Assessment of parameters influencing the blood flow velocities in cerebral arteries of the rat using ultrasonographic examination

Dorothee Kreis, Dirk Schulz, Marco Stein, Matthias Preuss, Ulf Nestler
Department of Neurosurgery, Justus Liebig University, Giessen, Germany Objectives: Rat models of cerebrovascular diseases are used for a variety of human pathologies comprising ischemic stroke or subarachnoid hemorrhage. Whereas in neuro-intensive care, Doppler ultrasonographic examination of major cerebral arteries is a common diagnostic tool, only few data exist concerning the animal model. We therefore studied cerebral blood flow velocities in the rat by ultrasonographic triplex mode. Methods: Female Wistar rats underwent a large craniectomy and baseline values for blood flow velocities were obtained by 399 examinations in 52 animals. Vessel diameters were assessed by 301 examinations in 39 animals. Finally, in 26 animals, continuous measurements of blood flow velocities were performed. For a duration of more than 30 minutes, values in the anterior trunk, the left carotid artery and the basilar artery were obtained every 6090 seconds with simultaneous detection of heart rate. Results: Blood flow velocities in the anterior part of cerebral circulation were faster than those in the posterior part and showed higher standard deviation. Flow velocities in arteries belonging to the anterior circulation changed in relation to carotid flow velocity and heart rate, whereas the velocity in the basilar artery showed much lower correlation to carotid flow velocity or heart rate. Discussion: Ultrasonographic triplex mode examination of cerebral vessels offers a reproducible method to study rat cerebral blood flow velocities and vessel diameters. In combination with monitoring of systemic hemodynamic parameters, it can provide a detailed description of the vascular response to drugs, experimental stroke or subarachnoid hemorrhage.
Keywords: Blood flow velocity, Cerebral vessels, Doppler mode, Rat, Ultrasonography

Introduction
Cerebrovascular diseases exert a considerable impact on human health. In order to improve treatment and to assess new therapeutic options, a number of animal models have been established, many of which employ rats. In the experimental setting, diagnostic work-up can be achieved with sophisticated equipments such as magnetic resonance imaging (MRI),1 angiography,2 or laser owmetry,3 but these modalities are not available on a daily base in most clinical settings. On the other hand, ultrasonographic examination of cerebral vessels is readily available on neuro-intensive care units but has only been described a few times in rat models of cerebrovascular disease.47 In order to further characterize this model and to assess the feasibility of ultrasonographic examination for experimental use, baseline values of cerebral blood ow velocities and vessel sizes in female
Correspondence to: Ulf Nestler, Department of Neurosurgery, Justus Liebig University, Klinikstrasse 29, D-35392 Giessen, Germany. Email: ulf.nestler@neuro.med.uni-giessen.de

Wistar rats were determined. Results were analyzed in regard to body weight, dosing of anesthesia and correlation of anterior to posterior circulation. A subset of animals underwent continuous measurements of blood ow velocities in three cerebral vessels with registration of the actual heart rate.

Materials and Methods

Female Wistar rats were obtained from the breeding facility at the laboratories of physiology at the University of Giessen. The experiments had been approved by the local animal welfare board and all animal procedures were performed according to the National Institutes of Health Principles of Laboratory Animal Care. The experimental techniques were performed as previously described in detail.4 After the extended craniectomy, the animals were given time for wound healing, so that the rst ultrasonographic examinations were performed 5 7 days later. After induction of anesthesia, the triplex mode of the linear matrix-array probe VFX 13-5 (Sonoline Elegra; Siemens, Erlangen, Germany) was

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used to display simultaneously B mode picture, color mode, and Doppler examination of selected vessels with angle correction. In short, the mean blood ow velocity (time averaged mean ow velocity) was derived graphically using the enveloping curves of the Doppler signals. After angle correction and having obtained a clear signal, the mean ow of several pulsations was averaged in a time window depicted manually by the examiner including about 1520 heartbeats, the number of which depends on heart rate and quality of the signals. The examination followed a standardized scheme with determination of ow velocities and vessel diameters in ve section planes from anterior to posterior and nally a sagittal view for the pericallosal artery. In 52 animals, blood ow velocities were determined, and in 39 of them, vessel diameters were recorded during the examination. For determining the baseline normative values, each animal was examined at least ve times, with the minimal interval between two examinations being 2 days. For determination of vessel diameters, B mode was combined with power mode. The power mode acquisition characteristics were set to a high spatial resolution with an increased sensitivity for small tissue movements. The ash-lter was tuned to medium accuracy in order to avoid estimation bias caused by the pulsatile velocity changes. After stabilization of the power mode signals, the picture was frozen and the diameters were assessed by setting the callipers on the edges of the color trace. In 26 of the 52 animals, continuous measurements were performed. For continuous assessment of ow velocities in the anterior trunk, in the left carotid artery and in the basilar artery, all 26 animals received an intraperitoneal injection of a mixed solution of ketamine and xylazine in physiological sodium chloride containing 25 mg ketamine/ml and 5 mg xylazine/ml. Narcotics dose was calculated as microliter solution per gram body weight. As soon as the animal stopped moving, measurements were performed until the animal woke up and withdrew its head from the ultrasonographic probe.

After induction of anesthesia, the ow velocities in the anterior cerebral trunk, the left carotid artery and the basilar artery were assessed serially one after another. These vessels all lie in the sagittal plane and can be visualized as linear structure in coronary views. Thus, there is no need for angle correction and the blood ow is directed upwards to the sonographic probe. Between the serial measurements, the heart rate was determined every 60 seconds. This scheme was repeated until the animal woke up, usually 45 60 minutes after the start of anesthesia. For calculation of baseline values, the measurements of every animal were averaged, resulting in 52 mean values. These mean values were averaged once more to give a normative value for the population (Table 1). Baseline values for vessel diameters were similarly calculated from data of 39 animals. In these 39 animals, the data for blood ow velocity and vessel diameter were used to calculate the volumetric ow rate, assuming a tubular shape of the vessels according to the following formula8
Q~Av~1=4pd 2 v

where Q is the volumetric ow rate (in cm3/s; Table 1), A is the cross-sectional area of the vessel (in cm2), v is the blood ow velocity (in cm/s), and d is the vessel diameter (in cm) (1 cm351 ml). The heart rate was derived from the frozen Doppler trace evaluating three heart cycles. After obtaining the velocity measurements, three systolic complexes were highlighted manually and the Elegra system calculated the heart rate from the systolic peak distances in relation to the examination time base. Statistical analysis was performed with Predictive Analytics Software Statistics 17.0 (SPSS Inc., Chicago, IL, USA) using non-parametric, two-sided tests. Results were considered to be signicant with P values below 0.05.

Results Normative values

The baseline values obtained for blood ow velocity and for vessel diameter are given in Table 1. In
diameters (301

Table 1 Normative values of blood ow velocities (399 measurements in 52 animals), vessel measurements in 39 animals), and calculated volumetric ow rates (301 measurements in 39 animals) Artery Pericallosal Anterior trunk Left anterior Right anterior Left carotid Right carotid Left middle Right middle Left posterior Right posterior Basilar Flow velocity (cm/s) 7.121.62 9.072.37 8.732.09 8.111.65 9.792.16 10.062.12 8.602.02 8.141.90 5.250.92 5.121.00 5.901.25 Vessel diameter (mm) 0.660.11 0.730.14 0.610.14 0.600.14 0.830.13 0.820.11 0.500.16 0.490.14 0.560.15 0.570.13 0.590.14

Volumetric flow rate (ml/s) 23.706.94 38.4211.83 27.9412.40 23.4510.82 53.6612.91 52.3410.35 18.5611.37 16.589.47 12.905.68 12.865.13 16.577.47

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general, blood ow velocities in the anterior circulation (comprising pericallosal artery, anterior trunk, anterior arteries, middle cerebral arteries, and carotid arteries) were 24 cm/s higher than those in the posterior circulation (basilar artery and posterior cerebral arteries). The anterior circulation velocities showed high standard deviations of 1.52.5 cm/s whereas deviations in the posterior circulation ranged around 1 cm/s. The vessel diameters were in the range of half a millimeter. Largest diameters up to and above 1 mm were found in the carotid arteries, followed by the unpaired cerebral arteries and the anterior arteries. Smallest sizes were measured in the paired vessels supplying hemispheres such as median arteries and posterior arteries. The volumetric ow rate ranged from 12 ml/s in the posterior arteries to more than 50 ml/s in the carotid arteries with considerable standard deviations.

When comparing the inter-vessel relationship, mean ow velocities in the anterior trunk correlated signicantly to velocities in all other vessels, except for the right middle cerebral artery. The left carotid artery velocities were in signicant relation to six of the 10 other arteries. The basilar velocity correlated signicantly to the anterior trunk and the pericallosal values, and a high signicance (P,0.01) was found concerning both middle and both posterior arteries. In contrast to the varying inter-vessel relationships for mean velocities, the mean vessel diameter and the calculated volumetric ow rate displayed for all vessel to vessel comparisons a highly signicant correlation (P,0.01).

Volumetric flow rate calculations

As internal control for the plausibility of the obtained data, estimated mean volume ow results were used to summarize blood streams in the cerebral vessels. The following assumptions were checked and conrmed (Table 1). On both hemispheres, the sum of the volume outow rates in median and anterior arteries was lower than the inowing volume rate from the carotid artery. The pericallosal volume ow rate (23.7 ml/s) was lower than the volume ow rate in the anterior trunk (38.4 ml/s) and the latter was lower than the sum of both anterior artery rates (51.4 ml/s). Concerning the posterior circulation, it is noteworthy that the inow volume rate from the basilar artery (16.6 ml/s) provided about 8 ml/s less than needed for the two posterior arteries (together 25.8 ml/s). This means that about one-third of the posterior artery volume ow rate was supplied from the carotid arteries, which is coherent with the result that the volume ow rate sum of anterior and middle arteries together with one-third of the posterior ow was less than the carotid volume ow rate.9

Comparison of values in the complete dataset (Table 2)

Overall relationship of velocity, diameter, volumetric ow rate, and weight, obtained in the 11 arteries, was analyzed using the two-sided Spearmans rank correlation coefcient (left column in Table 2). Blood ow velocity correlated signicantly with weight (n5572, P,0.01) and with vessel diameter (n5429, P,0.01). Heavier animals showed higher mean blood ow velocities and in larger vessels, a trend to higher velocities was found. In contrast to this, mean vessel diameters were negatively correlated to body weight (n5429, P,0.01). Heavier animals had more narrow vessels. Concerning the calculated values for volumetric ow rate, a slightly negative correlation to body weight was detected (n5429, P,0.05). Since the volume had been calculated using ow velocity and vessel diameter, highly signicant correlations (n5429, P,0.01) were found for these parameters.

Impact of narcotic drugs

During the continuous measurements, in addition to the detection of ow velocities in the three different vessels, heart rate was measured every minute and the overall duration of anesthesia was noted. In principle, during anesthesia, the heart rate rst dropped quickly, followed by a slower decrease to reach a minimum beats per minute, and this was followed by a quick rise of heart rate which then slowed asymptotically to the heart rate at waking up. Animals receiving a higher dose of narcotics per gram had deeper minimum heart rates and displayed longer duration of anesthesia when compared to animals with lower doses. Interestingly, the minimum heart rate correlated exponentially to the time point after injection at which the minimum heart rate was reached. Deeper minimal values were reached later during sleep than more shallow minimal values.

Comparison of values in individual vessels (Table 2)

The three parameters, velocity, diameter, and volumetric ow rate were then compared vessel by vessel to each other and to body weight, with special emphasis on the relations of the anterior trunk, the left carotid artery and the basilar artery (right columns in Table 2). It became evident that in several arteries, the mean velocities were signicantly correlated to vessel diameter but with inverse proportionality. Concerning the relationship between mean vessel diameter and weight, the negative correlation was conrmed in all arteries. With a view to the calculated volumetric ow rate, the relation to diameter was highly signicant in every vessel.

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Table 2 Correlations of mean values for velocity, diameter, volumetric ow rate and weight for the complete dataset and comparison on an individual vessel level

Individual vessels

2011

Correlations

Complete dataset

Pericallosal

Anterior trunk

Anterior left

Anterior right

Media left

Media right

Carotis left

Carotis right

Posterior left

Posterior right

Basilaris

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Yes** Yes**

NO .

Velocity to weight (n552) to diameter (n539) to anterior trunk to left carotid artery to basilar artery Yes** Yes** (2) Yes** Yes* Yes* No (2) Yes** Yes** No No No (2) Yes** Yes** No Yes** No Yes** No Yes** Yes* Yes* No No Yes** Yes** Yes** (2) Yes** No (2) Yes** Yes** (2) Yes** Yes** No

Yes** Yes** (2) Yes** No Yes*

Yes** Yes** (2) Yes** Yes** Yes**

Yes** Yes** (2) Yes** Yes* Yes**

Yes** No Yes* No (2)

Diameter No (2) Yes** Yes** No (2) Yes** Yes** Yes** Yes* (2) Yes** Yes** Yes** Yes** (2) Yes** Yes** Yes** Yes* (2) Yes** Yes** Yes** No (2) Yes** Yes** Yes* (2) Yes** Yes** Yes** Yes** (2) Yes** Yes** Yes** Yes* (2) Yes** Yes** Yes** Yes* (2) Yes** Yes**

to to to to

weight (n539) anterior trunk left carotid artery basilar artery

Yes** (2)

No (2) Yes** Yes** Yes**

Volumetric flow rate No No Yes** Yes** Yes** No (2) No Yes** Yes** Yes** Yes** No (2) No Yes** Yes** Yes** Yes** Yes* (2) Yes* Yes** Yes** Yes** Yes** No (2) Yes** Yes** Yes** Yes** Yes** No (2) No (2) Yes** Yes** Yes** No (2) No Yes** Yes** Yes** Yes** Yes* (2) No (2) Yes** Yes** Yes** Yes** No (2) No (2) Yes** Yes** Yes** Yes** No (2) Yes* Yes** Yes** Yes**

to to to to to to

weight (n539) velocity (n539) diameter (n539) anterior trunk left carotid artery basilar artery

Yes* (2) Yes** Yes**

No (2) No Yes** Yes** Yes** Yes**

Note: *Two-tailed correlation is significant at the 0.05 level. **Two-tailed correlation is significant at the 0.01 level. No: P.0.05. (2): Negative proportionality. : Not applicable.

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Figure 1 Correlation of mean blood flow velocities in three cerebral vessels to the heart rate. Illustrative plot of one animal, the incline of the regression line for the basilar artery is less than half of the incline for the two other arteries. This pattern was found in 19 out of 26 animals (73.1%).

Animals with a deep minimal value had longer lasting anesthesia, but this correlation was less pronounced (data not shown). In contrast, the heart rate at waking up neither correlated to the minimal heart rate nor to the duration of anesthesia nor to the weight of the animal.

Relationship of flow velocity to heart rate

In each of the three vessels (anterior trunk, left carotid artery, and basilar artery), an overall regression analysis of continuous measurements from all 26 animals was performed correlating the mean blood ow velocity versus the heart rate. The inclination of the regression lines was 0.009 for the carotid artery, 0.011 for the basilar artery and 0.015 for the anterior trunk. This reveals an increase in ow velocity of about 1 cm/s for every 100 beats per minute heart rate acceleration. A more detailed picture was obtained by analysis of the relationship on an individual animal level (Fig. 1). In 19 of the 26 animals (73.1%), the blood ow velocity in the basilar artery showed no or a low correlation to the heart rate, whereas velocities in the anterior trunk and left carotid artery correlated linearly. This was mirrored by the relationship of ow velocities in the vessels when compared to each other. Using linear regression analysis, the correlation coefcient between the increase in ow velocity in the basilar artery and that in the carotid artery was determined, and the same was done for the anterior artery. It became obvious that in all but two animals (92.3%), the correlation between anterior velocity and carotid velocity was more than two times higher than

the corresponding correlation between basilar artery and carotid artery (Fig. 2). There was no animal with a correlation coefcient of more than 0.5 between basilar artery and carotid artery; even more, in seven animals a negative correlation was found. In contrast to this, when comparing anterior and carotid artery, only two animals displayed a negative correlation, and the correlation coefcient of 15 animals (57.7%) had a proportionality of 0.5 or higher (Fig. 2). These different velocity relationships of the anterior trunk and the basilar artery to the carotid ow were similar to the inter-vessel comparisons obtained from the mean value population (Table 2).

Discussion
There are few comparable publications dealing with the ow velocity in rat cerebral arteries. Ultrasonographic examinations have been performed in newborn rats with slightly differing results,5 and in male adult Wistar rats, using a stereotactic micromanipulator for selective assessment of the basilar artery, providing a similar mean velocity.6 Most recently, transcranial measurement without prior craniectomy focusing on timeaveraged maximum velocities has been proposed.7 As examined in adult male SpragueDawley rats, the baseline maximum ow velocities were roughly in the range of the results in our model. One study used MRI to assess ow velocities and vessel diameters in adult male Wistar rats.1 Much higher ow velocities were described than in our model, and, contrasting to all ultrasonographic publications, more peripheral arteries showed higher ow velocities. Vessel diameters were about half of the sizes determined in the present study. For volumetric ow

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Figure 2 The correlations of increase in carotid flow velocity to that in basilar artery and of carotid to anterior artery were determined by linear regression analysis. On the x-axis, the coefficient for the basilar artery was plotted, on the y-axis, the coefficient for the anterior artery. The diagonal line shows y52x, meaning the increase in flow velocity in the anterior artery is more than twice-fold the increase in the basilar artery (per cm/s increase in the carotid flow velocity) when the point is above the line. Values near 0 indicate no correlation, and values near 1 indicate strong proportionality.

rate estimations, when considering the different vessel sizes, a good agreement of results for the middle cerebral arteries and the anterior arteries with the values presented here was found. In comparison with other publications describing cerebral vessel diameters, our method of power Doppler mode measurement constantly determined higher values.1013 This is partly due to the many different techniques employed for the measurement, which ranged from assessing the inner diameter of the vessels on histological slides over MRI to angiography. Since the diameter d of the vessel enters the formula for volumetric ow rate Q with second potency, small inaccuracies result in high deviations of the estimated owing volume.14 Thus, the absolute values of the volumetric ow rates presented here have to be interpreted cautiously, but relating them to each other allows for description of ow characteristics. In view of the results in the literature, we have already rened the ultrasonographic acquisition mode for vessel diameters. The power mode priority was set to high sensitivity for low ow with a medium correlation for smoothening of pulsatility. Thus, the detection of minute tissue movements with a high spatial resolution remains feasible. From a technical point of view, the lower limit of two-point discrimination is about 0.2 mm when using a 12 MHz ultrasonographic probe in B mode. All vessel diameters in the present study were at least twice this detection limit (Table 1). In heavier animals, we observed increased ow velocities and narrowed vessel diameters (Table 2). Since in our population older animals had higher

weights, this is consistent with an observational study in aging male Fischer-344 rats, in which older animals were heavier and had a higher cardiac output, resulting in a rather constant cardiac index.15 Among further interesting observations are the hemispheric lateralization of blood ow and the occurrence of different vessel sizes when comparing right to left, which both have been very pronounced in some animals (Table 1). Similarly, vascular asymmetries have been reported in different rat strains as well as in human subjects and the hemispheric variation of the main blood supply has been referred to as processes during fetal development.7,9,10 An intriguing nding is the apparent stability of blood ow velocities in the posterior circulation, especially in the basilar artery. Whereas the vessel diameter is anatomically determined, the functional parameter ow velocity seems to be regulated in the basilar artery. Whether this is a passive upstream ow reduction because of the winding anatomy and reduced size of vertebral arteries or whether this is an active down-regulation of ow in order to protect the fragile pontine arterial network has to be examined in further studies. Our results suggest an active regulation, because in the normative dataset, basilar ow velocity is independent from vessel diameter whereas ow velocities in the left carotid artery and the anterior trunk change with vessel size (Table 2). This is supported by certain histological ndings such as regional differences in potassium channel reactivity between supratentorial cerebral arterioles and brain stem vessels.16 A passive downstream regulation, exerted through the microvascular

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resistance of the dependent vascular territories, has to be taken into consideration, too. Many models of cerebral vasospasm after experimental subarachnoid hemorrhage focus on changes in the basilar artery. In view of the results presented here, it seems helpful to extend the examination to other vessels and to detect simultaneously vessel diameter and ow velocity, if necessary several times a day. This will allow describing the time course of the vasospastic response and to depict potential compensatory vasodilation in the non-vasospastic vessels.17 The ultrasonographic triplex mode enables observation of vessel occlusion in experimental stroke models.7 Real-time examination during intervention might reveal the extent and duration of occlusion, as well as volume diversion or cross-ow from other vascular territories into the zone of occlusion.

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Summary
Our results show the feasibility of ultrasonographic triplex mode examination for the assessment of blood ow in major basal cerebral vessels in a rat model. The technique enables real-time simultaneous monitoring of ow velocity, vessel diameter, and heart rate. In combination with continuous blood pressure assessment, the technique might be of use in stroke models, experimental subarachnoid hemorrhage, or in studying effects of specic drugs on cerebral autoregulation.

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References
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