle length 60 s, occlusion frequency 0.0167 Hz). Clamping the aorta caused a strong increase in cerebral perfusion pressure in the order of +20 mmHg. These periodic increases in carotid artery pressure were associated with tachycardia rather then bradycardia as would be expected from a baroreceptor-mediated heart rate response. This may be seen as an indication that the baroreceptor reflex was functionally inactive because of catheterization of the left carotid artery and placement of the Doppler flow probe on the right carotid artery. The tachycardia during aortic occlusion may be related to the Bainbridge reflex or other cardiopulmonary reflexes. Internal carotid artery blood flow initially increased in response to the rise in perfusion pressure. This increase in flow reached a steady state even before the full rise in perfusion pressure was established, indicating autoregulation of cerebral blood flow. The initial rise in internal cerebral artery blood flow was accompanied by an increase in vascular conduction and a decrease in vascular resistance secondary to the rise in perfusion pressure (passive distention). During the phase of steady-state blood flow, vascular conductance decreased and vascular resistance increased, which effectively opposed the rise in pressure and maintained internal carotid artery blood flow. When the aortic occlusion was opened, reverse effects, with elastic vascular recoil followed by active myogenic dilation, were observed. Nifedipine effectively blocked all active myogenic responses, and flow passively followed perfusion pressure. Thus changes in vascular conductance and resistance during Ca2+ channel blockade reflect passive vascular distension and elastic vascular recoil.


Figure 1
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  		Fig. 1. Original recording of carotid artery pressure (CAP), heart rate (HR), internal carotid artery blood flow (CBF), internal carotid artery conductance (CVC), and internal carotid artery resistance (CVR) during control conditions (Control, left) and Ca2+ channel blockade (Nifedipine, right). During this recording, the abdominal aorta was periodically occluded at a frequency of 0.0167 Hz (30 s occluded, 30 s open). The circles and arrows indicate active myogenic vasoconstrictions (left circles) and active myogenic vasodilatations (right circles). These active myogenic responses are absent during Ca2+ channel blockade. bpm, Beats/min.

 
At all periodic occlusion frequencies, systolic blood pressure and heart rate (except at the lowest frequency) were reduced by inhibition of myogenic vascular function by using the Ca2+ channel blocker nifedipine (Fig. 2). Again, the reduction in heart rate rather than a reflex tachycardia in response to nifedipine indicates that the baroreceptor reflex is not functional in this experimental setup. During control conditions, internal carotid artery blood flow was higher during the periodic aortic occlusion sequences than during the baseline recording (Fig. 2). This may be due to passive vascular distension in response to increased perfusion pressure, with myogenic vasoconstriction not fully restoring baseline levels of internal carotid artery blood flow. During Ca2+ channel blockade, no significant difference in internal carotid artery blood flow was observed between baseline conditions and periodic aortic occlusion, likely because baseline blood flow was already elevated during Ca2+ channel blockade. Nifedipine significantly reduced internal carotid artery resistance during baseline conditions, indicating loss of myogenic vascular tone (Fig. 2).


Figure 2
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  		Fig. 2. Group data for systolic blood pressure (SBP), CBF, HR, and internal carotid artery resistance (CR) during baseline conditions without aortic occlusion (base) and at increasing frequencies of periodic occlusion of the abdominal aorta during control conditions (open circles) and during inhibition of myogenic vascular function using the Ca2+ channel blocker nifedipine (closed circles) *P < 0.05 control vs. nifedipine; {dagger}P < 0.05 baseline conditions without occlusion vs. periodic aortic occlusion.

 
The amplitudes of the oscillations in mean blood pressure elicited by the periodic aortic occlusions are provided in Fig. 3. During control conditions, these amplitudes increased from high to low frequencies in a frequency-dependent manner. This frequency-dependent increase in the blood pressure amplitudes was less pronounced during Ca2+ channel blockade, resulting in lower amplitudes than during control conditions at occlusion frequencies of 0.05 Hz and below. The frequency-dependent increase in the blood pressure amplitudes with decreasing occlusion frequencies may be seen as a reflection of myogenic vascular function. Aortic occlusion increases perfusion pressure to vascular beds supplied from the aorta cranial to the occlusion site. These vascular beds respond to increased perfusion pressure with myogenic vasoconstriction, further increasing total peripheral resistance and blood pressure. During Ca2+ channel blockade, this effect is attenuated. The frequency dependency of the blood pressure amplitudes during control conditions suggests that myogenic vascular function is more efficient at lower frequencies (≤0.1 Hz in rats).


Figure 3
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  		Fig. 3. Amplitudes of mean blood pressure (BP) elicited by periodic aortic occlusion during control conditions (open circles) and during inhibition of myogenic vascular function using the Ca2+ channel blocker nifedipine (closed circles). *P < 0.05 control vs. nifedipine; {dagger}P < 0.05 baseline conditions without occlusion vs. periodic aortic occlusion.

 
During control conditions and during inhibition of myogenic vascular function by nifedipine, squared coherences between mean blood pressure and internal carotid artery blood flow and between mean blood pressure and internal carotid artery resistance at all aortic occlusion frequencies were greater than 0.5 (Fig. 4, top). This indicates that the oscillatory perturbations of cerebral perfusion pressure were translated into likewise oscillations of cerebral blood flow and cerebrovascular resistance.


Figure 4
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  		Fig. 4. Squared coherence (top) and normalized gain (middle) and phase (bottom) of the transfer function between mean arterial blood pressure (MAP) and CBF (left) or CR (right) during control conditions (open circles) and inhibition of myogenic vascular function using the Ca2+ channel blocker nifedipine (closed circles). For each animal, averages of the squared coherence, normalized gain, and phase values in frequency bands centered around the periodic aortic occlusion frequencies were extracted and used for statistical analyses. *P < 0.05 control vs. nifedipine; {dagger}P < 0.05 vs. values at highest occlusion frequency (0.5 Hz); #P < 0.05 vs. values at 0.05 Hz.

 
At aortic occlusion frequencies of 0.1 Hz and above, the normalized gains of the transfer functions between mean blood pressure and flow and between mean blood pressure and vascular resistance were ~2.0 and 1.0, respectively, and declined at occlusion frequencies below 0.1 Hz (Fig. 4, middle). The normalized gains of the transfer functions at occlusion frequencies below 0.1 Hz declined twice as much under control conditions (flow, –0.65 ± 0.09; resistance, –0.63 ± 0.09) than during inhibition of myogenic vascular function (flow, –0.31 ± 0.07; resistance, –0.26 ± 0.05; P < 0.05 vs. control conditions) by Ca2+ channel blockade (Fig. 4, middle).

During inhibition of myogenic vascular function, the phases of the transfer functions between mean blood pressure and flow and between mean blood pressure and resistance were close to 0 rad and –{pi} rad, respectively. The phase of 0 rad indicates that a change in pressure elicits an immediate (no time delay) change in flow in the same direction as the change in pressure. Thus a phase of 0 rad for the transfer function between pressure and flow is consistent with pure passive vascular responses, secondary to changes in pressure. The phase of –{pi} rad indicates that a change in pressure causes an immediate change in vascular resistance in the opposite direction. Thus a phase of –{pi} rad for the transfer function between pressure and vascular resistance is consistent with passive vascular distention (reduction in resistance) in response to an increase in pressure and with elastic vascular recoil (increase in resistance) in response to a decrease in pressure. It is important to note that, under control conditions (intact myogenic function), the phases of the transfer functions between pressure and flow were more positive, and the phases of the transfer functions between pressure and resistance were less negative than during inhibition of myogenic function (P < 0.05, 2-way ANOVA). This indicates that the passive vascular responses were opposed by active mechanisms, such as myogenic vascular function.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
The results of this study demonstrate that autoregulation of cerebral blood flow in rats is most effective for slow fluctuations in cerebral perfusion pressure with frequencies below 0.1 Hz. Faster fluctuations in cerebral perfusion pressure elicit passive changes in cerebral blood flow that are secondary to the fluctuations in pressure. These conclusions are based on transfer function analyses between cerebral perfusion pressure and cerebral blood flow and between cerebral perfusion pressure and cerebrovascular resistance calculated from recordings obtained during perturbations of cerebral perfusion pressure at eight different frequencies.

During aortic occlusion frequencies of 0.1 Hz and higher, the gains of the transfer functions did not differ between control conditions and Ca2+ channel blockade. In addition, the normalized gains did not change as the occlusion frequency was raised from 0.1 Hz to 0.25 Hz and to 0.5 Hz. These results indicate that cerebral blood flow in isoflurane-anesthetized rats responds in a purely passive manner to oscillations in perfusion pressure at frequencies of 0.1 Hz and higher. In contrast, when the aortic occlusion frequency was lowered below 0.1 Hz, the gains of the transfer functions declined significantly. Furthermore, the gains of the transfer functions declined twice as much during control conditions than during inhibition of myogenic vascular function at these lower occlusion frequencies. These findings indicate that the passive vascular responses seen at occlusion frequencies of 0.1 Hz and above are opposed by active vascular mechanisms, such as the myogenic vascular response, at occlusion frequencies below 0.1 Hz. The observation that the gains of the transfer functions also declined slightly during nifedipine application indicates that the dose of the Ca2+ channel blocker administered in this study did not completely block myogenic vascular function.

During Ca2+ channel blockade, blood pressure was lower than during control conditions. To account for the different blood pressure levels, we calculated normalized gains instead of absolute gains for the transfer functions. Nevertheless, for the purpose of this study, it is crucial that mean blood pressure remains above the lower limit of the operating range of cerebral blood flow autoregulation. The lower limit of cerebral blood flow autoregulation in rats has been reported to be at a mean blood pressure of ~60 mmHg (35). In our study, mean blood pressure was between 80 ± 3 mmHg (at baseline) and 87 ± 4 mmHg (at 0.025 Hz) during control conditions and between 61 ± 3 mmHg (at baseline) and 69 ± 4 mmHg (at 0.0167 Hz) during Ca2+ channel blockade, which is still within the operating range of cerebral blood flow autoregulation in rats. Although the mean blood pressure values were still in the operating range of cerebral blood flow autoregulation in rats, we cannot completely exclude the possibility that the lower blood pressure values during Ca2+ channel blockade have affected the gains and phases of the transfer functions.

The hypotensive action of Ca2+ channel blockers can induce a reflex-mediated increase in sympathetic nervous system activity (13, 21). In addition, autonomic neural control can have profound effects on dynamic cerebral autoregulation. Zhang et al. (39) reported that dynamic cerebral autoregulation was less effective after inhibition of autonomic nervous system activity by ganglionic blockade in humans. Thus one may speculate that increased sympathetic nervous system activity enhances effectiveness of cerebral autoregulation. However, it is unlikely that increased sympathetic nervous system activity in response to nifedipine infusion has enhanced effectiveness of dynamic autoregulation of cerebral blood flow in our experiments because autoregulation of cerebral blood flow largely depends on myogenic vascular function that relies on voltage-gated L-type Ca2+ channels (6, 7, 28, 36) that were blocked by nifedipine.

Another potential confounding factor is arterial carbon dioxide (CO2) (18). In this study, we did not measure blood gases. However, care was taken not to change the setting of the vaporizer used for anesthesia to keep blood gases constant throughout the experiments. In addition, the aortic occlusion frequencies were randomized. Therefore, time-dependent changes in arterial CO2 along the time course of the experiment should have affected all occlusion frequencies similarly. However, a limitation of our study is that we cannot completely rule out the possibility that blood gases differed between control conditions and Ca2+ channel blockade, because these two experimental conditions could not be randomized.

Interestingly, the dynamic properties of autoregulation of cerebral blood flow in rats are almost identical to those in humans. In our study, autoregulation of cerebral blood flow was found to be most effective in buffering oscillations of cerebral perfusion pressure at frequencies below 0.1 Hz. This corner frequency obtained in rats corresponds well with data in humans that reported upper limits for autoregulation of cerebral blood flow between 0.07 Hz and 0.15 Hz (12, 17, 22, 24, 38, 39). For example, Zhang et al. (38) performed transfer function analysis between arterial blood pressure and middle cerebral artery blood flow velocity, recorded by transcranial Doppler ultrasonography. Similar to our results obtained in rats, the gain of the transfer function declined substantially with decreasing frequency between 0.2 Hz and 0.07 Hz in humans (38). This fall in transfer function gain at lower frequencies was interpreted as a high-pass filter in the relationship between cerebral perfusion pressure and cerebral blood flow velocity, and the authors concluded that cerebral autoregulation is most effective at frequencies below 0.07 Hz. The authors further concluded that autoregulatory processes became less capable to stabilize cerebral blood flow in the face of changing perfusion pressure in the frequency range between 0.07 Hz and 0.2 Hz (38). In our study in anesthetized rats, the gain of the transfer functions decreased with decreasing frequency in the frequency range between 0.1 Hz and 0.0167 Hz, which overlaps with the corresponding frequency range in humans (38). Thus, our data suggest that dynamic properties of cerebral autoregulation in rats are very similar to those in humans.

Dynamic autoregulation of blood flow in rats has been studied in the mesenteric (1) and the renal (1, 5, 9, 11, 16) circulations. These studies suggest that dynamic autoregulation in rats operates up to ~0.2 Hz in the renal circulation and up to ~0.13 Hz in the mesenteric vasculature (1). Our results indicate that cerebrovascular autoregulation can operate up to 0.1 Hz. The slightly different frequency response characteristics in different vascular beds may be related to different mechanisms contributing to blood flow autoregulation in various local circulations. For example, in the renal circulation, myogenic vascular function mediates faster components of dynamic autoregulation than the tubuloglomerular feedback (16), which does not contribute to autoregulation of blood flow in other vascular beds. In addition, the time course of myogenic vascular responses to changes in perfusion pressure may differ in various vascular beds. Finally, different experimental conditions, such as mode of anesthesia, technique used to perturb perfusion pressure, strain of animals, and other factors, may also explain the slightly different dynamic properties of autoregulation found in different vascular beds in rats.

Another important aspect of our study concerns the use of blood pressure variability as an index of sympathetic modulation of vascular tone, the so-called Mayer waves (19). Previous studies (3, 15, 32) have demonstrated that sympathetic modulation of vascular tone specifically affects blood pressure variability in the low-frequency band between 0.2 Hz and 0.6 Hz in rats. Since autoregulation of blood flow requires continuous adjustments of vascular resistance, autoregulation of blood flow may add to blood pressure variability. Therefore, the question arises whether the frequency band of sympathetic modulation of vascular tone overlaps with the frequency band of blood pressure variability that is affected by myogenic vascular function and/or autoregulation of blood flow. Our data together with the data on dynamic autoregulation in the mesenteric (1) and renal (1, 5, 9, 11, 16) circulations suggest that this is not the case in rats. If myogenic vascular function and/or autoregulation of blood flow affect blood pressure variability, then the frequency range would be located below 0.2 Hz, the corner frequency of renal autoregulation. However, in humans, the low-frequency band of sympathetic-mediated blood pressure Mayer waves is located between 0.075 Hz and 0.15 Hz, and dynamic autoregulation of cerebral blood flow has been suggested to operate up to a frequency of 0.15 Hz (22, 27). Thus, in humans, there is substantial overlap in the frequencies of blood pressure variability affected by sympathetic modulation of vascular tone and myogenic vascular function and/or autoregulation of blood flow. Thus low-frequency blood pressure variability may not be an exclusive marker for sympathetic modulation of vascular tone in humans. In contrast, in rats, low-frequency blood pressure variability (0.2–0.6 Hz) is not affected by myogenic vascular function and/or autoregulation of blood flow, which affects very low frequency (0.02–0.2 Hz) blood pressure variability.

In conclusion, our study demonstrates that autoregulation of cerebral blood flow in rats is most effective in buffering fluctuations in perfusion pressure at frequencies below 0.1 Hz. These dynamic properties of cerebral autoregulation in rats are almost identical with those reported in humans.


   GRANTS
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This research was supported by a grant from the American Heart Association (AHA 0630329N) and a generous start-up package provided to H. M. Stauss by the College of Liberal Arts and Sciences at The University of Iowa (Iowa City, IA).


   FOOTNOTES
 

Address for reprint requests and other correspondence: H. M. Stauss, Dept. of Integrative Physiology, Univ. of Iowa, 410 Field House, Iowa City, IA 52242 (e-mail: harald-stauss{at}uiowa.edu)

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
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 METHODS
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 DISCUSSION
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