Regional blood flow of experimental brain tumors with special reference to effects of chemotherapy and radiotherapy

Regional blood flow and capillary permeability in the experimental brain tumors and their surrounding brain tissue of rats were measured with quantitative 14C-antipyrine and 14C-alpha-aminoisobutyric acid (AIB) autoradiographic method. The pharmacokinetic implications with respect to drug delivery to tumor tissue and the effect of ionizing irradiation were discussed in these physiological measurement. A suspension of 1 X 10(4) rat glioma cells (E239 RG 12) was stereotactically implanted into the right basal ganglia of CD-Fisher rats, and spherical brain tumors developed 10-17 days after implantation with a diameter of 1--5 mm. Autoradiographic investigations were performed for rats with small tumors (1--2 mm in diameter) and large tumors (4--5 mm in diameter). The uniform blood flow (91.7 +/- 13.1 ml/100 g/min: mean +/- S.E.) was observed in small tumors with the patchy low flow area (56.7 +/- 12.5 ml/100 g/min) surrounding the tumor. In large tumors, the blood flow was markedly decreased in the central part of the tumor (28.3 +/- 2.4 ml/100 g/min) with a ring shaped high flow area in the peripheral part (59.3 +/- 5.9 ml/100 mg/min). The blood flow in the brain adjacent to the tumor (30.5 +/- 2.5 ml/100 g/min) was lower than that in the peripheral part of the tumor. The uptake of 14C-AIB was quite similar to that of 14C-antipyrine suggesting the smaller permeability in the central part of the tumor. Neuropathological studies did not reveal necrotic foci, but viable cells in these areas.(ABSTRACT TRUNCATED AT 250 WORDS)     

Positron emission tomography (PET) study in patients with meningiomas

Regional hemocirculation and metabolism were evaluated in five patients with meningiomas using positron emission tomography (PET). Histological diagnoses were: two cases of meningotheliomatous type, one hemangiopericytic type, one fibroblastic type, and one transitional type. Regional cerebral blood flow (rCBF), blood volume (rCBV), oxygen extraction fraction (rOEF), and metabolic rates of oxygen (rCMRO2) and glucose (rCMRG1) were measured with 15O2, C15O. 15O2, and 18F-fluorodeoxyglucose tracers. For the quantitative analysis, regions of interest were delineated on tumors, the peritumoral region, and the contralateral gray matter in comparison with age-corresponding 5 malignant gliomas and 5 normal volunteers. Tumor hemocirculatory parameters (rCBF: 57.2 +/- 22.6 ml/100 ml/min, rCBV: 7.95 +/- 3.27 ml/100 ml, mean + SD, n = 5) were markedly higher than those of the contralateral gray matter (p less than 0.05 by a Student-t test). The high values were consistent with angiographic findings of tumor staining and with abundant tumor vessels demonstrated by pathological examination. rCMRO2 was 2.15 +/- 0.80 ml/100 ml/min, which were comparable to those of the contralateral gray matter. Tumor rCMRG1 showed 4.76 +/- 2.37 mg/100 ml/min; the values of two cases were similar to the respective gray matter. The raised metabolic rate (rCMRO2/rCMRG1) therefore suggests rather aerobic glycolysis as compared with gliomas. Low rOEF (0.26 +/- 0.16) reveals an excessive blood flow beyond oxygen demand of the tumor. In the peritumoral regions, rCBF and metabolism fell slightly but rOEF reached a level similar to the contralateral gray matter, possibly due to hemocirculatory stasis caused by intracranial hypertension; in contrast, an unmatched reduction of rCBF and rCMRO2 implies tumor cells infiltration in gliomas.(ABSTRACT TRUNCATED AT 250 WORDS)     

In vivo disturbance of the oxidative metabolism of glucose in human cerebral gliomas

Abnormalities in the oxidative metabolism of glucose in human cerebral gliomas have been studied in seven patients using positron emission tomography. Measurements of regional cerebral blood flow and oxygen consumption were obtained using the oxygen-15 steady-state inhalation technique. Values of regional cerebral glucose consumption were obtained using fluorine 18-labeled 2-fluoro-2-deoxy-D-glucose and a simplification of the method of Sokoloff. Functional values were obtained for regions of tumor and brain tissue in the middle cerebral artery territory of the contralateral cortex. Values of regional glucose consumption were calculated for both regions using a value of the lumped constant quoted for normal brain tissue (0.42). Tumor regional cerebral blood flow was comparable to that in the contralateral cortex, whereas regional cerebral oxygen consumption was depressed. This depression resulted in low tumor values of the fractional oxygen extraction ratio (0.21 +/- 0.07), indicating that oxygen supply exceeded the metabolic demand. In contrast, tumor regional cerebral glucose consumption was not depressed and regional glucose extraction ratios were similar for tumor and brain tissue. The metabolic uncoupling between regional oxygen consumption and regional glucose consumption (CMRO2/CMRGlu = 0.24 +/- 0.07 ml of oxygen per milligram of glucose) is indicative of increased aerobic glycolysis.     

Influence of total body hyperthermia on normal brain tissue

The influence of total body hyperthermia (TBHT) on normal brain tissue was studied in 40 dogs. The dogs were anesthetized with sodium thiopental (10 mg/kg/hr) intravenously, and were ventilated by artificial respirator. The TBHT was induced by extracorporeal circuit in cooperating a heat exchanger. Rectal temperature was raised to 41.5 degrees C and maintained at 41. 5 -42.0 degrees C for 2 hr (HT period) and was then fallen to normothermia by cooling, Regional cerebral blood flow (CBF) was measured by hydrogen clearance method before heating, during and after TBHT treatment. Brain temperature, rectal temperature, intracranial pressure (ICP), brain tissue pH and electroencephalography (EEG) were monitored continuously during TBHT. Histopathological changes of the brain tissue were studied in dogs killed just after TBHT and 2 weeks after TBHT. Autoregulation of the CBF during HT period was assessed by measuring the regional CBF and the ICP at a state of induced hypo- or hypertension. The brain temperature (at the depth of 5mm under the brain surface) was usually 0.6 degrees C lower than the rectal temperature during HT period. The regional CBF increased from 38.1 +/- 6.5 (mean +/- SD) to 49.1 +/- 9.8ml/100 g/min by raising rectal temperature, and it recovered to a normal value after cooling. The ICP increased from 10.3 +/- 4.2 to 16.8 +/- 3.4 mmHg by raising rectal temperature, and it returned to a normal value after cooling. Brain tissue pH decreased from 7.33 +/- 0.02 to 7.17 +/- 0.09 rapidly when the rectal temperature reached 41.0 degrees C, and then returned to a normal value gradually after the start of cooling.(ABSTRACT TRUNCATED AT 250 WORDS)     

Influence of moderate and profound hyperventilation on cerebral blood flow, oxygenation and metabolism

OBJECTIVE: The aim of the present study was to examine the impact of moderate and profound hyperventilation on regional cerebral blood flow (rCBF), oxygenation and metabolism. MATERIALS AND METHODS: Twelve anesthetized pigs were subjected to moderate (mHV) and profound (pHV) hyperventilation (target arterial pO(2): 30 and 20 mmHg, respectively) for 30 min each, after baseline normoventilation (BL) for 1 h. Local cerebral extracellular fluid (ECF) concentrations of glucose, lactate, pyruvate and glutamate as well as brain tissue oxygenation (p(ti)O(2)) were monitored using microdialysis and a Licox oxygen sensor, respectively. In nine pigs, regional cerebral blood flow (rCBF) was also continuously measured via a thermal diffusion system. RESULTS: Both moderate and profound hyperventilation resulted in a significant decrease in rCBF (BL: 37.9+/-4.3 ml/100 g/min; mHV: 29.4+/-3.6 ml/100 g/min; pHV: 23.6+/-4.7 ml/100 g/min; p<0.05) and p(ti)O(2) (BL: 22.7+/-4.1 mmHg; mHV: 18.9+/-4.9 mmHg; pHV: 13.0+/-2.2 mmHg; p<0.05). A p(ti)O(2) decrease below the critical threshold of 10 mmHg was induced in three animals by moderate hyperventilation and in five animals by profound hyperventilation. Furthermore, significant increases in lactate (BL: 1.06+/-0.18 mmol/l; mHV: 1.36+/-0.20 mmol/l; pHV: 1.67+/-0.17 mmol/l; p<0.005), pyruvate (BL: 46.4+/-7.8 micromol/l; mHV: 58.0+/-10.3 micromol/l; pHV: 66.1+/-12.7 micromol/l; p<0.05), and lactate/glucose ratio were observed during hyperventilation. (Data are presented as mean+/-S.E.M.) CONCLUSIONS: Both moderate and profound hyperventilation may result in insufficient regional oxygen supply and anaerobic metabolism, even in the uninjured brain. Therefore, the use of hyperventilation cannot be considered as a safe procedure and should either be avoided or used with extreme caution.     

Effect of hypertension on the integrity of blood brain and blood CSF barriers,cerebral blood flow and CSF secretion in the rat

Hypertension has been related to the development of brain damage, dementia and other CNS dysfunctions. Disruption of the blood-brain barrier (BBB) is thought to contribute to these disorders. In this study, the integrity of both blood-brain and blood-CSF barriers during chronic hypertension was investigated. For this, the entry of [14C]sucrose and of lanthanum into brain tissue, choroid plexus, and CSF was studied. Also brain regional blood flow and brain [14C]sucrose volume of distribution were measured using indicator fractionation and ventriculo-cisternal perfusion methods, respectively. The above measurements were performed in normotensive (WKY) rats and in the spontaneously hypertensive rats (SHR). Choroid plexus and CSF uptakes of [14C]sucrose were found to be significantly greater in SHR compared to WKY rats (P<0.05). Intercellular entry of lanthanum was observed in choroidal tissue of SHR but not in that of WKY rats and at the BBB. Choroid plexus blood flow was significantly greater in SHR, 2.82+/-0.21 ml g(-1) min(-1), compared to 2.4+/-0.08 ml g(-1) min(-1) in WKY (P<0.05). There were no significant differences (P>0.05) in brain % water content and extracellular fluid [14C]sucrose volume of distribution between SHR and WKY rats. However, choroid plexus showed greater % water content in SHR (85.7+/-1.9%) compared to the WKY rats (81.5+/-1.7%). These results suggest that chronic hypertension in SHR may cause more pronounced defects in the integrity of the blood-CSF barrier than in the BBB.     

Induced hypertension treatment to improve cerebral ischemic injury after transient forebrain ischemia

The effect of induced hypertension treatment on cerebral ischemia is still controversial. We investigated the preferred blood pressure manipulation level and pressor agent required to reduce cerebral ischemic injury following transient forebrain ischemia induced by bilateral occlusion of the common carotid arteries in anesthetized gerbils. Following 60-min cerebral ischemia, we evaluated the preferred blood pressure manipulation level and pressor agent required to treat cerebral ischemic injury after reperfusion by examining the effects of different levels of mean arterial blood pressure (MABP), increased with phenylephrine or angiotensin II or decreased by blood withdrawal, on cerebral blood flow (CBF), survival ratio, cerebral edema, and brain energy metabolism following transient forebrain ischemia in gerbils. Mild phenylephrine-induced hypertension treatment (21+/-4 mmHg) during post-cerebral ischemia-reperfusion improved the survival ratio and reduced cerebral edema, which was also associated with an increase in local CBF and a recovery of brain energy metabolism. However, intense phenylephrine-induced hypertension, angiotensin II-induced hypertension, or hypotension worsen the survival rate and produced extra cerebral edema, that were also associated with deterioration of brain energy metabolism. These results demonstrate that a mild induced hypertension with phenylephrine (21+/-4 mmHg above the baseline level) results in reduction of the cerebral edema and improves the survival ratio and brain energy metabolism. Furthermore, angiotensin II may have neurotoxic effect to use as the pressor agent for induced hypertension after cerebral ischemia.     

Effects of intra-ischemic blood pressure on outcome from 2-vessel occlusion forebrain ischemia in the rat.

Halothane anesthetized Sprague-Dawley rats underwent 10 min of bilateral carotid artery occlusion with mean arterial pressure (MAP) held at 30, 50 or 60 mmHg. Sham rats did not undergo ischemia. A 7-day recovery interval was allowed. Intra-ischemic electroencephalographic (EEG) changes, behavioral function (Days 5-7), and histologic injury (Day 7) were evaluated. Under similar conditions, cerebral blood flow was determined after 10 min ischemia by the [3H]nicotine indicator fractionation technique. EEG isoelectricity was observed in 11 of 11, 5 of 10, and 2 of 11 rats in the 30 mmHg, 50 mmHg, and 60 mmHg groups respectively. Neither passive avoidance cross-over latencies nor general motor scores were affected by intra-ischemic MAP and no differences from sham performance were observed. The per cent of CA1 neurons counted as dead (left and right hemispheres combined) was significantly affected by intra-ischemic MAP (72, 46 and 28% in the 30 mmHg, 50 mmHg, and 60 mmHg groups, respectively; P less than 0.001). A greater than 50% CA1 neuronal mortality rate was present only in those rats exhibiting EEG isoelectricity. However, the number of rats demonstrating greater than a 25% interhemispheric difference in CA1 neuronal loss was greatest in the 50 mmHg group (P less than 0.02). Hippocampal blood flow decreased in association with severity of hypotension (8 +/- 1, 35 +/- 8, and 48 +/- 2 ml/100 g/min (mean +/- S.E.M.) for 30, 50, and 60 mmHg, respectively; P less than 0.01). Again, however, the greatest variability in blood flow was observed at MAP = 50 mmHg.(ABSTRACT TRUNCATED AT 250 WORDS)     

Blood to brain sodium transport and interstitial fluid potassium concentration during early focal ischemia in the rat.

During partial ischemia, sodium and potassium ions exchange across the blood-brain barrier, resulting in a net increase in cations and brain edema. Since this exchange is likely mediated by specific transporters such as Na,K-ATPase in the capillary endothelium and because brain capillary Na,K-ATPase activity is stimulated by increased extracellular potassium in vitro, this study was designed to determine if the rate of blood to brain sodium transport is increased in ischemic tissue having an elevated interstitial fluid potassium concentration ([K]ISF) in vivo. Sprague-Dawley rats were studied between 2-3 h after occlusion of the right middle cerebral artery. To identify where cortical tissue with an elevated [K]ISF could be sampled for transport studies, the regional pattern of cerebral blood flow and [K]ISF was obtained in a group of 17 rats using hydrogen clearance and potassium-selective microelectrode techniques. We observed severely elevated [K]ISF (greater than 10 mM) when CBF was less than 20 ml 100 g-1 min-1 and mildly elevated levels at CBF between 20-45 ml 100 g-1 min-1. In a second group of seven rats, permeability-surface area products (PS products) for 22Na and [3H]alpha-aminoisobutyric acid ([3H]AIB) were determined in ischemic cortex with elevated [K]ISF and in nonischemic cortex. The PS products for AIB were similar in both tissues (2.2 +/- 0.7 and 2.1 +/- 0.4 microliters/g/min) while the PS products for sodium was significantly increased in the ischemic tissue (1.5 +/- 0.2 and 2.4 +/- 1.1 microliters/g/min).(ABSTRACT TRUNCATED AT 250 WORDS)     

Intravenous adenosine selectively increases blood flow to xenotransplanted intracerebral gliomas

Adenosine was infused intravenously at 10 mumol/(kg.min) into athymic ("nude") rats with intracerebral D-54MG xenotransplanted brain tumors, in an attempt to increase tumor blood flow. Cerebral blood flow (F) was measured with 14C-iodoantipyrine and quantitative autoradiography. Mean arterial blood pressure was 95 +/- 9.4 (SE) mm Hg in the adenosine group and 112 +/- 6.0 mm Hg in the controls. Averaged mean whole tumor F was significantly higher in adenosine-treated brain tumors (117.6 +/- 20.8 ml/[hg.min]) than in controls (62.2 +/- 9.7 ml/[hg.min]). Regionally, there were significant increases of F in tumor periphery and brain around tumor, but not in tumor center or any tumor-free brain regions. Focal values of F less than 5 ml/(hg.min) were present in some necrotic regions of adenosine-treated tumors. These results, obtained in unanesthetized rats with transplanted gliomas from a human cell line, confirm our earlier observations in avian sarcoma virus-induced brain sarcomas in dogs, and suggest that adenosine or perhaps other vasodilators could be used to selectively increase the delivery of lipid-soluble chemotherapeutic drugs to brain tumors.     

Phenylephrine-induced hypertension reduces ischemia following middle cerebral artery occlusion in rats

We studied the influence of phenylephrine-induced hypertension on the area of ischemia during brief middle cerebral artery occlusion. Rats were anesthetized with 1.2 minimal alveolar concentration (MAC) isoflurane, and the middle cerebral artery was occluded via a subtemporal craniectomy. Immediately thereafter, in one group (n = 9) arterial blood pressure was increased 30-35 mm Hg above the preocclusion level by intravenous infusion of phenylephrine. In a second, control, group (n = 10) there was no manipulation of blood pressure. Local cerebral blood flow was determined autoradiographically 15 minutes after occlusion. The areas (expressed as a percentage of the total coronal cross-sectional area) in which local cerebral blood flow decreased to three ranges (0-6 ml/100 g/min [rapid neuronal death probable], 6-15 ml/100 g/min [delayed neuronal death probable], and 15-23 ml/100 g/min [electrophysiologic dysfunction with prolonged survival probable]) were measured. The areas in which local cerebral blood flow decreased to the two more severely ischemic ranges were smaller in the phenylephrine group than in the control group. For example, in the coronal section in the center of the middle cerebral artery distribution, local cerebral blood flow was 0-6 ml/100 g/min in 6.7 +/- 1.4% of the section in normotensive rats but was in that range in only 1.7 +/- 0.6% of the section during phenylephrine-induced hypertension (p less than 0.05). For the 6-15 ml/100 g/min range, the areas were 6.8 +/- 0.8% and 3.8 +/- 0.7%, respectively (p less than 0.05). For the 15-23 ml/100 g/min range, there were no differences between groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparative studies of regional CNS blood flow autoregulation and responses to CO2 in the cat. Effects of altering arterial blood pressure and PaCO2 on rCBF of cerebrum, cerebellum, and spinal cord

Autoregulation and CO2 responses were investigated concurrently in cerebrum, cerebellum, and spinal cord of 19 cats by means of hydrogen clearance. Under ketamine and nitrous oxide anesthesia at normal systemic mean arterial blood pressure (MABP 123 +/- 18.4 mmHg, mean +/- standard deviation) blood flow was 86 +/- 30.0 ml/100 g/min in the cerebrum, 48 +/- 13.6 ml/100 g/min in the cerebellum, and 46 +/- 18.7 ml/100 g/min in the spinal cord. During normocapnia (PaCO2 27-33 mmHg) for every mmHg of PaCO2 variation an average flow change of 1.7 ml/100 g/min was found in the cerebrum, corresponding change rates in the cerebellum and in the spinal cord were 1.1 and 0.9 ml/100 g/min/mmHg, respectively. Thus, the effect of carbon dioxide appears to be positively correlated with the normal level of regional perfusion and metabolism. Flow values within 10% of control were recorded in the cerebrum at MABPs ranging from 79 to 123% of normal blood pressure, 53 to 146% in the cerebellum, and 83 to 128% in the spinal cord. These results suggest greater susceptibility to pressure dependent ischemia of cerebrum and spinal cord, with relative resistance of the cerebellum.     

Effect of pentobarbital on cerebral regional venous O2 saturation heterogeneity.

Observed venous O2 saturation inhomogeneity in the brain implies a microregional imbalance in O2 supply/consumption. We hypothesized that this heterogeneity should be decreased by pentobarbital anesthesia through a reduction in regional metabolic heterogeneity. Male, Long-Evans, approximately 350 g rats were either anesthetized with 50 mg/kg pentobarbital (n = 10) or used as a conscious control group (n = 10, catheters inserted two hours earlier under ether anesthesia). In each rat, regional cerebral blood flow was determined by [14C]iodoantipyrine and regional arterial and venous O2 saturation were determined by microspectrophotometry. In the PB group, the mean blood pressure (107 +/- 7 Torr), heart rate (362 +/- 29/min), average cerebral blood flow (63 +/- 19 ml/min/100 g), and average cerebral O2 consumption (3.7 +/- 1.2 ml O2/min/100 g) were lower than those values in the conscious group (128 +/- 15, 474 +/- 44, 112 +/- 40, and 7 +/- 3), respectively. O2 extraction did not change after pentobarbital anesthesia. However, the dispersion of venous O2 saturation narrowed. The distribution of O2 saturations in 373 cerebral veins of anesthetized rats had a significantly reduced coefficient of variation [C.V. = 100 x (S.D./mean) = 13] as compared to a C.V. of 18 in 320 veins in conscious rats. Thus, pentobarbital anesthesia reduced the microregional venous O2 saturation inhomogeneity in the brain, creating a more uniform balance of oxygen supply and consumption.     

Regional cerebral blood flow and distribution of [99mTc]ethyl cysteinate dimer in nonhuman primates

Increases in regional cerebral blood flow have been described in a variety of cerebral pathologic states, including stroke and seizure disorders. The usefulness of technetium-99m-labeled cysteinate dimer as a marker in the measurement of regional cerebral blood flow was tested in five cynomolgus monkeys. To expand the range of blood flow to beyond the normal limits, 40 mg/kg i.v. of the carbonic anhydrase inhibitor acetazolamide was administered. Regional cerebral blood flow in all five monkeys was measured using radiolabeled microspheres (before and after acetazolamide) and the marker (after acetazolamide) in 60-70 samples from 12 brain regions. Acetazolamide significantly increased the mean +/- SEM regional cerebral blood flow measured using microspheres from 0.56 +/- 0.21 to 1.71 +/- 0.9 ml/min/g (p less than 0.01 for each region). A significant positive correlation was found between regional cerebral blood flow values calculated using microspheres and the marker after normalizing the values to those in the cerebellum (r = 0.773, p less than 0.0001). The mean +/- SEM regional cerebral blood flow determined using the marker in a single monkey (1.21 +/- 0.04 ml/min/g) did not differ significantly from that determined in the same monkey using microspheres (1.13 +/- 0.04 ml/min/g). These data support the potential use of this new brain perfusion imaging agent to assess regional cerebral blood flow over a clinically relevant range of blood flows.     

Chemical stimulation of the rostral ventrolateral medullary pressor area decreases cerebral blood flow in anesthetized rats.

In urethane-anesthetized, paralyzed and artificially ventilated rats, the neurons in the rostral ventrolateral medullary pressor area (VLPA) were chemically stimulated by microinjections of L-glutamate (1.7-5.0 nmole in 100 nl of 0.9% sodium chloride solution) and the cerebral blood flow (CBF) was determined using a combination of labeled microspheres (57Co, 113Sn and 46Sc). In one group of rats (n = 11), unilateral chemical stimulation of the VLPA produced a significant (P less than 0.01) increase in arterial blood pressure (ABP), a significant (P less than 0.05) decrease in CBF, and a significant (P less than 0.01) increase in cerebrovascular resistance (CVR) in the cerebral cortex ipsilateral to the stimulated VLPA. The CBF was 52 +/- 3 (mean +/- S.E.M.) and 48 +/- 4 ml.min-1.(100 g)-1 before and during the chemical stimulation of VLPA; the CVR was 1.9 +/- 0.1 and 2.6 +/- 0.3 mmHg per ml.min-1.(100 g)-1 before and during the stimulation. In order to measure CBF at normotension, moderate hypotension was induced by controlled hemorrhage in another group of rats (n = 8). Unilateral chemical stimulation of the VLPA in these rats increased ABP but it remained within normotensive range. The CBFs of ipsilateral and contralateral cerebral cortices decreased significantly (P less than 0.05) from 57 +/- 14 to 41 +/- 9 and from 50 +/- 12 to 39 +/- 9 ml.min-1.(100 g)-1, respectively. The CVRs of ipsilateral and contralateral cortices increased significantly (P less than 0.05) from 2.6 +/- 0.6 to 3.5 +/- 0.8 and from 2.7 +/- 0.5 to 3.5 +/- 0.8 mmHg/[ml.min-1.(100 g)-1], respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cerebral blood flow during dihydralazine-induced hypotension in hypertensive rats

The cerebrovascular effects of graded, controlled dihydralazine-induced hypotension were studied in rats with renal hypertension (RHR) and spontaneous hypertension (SHR). Repeated measurements of cerebral blood flow (CBF) were made using the intraarterial 133Xenon injection technique in anaesthetised normocapnic animals. Dihydralazine was administered in single increasing i.v. doses (0.1 to 2 mg/kg), and CBF measured after each dose when a stable blood pressure had been reached. From a resting level of 145 +/- 7 mm Hg in RHR and 138 +/- 11 mm Hg in SHR, mean arterial pressure (MAP) fell stepwise to a minimum of around 50 mm Hg. CBF was preserved during dihydralazine induced hypotension, and remained at the resting level of 79 +/- 13 ml/100 g . min in RHR and 88 +/- 16 ml/100 g . min in SHR. Following 2 hours hypotension at the lowest pressure reached, the rats were sacrificed by perfusion fixation and the brains processed for light microscopy. Evidence of regional ischaemic brain damage was found in 4 of 11 animals: in 2 cases the damage appeared to be accentuated in the arterial boundary zones. Although the lower limit of CBF autoregulation in these rats is around 100 mm Hg during haemorrhagic hypotension, dihydralazine brought MAP to around 50 mm Hg without any concomitant fall in CBF. This was interpreted as being due to direct dilatation of cerebral resistance vessels. The combination of low pressure and direct dilatation may have resulted in uneven perfusion, thus accounting for the regional ischaemic lesions.     

Effect of amphetamine on cerebral blood flow and capillary perfusion

The purpose of this study was to determine the cerebral regional microvascular and vascular responses to amphetamine sulfate at a dose (5 mg/kg) known to affect neuronal function. Cerebral blood flow (14C-iodoantipyrine method) and percent of perfused capillaries (fluorescein isothiocyanate-dextran and alkaline phosphatase staining method) were determined during control and after intravenous administration of amphetamine in conscious Long-Evans rats. Amphetamine caused an increase in blood pressure (34%) and heart rate (31%). There was a significant increase in averaged cerebral blood flow from 98 +/- 8 to 166 +/- 9 ml/min/100 g after amphetamine. This flow increase was significant in the cortex, basal ganglia, pons and medulla, however the increase was not significant in the hypothalamus. In control rats, there were approximately 325 +/- 17 capillaries/mm2 of brain tissue and 52 +/- 1% of them were perfused. Amphetamine increased the percent perfused significantly to 72 +/- 1% in all examined regions. There was a similar significant increase in the percent of perfused cerebral capillary volume fraction. There were both vascular and microvascular responses to amphetamine, increasing cerebral blood flow as well as reducing the diffusion distance for oxygen.     

Relation between distribution of DNA synthesizing cells and blood flow and glucose metabolism in Rous sarcoma virus-induced rat brain tumors

The correlations between blood flow or glucose metabolism and distribution of DNA synthesizing cells were simultaneously investigated in the same rat brain tumors using autoradiographic technique and immunoperoxidase stain. Two rat brain tumor strains (A and B) induced by Rous sarcoma virus were used. A suspension of 1 X 10(4) rat brain tumor cells was stereotactically implanted into the right basal ganglia of syngenic Fischer 344/Du Crj rats. The tumor strain A bearing rats died 12.0 +/- 1.8 days and the tumor strain B bearing rats died 17.6 +/- 1.3 days after the tumor implantation. Blood flow and glucose metabolism were measured with 14C-iodoantipyrine and 14C-2-deoxy-D-glucose autoradiography. All rats also received a 1-h i.v. infusion of BrdU, 5-20 mg, at the autoradiographic procedure. The immunoperoxidase staining for BrdU (Avidin Biotin peroxidase complex method) and other conventional stainings were performed in the sections alternating with the autoradiographic sections. BrdU-positive nuclei (S-phase cells) were heterogeneously distributed and labeling index ranged from less than 1% to more than 40% in the tumors. Neoplastic vessels tended to be distributed in the peripheral part of the tumor and were surrounded with S-phase cells in a part of the tumor. The blood flow was heterogeneously distributed in the tumor and the average blood flow reduced to about 50% in the tumor strain A and to about 60% in the tumor strain B, respectively in comparison with contralateral cortex. The distribution of blood flow did not correlate with the distribution of S-phase cells nor the distribution of neoplastic vessels.(ABSTRACT TRUNCATED AT 250 WORDS)     

Interaction between neurogenic and metabolic factors upon deterioration in cerebrovascular tonus--experimental study on the etiology of cerebral vasoparesis

It is widely accepted that a tremendous increase in cerebral blood volume (CBV) due to progressive cerebral vasoparesis is an essential to the development of acute brain swelling. This study was designed to determine whether neurogenic and/or metabolic factors are predominant and how these interact with each other in producing cerebral vasoparesis. Fifty-one awake cats immobilized with pancuronium bromide were divided into 4 groups: group I, control; group II, normocapnic hypoxia (PaO2 = 50 mmHg); group III, normoxic hypercapnia (Pa-CO2 = 70 mmHg), and group IV, increased intracranial pressure (ICP = 40 mmHg) by brain compression. Systemic arterial pressure (BP), CBV (photoelectric method), and ICP (epidural pressure) were continuously recorded. The dorsomedial hypothalamic nucleus (DM) and the reticular formation of the midbrain (MB-RF) were bilaterally coagulated by a stereotaxic technique (3mA, 1 min). Therefore alterations in cerebrovascular tonus created by destruction of the cerebral vasomotor centers were examined in the animals with metabolically induced cerebral vasodilatation to various degree's. In group I, vasomotor center destruction resulted in an immediate and transient decrease in BP (DM; -14.1 +/- 6.7 mmHg, MB-RF; -10.2 +/- 4.8 mmHg) and simultaneous increase in CBV and ICP (DM; 7.6 +/- 7.0 mmHg, MB-RF; 6.0 +/- 5.6 mmHg) for 3 to 4 minutes. Increase in ICP by destruction of vasomotor centers reduced significantly in group II (DM; 2.3 +/- 2.6 mmHg, MB-RF; 1.6 +/- 1.2 mmHg) and reduced slightly in group IV (DM; 7.5 +/- 4.0 mmHg, MB-RF; 4.8 +/- 3.2 mmHg). In these 3 groups, autoregulation of cerebral blood flow and CO2 vasoreactivity were not changed by destruction of vasomotor centers.(ABSTRACT TRUNCATED AT 250 WORDS)     

Acute cerebral tissue oxygenation changes following experimental subarachnoid hemorrhage

Primary brain ischemia following subarachnoid hemorrhage is a major cause of morbidity and mortality. This study aims to determine whether changes in cerebral tissue oxygenation are related to cerebral blood flow changes in the acute phase following experimental subarachnoid hemorrhage. The endovascular puncture model was used to study subarachnoid hemorrhage in male Wistar rats with a tissue oxygenation probe and a laser Doppler probe placed contralateral to the side of hemorrhage. Following the subarachnoid hemorrhage intracranial pressure rose to 53.0 +/- 9.8 mmHg (mean +/- SEM). This was associated with a fall in cerebral blood flow to 43.9% +/- 7.1% of its baseline value and a fall in tissue oxygenation to 42.8% +/- 7.7% of baseline. The time course of the fall and recovery in tissue oxygenation was closely correlated to that of the cerebral blood flow (r = 0.66, p = 0.02). The fall in cerebral blood flow was associated with a 42.1% +/- 6.47% fall in the concentration of moving blood cells and a rise of 181.2% +/- 27.2% in velocity indicating acute microcirculatory vasoconstriction. Interstitial tissue oxygenation changes mirrored changes in cerebral blood flow indicating that a change in oxygen delivery was occurring.