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(Stroke. 1995;26:473-479.)
© 1995 American Heart Association, Inc.
Articles |
Effect of Intracarotid Administration of 6-Aminonicotinamide on Cerebral Blood Flow in Cats
From the Department of Neurosurgery, Nagoya University School of Medicine, Nagoya, Japan.
Correspondence to Hiroji Kuchiwaki, MD, 65 Tsurumai-cho, Showa-ku, Nagoya 466, Japan.
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Background and Purpose We evaluated the effects of an adenosine triphosphate blocker, 6-aminonicotinamide (6-ANA), on the cerebral blood flow (CBF), cerebral metabolism, and electroencephalogram of cats.
Methods Catheters were inserted into the common carotid artery of 16 adult cats anesthetized with ketamine via the lingual artery. We measured CBF in the infused area by the inhaled hydrogen gas clearance method and analyzed the electroencephalogram frequency. Cerebral metabolism was estimated by oxygen extraction (vol/%) and glucose utilization (millimoles) using data arterial (aorta) and sagittal sinus blood samplings. A solution of 6-ANA (6.0 mg/mL) (n=8) or saline (n=8) was infused via catheter at 2.0 mL/min for 3 minutes followed by a 60-minute observation of CBF, cerebral metabolism, vascular resistance, and the electroencephalogram components, alpha-2 ratio [=alpha-2/(alpha-1+alpha-2)]. The effect of 6-ANA on capillaries was evaluated by extravasation of Evans blue dye and electron microscopic findings.
Results Moderate reductions in CBF, cerebral metabolism, and the alpha-2 ratio were observed during the infusion of 6-ANA versus saline infusion (P<.05 by paired t test and ANOVA). Vascular resistance was significantly increased (P<.05). No abnormalities were observed in the capillaries of the infused hemisphere.
Conclusions Results indicated that 6-ANA produced a downregulation of cerebral blood flow in cats.
Key Words: adenosine • electroencephalography • cerebral blood flow • cats
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Introduction |
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Cerebral metabolism is related to cerebral blood flow (CBF),1 with changes in cerebral metabolism producing changes in CBF.2 3 4 5 6 Alterations in brain metabolism as a consequence of a decrease in CBF are usually associated with severe brain ischemia. An increase in CBF associated with an increase in brain metabolism is important to brain function,7 8 9 as is the matching of CBF to brain metabolism.9 10 Experimental evidence supports the concept that a decrease in CBF reduces brain metabolism,11 12 13 as opposed to the concept that a reduction in brain metabolism reduces CBF.14 15 16 17 That barbiturates and hypothermia reduce the cerebral metabolic ratio of oxygen (CMRO2) to 40% to 60% of the normal value14 15 and to 75% of the normal value,17 18 respectively, is well documented. In contrast to most anesthetic agents, ketamine slightly raises the CMRO2,19 whereas most anesthetic agents reduce it.20 Results of several studies with metabolic depressants in nonischemic models indicate that the reduction in cerebral metabolism ranges from 10% to 30%.16 20 21 22 23 While several studies on CBF using selective metabolic depressants have been reported in a nonischemic model, specific changes in CBF as related to brain metabolism have not been studied in detail using agents that selectively depress the metabolism of adenosine triphosphate (ATP).
The ATP blocker 6-aminonicotinamide (6-ANA)24 acts on 6-phosphogluconate dehydrogenase25 and on nicotinamide phosphoribosyl transferase.26 The enzyme
6-phosphogluconate dehydrogenase is involved in the metabolism of
6-phospho-D-gluconate to
D-glyceroaldehyde-3-phosphate via
2-keto-3-deoxy-6-phosphate-D-gluconate. Nicotinamide
phosphoribosyl transferase is involved in the metabolism of
nicotinamide to nicotinate ribonucleotide via nicotinate, a process
that is related to the production of nicotine adenine dinucleotide
(NAD). The change from nicotinate to nicotinate ribonucleotide involves
5-phosphate-
-D-ribosylpyrophosphate, from which
adenylate to AMP is induced by amidophosphoribosyl transferase. Thus,
6-ANA influences both the utilization of glucose and the production of
NAD in the brain.
We designed the present study to measure changes in CBF, cerebrovascular resistance, cerebral metabolism, and alpha band activities on the electroencephalogram (EEG) after the administration of 6-ANA, a metabolic depressant and selective ATP blocker. To exclude effects on the brain that would distort the experimental data, we required that the model not be affected by hypoxic insult to the brain, that it would require only a minimal dose of the metabolic depressant, and that it would have a limited experimental time. Also, the anesthetic agent used should have a minimal effect on brain metabolism. The presence of severe morphological changes in the capillaries should be excluded before the extent of 6-ANA action is determined in brain tissue. The cat was selected as the animal model because minimal insults to blood flow through the internal carotid artery are produced by an infusion catheter. The diameter of this artery in the cat is large enough to allow catheterization through the lingual artery. Our objective was to determine whether the reduction in brain function and me- tabolism produced by the presence of this ATP blocker would be associated with a decrease or increase in CBF.
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Materials and Methods |
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Laboratory Preparation
Sixteen adult cats of either sex weighing 2.6 to 4.6 kg were anesthetized with an intramuscular injection of ketamine HCl (Ketalar 50, Sankyo Co, Ltd) (30 mg/kg), in accordance with the Guide to Animal Experimentation of the Nagoya University School of Medicine.
A tracheal cannula was introduced through a tracheostomy. Each animal was immobilized by an intravenous injection of pancuronium bromide (Mioblock injection, Sankyo Co, Ltd) under controlled respiration (respirator for animal experiments, Shinano Seisakusho) using room air. Body temperature was maintained at 36°C with a heating pad. Systemic arterial pressure (SAP) was monitored continuously by a catheter placed in the aorta and connected to a strain gauge pressure transducer (TICP-II, Toyota Central Research Co, Ltd). For the intracarotid injection of a solution of saline or 6-ANA (Sigma Chemical Co), a thin polyethylene catheter (1.0 mm OD) was inserted into the exposed lingual artery with the tip placed at the junction with the common carotid artery. The external carotid artery then was ligated. To maintain the patency of the indwelling catheter, a saline solution containing heparin sodium (100 IU/mL) (Novo Heparin, Kodama Co, Ltd) was continuously infused by catheter at a rate of 0.02 mL/min by a Harvard pump (model 901, Harvard Apparatus) throughout each experiment. After the administration of a second intramuscular injection of ketamine HCl (15 mg/kg), the animal was placed prone on a stereotaxic operating table (Summit Medical Co, Ltd) with the head secured with ear bars.
The skull was exposed, and small burr holes were made over the ectosylvian gyrus of the perfused hemisphere for measurement of CBF using the inhaled hydrogen gas (H2) clearance method.27 Three electrodes for measuring CBF (platinum iridium; diameter, 300 µm; tip diameter, 70 µm; 7 cm long; Unique Medical Co, Ltd) were placed obliquely into the perfused area of the cortex under microscopic guidance, fixed with bone wax to the burr holes, and connected to the apparatus (hydrogen monitor PHG 200, World Medical Co, Ltd). The output voltage was recorded (National Multipen Recorder, VP6620A, Matsushita Communication Industrial Co, Ltd) as a decay curve of the clearance of H2. Pure H2 gas was given by flushing for less than 20 seconds through a tube placed in the trachea.
The oxygen extraction ratio (vol/%) and glucose utilization were evaluated to study the states of cerebral metabolism. Arterial blood was sampled through a catheter in the abdominal aorta. A cranial window was made on the superior sagittal sinus, into which a catheter (0.9 mm OD) was inserted with its tip directed to the confluence. Venous blood samples were obtained through the catheter. Blood gases were analyzed using a blood gas analyzer (ABL-300, Acid-Base Laboratory, Radiometer Copenhagen). Serum glucose levels were measured by the enzymatic method. Blood samples were obtained at control and at each experimental time.
EEGs were recorded with brass screw electrodes fastened in the skull of the perfused hemisphere, with monopolar recording using an EEG apparatus (model 3G26, NEC-Sanei Co, Ltd). The active electrode was set in the skull, covering the perfused ectosylvian gyrus, while the reference electrode was placed at the nasion. A low cutoff filter (0.032 Hz) and a high cutoff filter (30 Hz) were used. EEG data were recorded for 3 minutes at each time point on a cassette data recorder (MR-10, TEAC Co, Ltd).
The concentration of CO2 in the expired gas was continuously monitored using a CO2 gas analyzer (type 1H21, NEC-Sanei Co, Ltd) and was maintained in the range of 3.5% to 4.2% in end-tidal CO2 concentration. Blood gases were intermittently sampled with an aortic catheter to collect the data needed to adjust the respirator.
Study Design and Experimental Protocol
Animals were divided into two groups, 8 in the 6-ANA group and 8
in the control group. A 3-minute infusion of 6-ANA solution (6 mg/mL of
6-ANA dissolved in distilled water at 36°C; total dose, 37.8 mg at pH
7.25) was given at a rate of 2.0 mL/min by a Harvard pump. Controls
received the same volume of physiological saline solution (36°C)
infused in the same manner.
CBF measurements and EEG recordings were made before the infusion of saline (n=4) or of 6-ANA solution (n=4) to obtain baseline readings and were repeated at 5, 30, and 60 minutes. EEGs were recorded just before each CBF measurement. Blood sampling for determination of oxygen extraction (OE) and glucose utilization followed the same time course in the 6-ANA (n=4) and saline groups (n=4). Baseline data were obtained within 30 minutes of completing the laboratory setup. Experiments then were begun after the intracarotid perfusion of saline or 6-ANA.
Calculation of CBF
Each decay curve of H2 clearance versus time during
the first 3 minutes was plotted on a semilogarithmic scale.
Monoexponential curves were estimated using linear regression
analysis. Half-life (t1/2), the time required for the
estimated initial value to decrease by 50%, was expressed in minutes.
CBF values were calculated according to the following formula:
[0.693/(t1/2)]x100 (mL · 100
g-1 · min-1). The median value of CBF
measured at three points in each animal was obtained at the scheduled
times in each group. The arithmetic mean values in 4 cats then were
calculated at baseline and at 5, 30, and 60 minutes. CBF values
obtained in each experiment were analyzed statistically.
Cerebrovascular resistance was obtained by dividing the mean SAP at
each time point minus the normal intracranial pressure (ICP) in each
cat by the CBF values. The normal value for ICP (6.5 mm Hg) was
obtained in another series of cats.
Calculation of Oxygen Extraction and Glucose Utilization
OE (A vol/%) was determined by multiplying the arteriovenous
oxygen difference by the hemoglobin concentration (g/dL) times 1.34 and
the oxygen saturation (%). Oxygen partial pressure was multiplied by
0.0031 according to Henry's law (B vol/%). A total vol/% (=A+B) was
used as OE. Glucose utilization (millimoles) was obtained from the
differences between the arterial and venous blood levels of glucose.
The arithmetic mean values in 4 cats were calculated in each group at
baseline and at 5, 30, and 60 minutes. OE values and glucose
utilization obtained in each experiment were evaluated
statistically.
EEG Analysis
Off-line analysis of the EEG power spectrum was performed by
fast Fourier transform with a signal processor (7T-17, NEC-Sanei Co,
Ltd) using software for EEG power analysis (NEC-Sanei Co, Ltd).
Frequency analysis of the EEG was applied to the range of 1 to 25
Hz. The sampling time was 8 seconds. The frequency range (1 to 25 Hz)
was displayed at 512 points for each sampling. The power spectrum was
divided into the delta wave (2 to 3.75 Hz), theta wave (4 to 7.75 Hz),
alpha-1 wave (8 to 9.75 Hz), alpha-2 wave (10 to 12.75 Hz), and beta
wave (13 to 25 Hz) components. To detect changes in brain electrical
activity, the theta ratio, theta/(alpha-1+alpha-2+theta), and the
alpha-2 ratio, alpha-2/(alpha-1+alpha-2), were determined as
percentages before and after the administration of saline or 6-ANA.
Pathological Study
We administered Evans blue dye (40 mg/kg IV) about 10 minutes
before the end of each experiment to evaluate any impairment of the
blood-brain barrier (BBB). The brain of each animal was removed after
the infusion of a saturated solution of potassium chloride.
Extravasation of Evans blue dye was determined by observing the blue
staining of the cut surface of brain samples from the perfused
ectosylvian gyrus. At the end of the experiment, the brain was perfused
with saline and then was perfused for fixation with 2.3%
glutaraldehyde–phosphate buffer solution, pH 7.40 (Katayama Chemical
Co, Ltd). To observe the capillaries of the perfused hemisphere with a
transmission electron microscope (H-800, Hitachi Co, Ltd), samples of
brain were additionally fixed with a 0.5% glutaraldehyde–phosphate
buffer solution (pH 7.40) followed by osmium solution, pH 7.40
(Katayama Chemical Co, Ltd).
Statistical Analysis
Data are presented as mean±SD. Values at different
experimental times after the infusion of saline or 6-ANA versus
baseline values in each group were compared using a paired t
test and one-way analysis of variance (ANOVA) using a computer
program (HIGH-QUALITY ANALYSIS LIBRARIES OR BUSINESS AND ACADEMIC
USERS, version 3.33, Gendaisugakusha). Differences were
considered statistically significant when P values were less
than .05.
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Results |
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Physiological Parameters
Arterial blood gases and pH for the control group and the 6-ANA group remained in the range of normal: PaO2, 118.6±4.9 mm Hg (mean±SD) in the control group and 114.2±9.7 in the 6-ANA group; PaCO2, 40.7±2.3 mm Hg in the control group and 38.7±2.5 in the 6-ANA group; and pH, 7.37±0.03 in the control group and 7.36±0.02 in the 6-ANA group. Neither the control group nor the 6-ANA group exhibited any significant decline in SAP during the experiment. However, just after the administration of 6-ANA, each animal showed a transient maximal fall in SAP of 10 mm Hg, which returned to the previous level within minutes. The systolic and diastolic arterial pressures were 129.2±4.8 mm Hg and 87.2±7.4 mm Hg, respectively, at the beginning and 127.3±6.6 mm Hg and 89.2±4.1 mm Hg, respectively, at the end of each experiment in the experimental and control groups. There were no significant changes in physiological parameters during these experiments in either group.
CBF Studies
CBF (mL · 100 g-1 · min-1)
values before and after the infusion of saline or 6-ANA with the
results of statistical analysis appear in Table 1
and Fig 1. The baseline CBF values of 54.3±3.2
mL · 100 g-1 · min-1 in the control
group and 49.0±3.8 mL · 100
g-1 · min-1 in the 6-ANA group did not
differ significantly. The values for CBF after the infusion of saline
in the control group did not differ significantly from the baseline
value. The CBF value decreased significantly from 5 minutes to 60
minutes in the 6-ANA group (P=.04). We noted a trend toward
a decrease in CBF during the experimental period in the 6-ANA group.
The lowest level of CBF was observed in the 6-ANA–treated group,
29.9±4.5 at 60 minutes of infusion. All decreases observed after the
infusion of 6-ANA were statistically significant compared with the
baseline values for that group (P=.01 and .04).
Cerebrovascular resistance did not change significantly in the control
group (NS), but those values increased significantly after the
administration of 6-ANA (P<.05).
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Oxygen Extraction Ratio and Glucose Utilization
As shown in Table 2, OE ratios in the control group
at baseline were 5.4±0.2 vol/%, ranging from 5.4±0.4 to 5.0±0.1
vol/% after the injection of saline solution. In the 6-ANA group, OE
ratios were 5.5±0.4 at baseline, ranging from 4.1±0.1 to 3.7±0.2
vol/% after drug administration. After the administration of 6-ANA, OE
ratios were significantly decreased versus baseline in the 6-ANA group
(P<.05) and also versus the control group
(P<.05). In the control group, glucose utilization was
0.98±0.14 mmol at baseline, ranging from 1.02±0.11 to 0.96±0.09 mmol
after the injection of saline solution. Glucose utilization in the
6-ANA group was 1.02±0.1 mmol at baseline and ranged from 0.68±0.09
to 0.62±0.08 mmol after drug administration. Reductions in glucose
utilization after the administration of 6-ANA differed significantly
versus baseline and versus the control group (P<.05).
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EEG Studies
In the 6-ANA group, the alpha-2 component of the EEG was
significantly decreased below the baseline both at 5 minutes
(P<.04) and 30 minutes (P<.01). The baseline
alpha-2 ratio did not differ significantly between the control and
6-ANA groups. The alpha-2 ratio did not change significantly in the
control group after saline infusion, whereas after the infusion of
6-ANA it decreased significantly versus baseline (P=.004,
.04, and .01) (Table 1
). The decrease in this ratio was fairly
consistent after the 6-ANA infusion. The mean values of the theta and
alpha-1 components in each group did not differ significantly from
baseline.
Histological Findings
Slices from the perfused region of the brain appeared
macroscopically normal, and the BBB was intact except for needle tracks
produced by the CBF electrodes in each group. Endothelial swelling was
absent, the basement membranes exhibited a normal thickness and
architecture, and tight junctions were normally present in the
control and the 6-ANA groups (Fig 2).
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Discussion |
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We observed significant reductions in CBF ranging from 35.9±1.7 to 29.9±4.5 mL · 100 g-1 · min-1 in the 6-ANA–treated group. The significant reductions in OE values and in glucose utilization indicated a decrease in brain metabolism. Within these CBF levels and the reduced metabolic state, the alpha-2 component and ratio were significantly decreased from the baseline level, while the theta ratio and the other EEG components showed no significant change.
The niacin antagonist 6-aminonicotinamide blocks reactions mediated by ATP.24 It is thought to reduce the metabolism of perfused brain tissue and brain microvessels. 6-ANA disturbs the pentose pathway and the electron transport mediated by pyridine-linked dehydrogenases in the mitochondria acting on NAD or on nicotinamide-adenine dinucleotide phosphate (NADP), as discussed previously.24
There are two possible explanations for the effects of 6-ANA in our model. The first hypothesis states that 6-ANA reaches the brain tissue through the vessel wall and reduces ATP production and the pentose pathway in the adjacent brain tissue. Creatine kinase activity in brain tissue exceeds that in brain microvessels.28 Therefore, such effects of 6-ANA are thought to be apparent earlier in brain function than in brain microvessels. We observed a significant decrease in glucose utilization only 5 minutes after the administration of 6-ANA as well as a gradual decrease in CBF with time. The occurrence of a reduction in the alpha-2 components with a lack of change in the theta ratio does not favor a progressive uncoupling state of the reduced brain function and decrease in CBF. Although we do not know why a reduction in the alpha-2 ratio would be associated with a reduction in CBF, a moderate reduction in cerebral metabolism due to 6-ANA in brain tissue may be involved. The second hypothesis states that 6-ANA decreases the pentose pathway or ATP utilization in the walls of brain vessels. When this occurs, the arterioles partially lose their ability to regulate CBF, producing a concomitant reduction in brain metabolism.11 29 Vascular resistance was increased in the present study. Our results indicated that the cerebrovascular system may regulate CBF. A marked reduction in ATP in the cerebrovascular wall has been proposed as a mechanism for chronic vasospasm.30 However, vasospasm causes severe brain ischemia and EEG slowing. Our model, however, suggests downregulation between CBF and metabolism. CBF and cerebral metabolism decreased moderately and alpha-2 ratios decreased nonsignificantly, whereas theta ratio did not increase in our model.
It was difficult to find clear or consistent changes in the theta wave ratio in our model, since this ratio did not increase significantly toward the end of the experiment. The significant decreases observed in the alpha-2 component ratios, metabolism, and CBF 5 minutes after the 6-ANA infusion support the idea that 6-ANA depressed brain activity. Thus, a hypoxic insult to the brain would be minimized by infusing the brain with this agent. The coupled reduction in both brain metabolism and CBF such as the alteration of EEG components limited to the alpha wave components is suggested. The relation between cerebral metabolism and EEG changes has been described.11 12 31 32 It has been proposed that the correlation between the alpha-2 component and cerebral metabolism is driven by ATP consumption.33 34 35 Our results indicate that a reduction in the EEG components is limited to the alpha-2 wave component and alpha-2 ratio in electrophysiological activity of the brain.
Keaney et al22 found that changes in EEG precede those in cerebrovascular resistance and postulated an indirect effect of administering a steroid anesthetic agent intravenously on CBF and brain metabolism. We observed that the reduction in alpha-2 ratio at 5 minutes remained relatively consistent after the 6-ANA infusion, but there was a trend toward a progressive reduction in CBF between 5 and 60 minutes. Ultrastructural study showed no impairment of the vasculature, and the BBB remained normal. Our results lead to a conclusion similar to that of Keaney et al, namely that our experimental model indicates a downregulation in which the decrease in brain activity and metabolism induced by administering a metabolic depressant is coupled with a gradual reduction in CBF.
In previous studies, doses of 6-ANA administered intraperitoneally to experimental animals ranged from 4 to 120 mg/kg.36 37 38 We previously studied the role of 6-ANA in the development of cytotoxic edema, which was not detected within 3 hours of administering a large dose (120 mg/kg) of 6-ANA.37 To eliminate the toxic effects of 6-ANA on the BBB other than cerebral metabolism, we recommended that the study period be limited to less than 3 hours after the intracarotid injection of 6-ANA. The dose of 6-ANA infused in the present experiment was much lower than that used to produce edema.36 37 38 To exclude any toxic or hypoxic effects of 6-ANA on brain microvessels and brain tissue, we limited the study period to 1 hour. The ketamine used as an anesthetic agent in the present study would not reduce brain metabolism.
In this study, we obtained evidence confirming a decrease in oxygen extraction and in glucose utilization by measuring brain metabolites. Findings indicated a coupled reduction of brain metabolism and CBF resembling that seen with the reduction produced by 6-ANA in adjacent brain areas and the perfused vessels.
Conclusions
The decreases in CBF, brain metabolism, and alpha-2 ratios may
reflect a downregulation of cerebral hemodynamics produced by the
administration of a metabolic depressant.
Received March 31, 1994; revision received October 10, 1994; accepted November 15, 1994.
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