Chronic hyperglycemic diabetes in the rat is associated with a selective impairment of cerebral vasodilatory responses

Diabetes has been reported to impair vasodilatory responses in the peripheral vascular tissue. However, little is known about vasodilatory function in the diabetic brain. We therefore studied, in the N2O-sedated, paralyzed, and artificially ventilated rat, the effects of chronic hyperglycemic diabetes on the cerebral blood flow (CBF) responses to 3 acutely imposed vasodilatory stimuli: hypoglycemia (HG) (plasma glucose = 1.6-1.9 mumol ml-1), hypoxia (HX) (PaO2 = 35-38 mm Hg), or hypercarbia HC) (PaCO2 = 75-78 mm Hg). In addition, we evaluated the somatosensory evoked potential (SSEP) and plasma catecholamine changes in rats exposed to acute glycemic reductions. Diabetes was induced via streptozotocin (STZ, 60 mg kg-1 i.p.). All results in diabetic rats were compared to those obtained in age-matched nondiabetic controls. The animals were studied at 6-8 weeks (HG experiments) or 4-6 months (HG, HX, and HC experiments) post-STZ. Values for CBF were obtained for the cortex (CX), subcortex (SC), brainstem (BS), and cerebellum (CE) employing radiolabeled microspheres. Up to three CBF determinations were made in each animal. In 6-8 week diabetics vs. controls, CBF increased to a lesser value in the CX, SC, and BS (p less than 0.05). Thus, in the diabetics, going from chronic hyperglycemia to acute hypoglycemia, CBF values (in ml 100 g-1 min-1 +/- SD) increased (p less than 0.05) from 89 +/- 22 to 221 +/- 57 in the CX, from 82 +/- 21 to 160 +/- 52 in the SC, and from 79 +/- 34 to 237 +/- 125 in the BS. In controls, going from normoglycemia to acute hypoglycemia, the CBF changes (p less than 0.05) were 128 +/- 27 to 350 +/- 219 (CX), 117 +/- 11 to 358 +/- 206 (SC), and 130 +/- 29 to 452 +/- 254 (BS). CBF changes and absolute values in the CE were similar in the two groups. At 4-6 months post-STZ, a complete loss of the hypoglycemic CBF response was found in the CX, SC, and CE. In the BS, a CBF response to hypoglycemia was seen in the diabetic rats, with the CBF increasing from 114 +/- 28 (hyperglycemia) to 270 +/- 204 ml 100 g-1 min-1 (p less than 0.05), compared to a change from 147 +/- 36 (normoglycemia) to 455 +/- 299 ml 100 g-1 min-1 (p less than 0.05) in the control group.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cerebrovascular and cerebrometabolic effects of intracarotid infused platelet-activating factor in rats

Platelet-activating factor has been implicated in a variety of disease processes including ischemic brain injury and endotoxic shock, but its effects on cerebral blood flow (CBF) and metabolism in normal brain have not been described. The effects of platelet-activating factor on global CBF (hydrogen clearance) and the global cerebral metabolic rate for oxygen (CMRO2) were studied in halothane-N2O anesthetized Wistar rats. Hexadecyl-platelet-activating factor infused into the right carotid artery (67 pmol/min) for 60 min decreased mean arterial pressure (MAP) from 122 +/- 4 (x +/- SEM) to 77 +/- 6 mm Hg and CBF from 159 +/- 12 to 116 +/- 14 ml/100 g/min (p less than 0.002). In contrast, CMRO2 increased from 9.7 +/- 0.9 to 11.7 +/- 1.1 ml/100 g/min after 15 min (p less than 0.05). In controls rendered similarly hypotensive by blood withdrawal and infused with the platelet-activating factor vehicle, CMRO2 was unchanged, whereas CBF transiently decreased then returned to baseline at 60 min. These cerebrovascular and cerebrometabolic effects of PAF are reminiscent of and may be relevant to hypoperfusion and hypermetabolism observed after global brain ischemia and in endotoxic shock.     

Local cerebral blood flow is preserved in sepsis

Sepsis is often complicated by encephalopathy, neuroendocrine dysfunction and cardiovascular autonomic failure. The cause of septic brain dysfunction is not fully understood. The aim of the present study is to explore whether septic brain dysfunction in a common septic model in the rat correlates with abnormalities either of local cerebral blood flow (LCBF) of defined brain areas or of whole brain blood flow (CBF). 45 male Wistar rats (320+/-13 g) were randomly assigned to a sepsis group (31 rats, cecal ligature and puncture, CLP) or a control group (14 rats, sham operation). Of these 45 rats, 16 rats were used for blood analysis; the remaining 29 rats were used for CBF/LCBF measurements. LCBF measurements were performed 24h after initial surgery using quantitative autoradiography with 4-iodo[N-methyl-(14)C]antipyrine, which allows to analyze CBF on a regional/local and global basis. In 42 different brain regions bilateral optical density measurements were performed. Septic rats (vs. control) presented tachycardia (507+/-37 vs. 452+/-44 min(-1), P<0.05), leukocytopenia (2.96+/-2.37 vs. 8.83+/-2.9710(9) x L(-1), P<0.05), hypocapnia (29.3+/-4.6 vs. 36.4+/-3.9 mmHg, P<0.05), and higher serum lactate concentrations (5.7+/-3.9 vs. 2.2+/-2.0 mmol x L(-1), P<0.05). LCBF of all 42 areas, as well as, CBF (116+/-59 vs. 115+/-52 m x 100 g(-1)min(-1), n.s.) did not differ. The results showed that severe sepsis (mortality rate of 43 %) did not induce alterations in mean CBF and LCBF. It is concluded that brain dysfunction is not reflected in changes of CBF during severe sepsis.     

Cerebral blood flow and metabolism in soman-induced convulsions

Regional cerebral blood flow (CBF) and regional cerebral glucose utilization (CGU) were studied by quantitative autoradiographic techniques in rats. Animals were treated either with a toxic dose of soman, an irreversible organophosphorus cholinesterase inhibitor, that produced convulsions or with saline as controls. An increased arterial blood pressure (mean increase = 41% of control) always preceded onset of convulsions. Convulsive activity was associated with an increase of plasma glucose concentration and marked increases over controls of CGU [average of all regions: control = 75 +/- 5 mumol.100 g-1.min-1, n = regions/animals (304/8); seizures = 451 +/- 20 mumol.100 g-1.min-1, n = 190/5] and CBF [average of all regions: control = 135 +/- 6 ml.100 g-1.min-1, n = 190/5; seizures = 619 +/- 29 ml.100 g-1.min-1, n = 190/5). Regional distribution of these effects revealed a greater proportional increase of CBF over CGU in cingulate, motor, and occipital cortex and caudate-putamen. In contrast, a lower proportional increase of CBF over CGU in CA3 region of hippocampus, dentate gyrus, medial thalamus, and substantia nigra was observed, implying the existence of a relative ischemia in these brain areas. These findings may be relevant to the pathogenesis of brain lesions associated with soman-induced convulsions.     

Disruption of blood-brain barrier following bilateral carotid artery occlusion in spontaneously hypertensive rats. A quantitative study

The present study was designed to clarify the relationship of cerebral blood flow (CBF) to blood-brain barrier (BBB) in the ischemic brains with or without recirculation, which were produced by clipping of both common carotid arteries in spontaneously hypertensive rats. CBF was measured by the hydrogen clearance method and BBB function was evaluated by the permeability of 131I-albumin and Evans blue dye. Cortical CBF was reduced from 48.8 +/- 9.5 to 4.0 +/- 1.2 ml/100 gm/min during 1 hr ischemia and further to 2.6 +/- 0.3 ml/100 gm/min during 3 hrs ischemia, while thalamic CBF was reduced much less from 50.0 +/- 3.6 to 17.9 +/- 6.5 ml/100 gm/min and to 17.5 +/- 11.0 ml/100 gm/min, respectively. There was no increase in permeability to protein tracers observed in such 1 hr or 3 hrs ischemic brain. Both cortical and thalamic CBF were markedly increased 2.5 to 6 fold of resting values at 5 min after recirculation in the 1 hr ischemic brain. In the 3 hrs ischemic brain, however, both CBF were only slightly increased but never restored to the resting level even at 30 min after recirculation. In such reperfused brains, exudation to Evans blue dye was observed in none of 16 animals with 1 hr ischemia, but in 18 of 23 with 3 hrs ischemia. Disruption of BBB was twice more frequent in the cortex (77.8%) than in either thalamus (33.3%) or hippocampus (33.3%). Permeability index of 131I-albumin (brain albumin/blood albumin) was significantly higher in the ischemic areas stained with blue dye (2.07 +/- 0.45%) than in non-ischemic control brain (0.10 +/- 0.01%).(ABSTRACT TRUNCATED AT 250 WORDS)     

Chemical stimulation of the nucleus tractus solitarii decreases cerebral blood flow in anesthetized rats

In anesthetized (chloralose and urethane), paralyzed and artificially ventilated rats, the neurons in the nucleus tractus solitarius (NTS) were chemically stimulated by microinjections of L-glutamate and the cerebral blood flow (CBF) was determined using a combination of labeled microspheres (either 57Co, 113Sn and 46Sc or 141Ce, 85Sr and 46Sc). Unilateral chemical stimulation of the NTS (n = 14) decreased CBF significantly in most brain areas. The decrease in CBF was not due to the decrease in arterial blood pressure (ABP) because the CBF of the whole cerebral cortex during the chemical stimulation of the NTS was significantly smaller (P less than 0.05) than the CBF during controlled hemorrhagic hypotension (n = 10). In another group of rats (n = 6), moderate hypertension was induced by blood transfusion. Unilateral chemical stimulation of the NTS in these rats decreased ABP but it remained within normotensive range. A significant (P less than 0.05) decrease in CBF (from 62 +/- 28 (mean +/- S.D.) to 48 +/- 23 ml.min-1.(100 g)-1) and increase in cerebrovascular resistance (from 1.9 +/- 1.2 to 2.6 +/- 1.2 mm Hg per [ml.min-1.(100 g)-1]) was observed in the whole cerebral cortex of these rats. Chemical stimulation of the NTS did not affect the reactivity of the cerebral vessels to hypercapnea (n = 5). These results suggest that the cell bodies within the NTS may play a role in the control of cerebral circulation.     

Regional cerebral hemodynamics among hypertensive patients with lacunar infarctions during blood pressure control in subacute and chronic phases.

In hypertensive acute stroke patients, the use of antihypertensive treatment is often delayed because autoregulation of cerebral blood flow (CBF) is often impaired during the first 4 weeks after large brain infarctions. However, little is known as to whether such delay is necessary in cases of small to moderate size brain infarction. We compared changes of regional CBF during antihypertensive treatment in subacute and chronic phases of lacunar infarction. Blood pressure was controlled with an angiotensin-converting enzyme inhibitor (n=6) or dihydropyridine calcium antagonist (n=8), administered orally for 2 weeks during the subacute (n=7) and chronic phases after (n=7) lacunar infarction. CBF was measured by the stable xenon-computed tomography (CT) method. Blood pressure decreased significantly from 132+/-20 mm Hg (mean+/-standard deviation) to 118+/-14 mm Hg (P<.05, paired t-test) in subacute patients and from 135+/-17 mm Hg to 113+/-12 mm Hg (P<.001, paired t-test) in chronic patients. There was no significant reduction either in mean hemispheric blood flow or in deep white matter blood flow during each phase. We condlude that mild control of blood pressure among hypertensive patients with lacunar infarctions does not produce clinically significant decreases in regional CBF during subacute phases of infarction.     

Regional cerebral blood flow and BOLD responses in conscious and anesthetized rats under basal and hypercapnic conditions: implications for functional MRI studies.

Anesthetics, widely used in magnetic resonance imaging (MRI) studies to avoid movement artifacts, could have profound effects on cerebral blood flow (CBF) and cerebrovascular coupling relative to the awake condition. Quantitative CBF and tissue oxygenation (blood oxygen level-dependent [BOLD]) were measured, using the continuous arterial-spin-labeling technique with echo-planar-imaging acquisition, in awake and anesthetized (2% isoflurane) rats under basal and hypercapnic conditions. All basal blood gases were within physiologic ranges. Blood pressure, respiration, and heart rates were within physiologic ranges in the awake condition but were depressed under anesthesia (P < 0.05). Regional CBF was heterogeneous with whole-brain CBF values of 0.86 +/- 0.25 and 1.27 +/- 0.29 mL. g-1. min-1 under awake and anesthetized conditions, respectively. Surprisingly, CBF was markedly higher (20% to 70% across different brain conditions) under isoflurane-anesthetized condition compared with the awake state (P < 0.01). Hypercapnia decreased pH, and increased Pco(2) and Po(2). During 5% CO(2) challenge, under awake and anesthetized conditions, respectively, CBF increased 51 +/- 11% and 25 +/- 4%, and BOLD increased 7.3 +/- 0.7% and 5.4 +/- 0.4%. During 10% CO(2) challenge, CBF increased 158 +/- 28% and 47 +/- 11%, and BOLD increased 12.5 +/- 0.9% and 7.2 +/- 0.5%. Since CBF and BOLD responses were substantially higher under awake condition whereas blood gases were not statistically different, it was concluded that cerebrovascular reactivity was suppressed by anesthetics. This study also shows that perfusion and perfusion-based functional MRI can be performed in awake animals.     

Effect of salbutamol on regional cerebral oxygen consumption, flow and capillary and arteriolar perfusion

This study quantitatively determined the effect of salbutamol (1 microgram kg-1), a beta 2-adrenoceptor agonist, on the perfusion of the brain microvasculature, cerebral O2 consumption, O2 extraction and cerebral blood flow (CBF) in conscious rat. Indices of arteriolar and capillary structure and the percentage of the total cerebral microvascular volume/mm3 (% Vv) and number/mm2 (% Na) perfused were determined. These parameters were obtained from the perfused microvessels, identified by the presence of fluorescein isothiocyanate (FITC) - dextran, and compared with the entire microvascular bed, identified by alkaline phosphatase stain. Cerebral O2 extraction was determined microspectrophotometrically and CBF was determined using 14[C]iodoantipyrine in another group of salbutamol-treated rats. The acute administration of salbutamol did not alter systemic arterial blood pressure. Significant tachycardia was noted in the salbutamol-treated rats. Salbutamol resulted in a significant increase in the percentage of arterioles perfused. Average percentage perfused capillary Na increased significantly from 46 +/- 2 to 88 +/- 1%; %Vv increased significantly and similarly in the arteriolar and capillary beds in all brain regions examined. Average cerebral O2 consumption increased significantly from 3.0 +/- 0.2 to 7.4 +/- 0.7 ml O2 min-1 100 g-1 with salbutamol, while cerebral O2 extraction was unchanged. Average CBF increased from 50 +/- 2 to 142 +/- 9 ml min-1 100 g-1 with salbutamol. Salbutamol may increase the perfusion of the regional microvasculature by increasing cerebral O2 consumption (metabolic vasodilation) and CBF and microvascular perfusion secondarily, although a direct effect of salbutamol on cerebral microvessels cannot be ruled out.     

In vivo measurements of brain glucose transport using the reversible Michaelis-Menten model and simultaneous measurements of cerebral blood flow changes during hypoglycemia.

Glucose is the major substrate that sustains normal brain function. When the brain glucose concentration approaches zero, glucose transport across the blood-brain barrier becomes rate limiting for metabolism during, for example, increased metabolic activity and hypoglycemia. Steady-state brain glucose concentrations in alpha-chloralose anesthetized rats were measured noninvasively as a function of plasma glucose. The relation between brain and plasma glucose was linear at 4.5 to 30 mmol/L plasma glucose, which is consistent with the reversible Michaelis-Menten model. When the model was fitted to the brain glucose measurements, the apparent Michaelis-Menten constant, Kt, was 3.3 +/- 1.0 mmol/L, and the ratio of the maximal transport rate relative to CMRglc, Tmax/CMRglc, was 2.7 +/- 0.1. This Kt is comparable to the authors' previous human data, suggesting that glucose transport kinetics in humans and rats are similar. Cerebral blood flow (CBF) was simultaneously assessed and constant above 2 mmol/L plasma glucose at 73 +/- 6 mL 100 g(-1) min(-1). Extrapolation of the reversible Michaelis-Menten model to hypoglycemia correctly predicted the plasma glucose concentration (2.1 +/- 0.6 mmol/L) at which brain glucose concentrations approached zero. At this point, CBF increased sharply by 57% +/- 22%, suggesting that brain glucose concentration is the signal that triggers defense mechanisms aimed at improving glucose delivery to the brain during hypoglycemia.     

The angiotensin II type 1-receptor blocker candesartan increases cerebral blood flow, reduces infarct size, and improves neurologic outcome after transient cerebral ischemia in rats.

The goal of the present study was to test the impact of administration time of the angiotensin II type 1-receptor blocker candesartan on cerebral blood flow (CBF), infarct size, and neuroscore in transient cerebral ischemia. Therefore, 1-hour middle cerebral artery occlusion (MCAO) was followed by reperfusion. Rats received 0.5-mg/kg candesartan intravenously 2 hours before MCAO (pretreatment), 24 hours after MCAO, every 24 hours after MCAO, or 2 hours before and every 24 hours after MCAO. Infarct size (mm3) and a neuroscore at day 7 were compared with controls. CBF was quantified by radiolabeled microspheres and laser-Doppler flowmetry. Compared with controls (95 +/- 8), infarct size in candesartan-treated groups was smaller (59 +/- 5, 68 +/- 10, 28 +/- 3, and 15 +/- 3, respectively; P<0.05). Although there was no difference in neuroscore between pretreatment and controls (1.55 +/- 0.18, 1.80 +/- 0.13), other treatment regimens resulted in improved neuroscores (1.33 +/- 0.16, 1.11 +/- 0.11, 0.73 +/- 0.15; P<0.05). CBF in pretreated animals at 0.5 hours after MCAO was significantly higher than in controls (0.58 +/- 0.09 mL x g(-1) x min(-1) and 44% +/- 7% of baseline compared with 0.49 +/- 0.06 mL x g(-1) x min(-1) and 37% +/- 6%, microspheres and laser-Doppler flowmetry; P<0.05). Thus, candesartan reduces infarct size even if administered only during reperfusion. Apart from pretreatment, other treatment regimens result in significantly improved neuroscores. In the acute phase of cerebral ischemia, candesartan increases CBF.     

CBF and transcranial Doppler sonography during vasodilatory stress tests in patients with common carotid artery occlusion.

Cerebral blood flow (CBF) and the cerebral vasoreactivity was measured in patients with cerebrovascular disease and longstanding occlusion of the common carotid artery (CCA). In addition, regional CBF was correlated with transcranial doppler (TCD) measurements at baseline and during 6% CO2 inhalation and after intravenous administration of 1 g of acetazolamide. Twelve patients with a mean age of 62 years (range 45 to 71 years) were included, and the data compared to age-matched healthy controls. CBF was measured by intravenous injection of xenon-133 and SPECT (Tomomatic 564). TCD of the middle cerebral artery (MCA) was done by EME TC-64B. A very low global CBF value of 28 +/- 5 (SD) ml 100 g-1 min-1 was found at baseline as compared to 55 +/- 5 ml 100 g-1 min-1 in the normal controls. During 6% CO2-inhalation and after acetazolamide administration, CBF increased by 58 +/- 24% and 51 +/- 21%, respectively, indicating substantial collateral supply. Correlative analysis of CBF in the MCA territory and TCD in the MCA showed statistical significance only for the pooled data, i.e. compiling the data obtained during baseline and the two vasodilatory tests, and then only for the mean and peak TCD velocity (e.g. r = 0.59, p less than 0.002, n = 35, mean velocity, right side). We conclude that TCD measurements do not predict regional CBF in patients with CCA occlusion. The study emphasizes that these two methods yield supplementary information, with TCD measurements providing information of the circle of Willis and CBF studies of the flow distribution.     

Intra-aortic balloon counterpulsation: a treatment for ischaemic stroke?

Intra-aortic balloon counterpulsation (IABC) augments cardiac output (CO) and pulse pressure (PP) allowing patients with low output heart failure to be supported for a period of time. Augmentation of CO and PP may also be beneficial to the patient with acute cerebral ischaemia. In this paper we investigated the possibility of using IABC to increase local cerebral blood flow (CBF) in ischaemic brain. In 12 anaesthetized mongrel dogs, a canine stroke model was produced by occluding the left internal carotid and middle cerebral arteries with aneurysm clips. Six dogs were then treated with IABC for 2 h, and 6 other dogs acted as controls (no IABC). Haemodynamic data were measured continuously and CBF (microsphere technique) and CO measurements were performed pre- and post-occlusion, and then twice during the treatment period. In the IABC-treated animals, PP increased from 32 +/- 5.9 to 39 +/- 7.8 mmHg (p less than 0.01) but CO and local CBF in the ischaemic brain did not change significantly during IABC. However, in 4 dogs with significant increases in CO due to IABC [1.7 +/- 0.3 to 2.8 +/- 0.7 l/min (p less than 0.05)], local CBF in ischaemic brain also increased significantly from 22 +/- 12 to 26 +/- 11 cc/100 g/min (p less than 0.05). In the control animals, CO and local CBF did not change significantly during the observation period. These data suggest that augmentation of CO and PP by IABC results in an increase in local CBF in ischaemic brain. IABC may be an effective treatment for ischaemic stroke in those patients with compromised cardiac performance whose cardiac output and pulse pressure can be augmented by IABC.     

The development of cerebral perfusion in healthy preterm and term neonates

Quantitative measurement of cerebral blood flow (CBF) volume was performed by sonographic flowmetry of both internal carotid (ICA) and vertebral arteries (VA) in 113 healthy preterm and term infants of 32 - 42 weeks postmenstrual age (PA) in order to delineate the physiological characteristics of brain perfusion in a time period very sensitive to brain injury. Mean CBF volume increased with PA, beginning with 33 +/- 9 ml/min in neonates of 32 - 34 weeks and rising to 45 +/- 10, 58 +/- 13, 69 +/- 14, and 83 +/- 16 ml/min, respectively, in the PA groups of 35 - 36, 37 - 38, 39 - 40 and 41 - 42 weeks. There was no difference in CBF volume between the sexes. The bilateral sum of flow volumes in both ICA and VA rose markedly with PA. The relative contribution of bilateral VA flow volume to total CBF volume was 26 +/- 8 % and remained constant with PA. In addition, we calculated the approximate CBF (ml/100 g brain weight/min) using the brain weights of each child as estimated by means of an equation based on head circumference measurements. Estimated CBF correlated significantly with PA (r = 0.49; p 相似文献   

Chemical stimulation of the ventrolateral medullary depressor area decreases ipsilateral cerebral blood flow in anesthetized rats.

In anesthetized (chloralose and urethane), paralyzed and artificially ventilated rats, the neurons in the ventrolateral medullary depressor area (VLDA) were chemically stimulated by microinjections of L-glutamate (2.5-5 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). Unilateral chemical stimulation of the VLDA (n = 11) produced a significant (P less than 0.05) decrease in CBF of the cerebral cortex ipsilateral to the stimulated VLDA; the CBF was 41 +/- 5 (mean +/- S.E.M.) and 29 +/- 4 ml.min-1.(100 g)-1 before and during the chemical stimulation of VLDA. The decrease in CBF was not due to the decrease in arterial blood pressure (ABP) caused by the chemical stimulation of the VLDA because the CBF during the chemical stimulation of the VLDA was significantly smaller (P less than 0.01) than the CBF during controlled hemorrhagic hypotension (n = 10). In another group of rats (n = 6), moderate hypertension was induced by blood transfusion. Unilateral chemical stimulation of the VLDA in these rats decreased ABP but it remained within normotensive range. A significant (P less than 0.05) decrease in CBF (from 46 +/- 12 to 29 +/- 7 ml.min-1.(100 g)-1) and a significant (P less than 0.01) increase in cerebrovascular resistance (from 2.7 +/- 0.4 to 4.3 +/- 0.6 mmHg per [ml.min-1.(100 g)-1]) was observed in the ipsilateral cerebral cortex of these rats. Chemical stimulation of the VLDA did not affect the reactivity of the cerebral vessels to hypercapnea (n = 5).(ABSTRACT TRUNCATED AT 250 WORDS)     

Incidence and mechanisms of cerebral ischemia in early clinical head injury.

Antemortem demonstration of ischemia has proved elusive in head injury because regional CBF reductions may represent hypoperfusion appropriately coupled to hypometabolism. Fifteen patients underwent positron emission tomography within 24 hours of head injury to map cerebral blood flow (CBF), cerebral oxygen metabolism (CMRO2), and oxygen extraction fraction (OEF). We estimated the volume of ischemic brain (IBV) and used the standard deviation of the OEF distribution to estimate the efficiency of coupling between CBF and CMRO2. The IBV in patients was significantly higher than controls (67 +/- 69 vs. 2 +/- 3 mL; P < 0.01). The coexistence of relative ischemia and hyperemia in some patients implies mismatching of perfusion to oxygen use. Whereas the saturation of jugular bulb blood (SjO2) correlated with the IBV (r = 0.8, P < 0.01), SjO2 values of 50% were only achieved at an IBV of 170 +/- 63 mL (mean +/- 95% CI), which equates to 13 +/- 5% of the brain. Increases in IBV correlated with a poor Glasgow Outcome Score 6 months after injury (rho = -0.6, P < 0.05). These results suggest significant ischemia within the first day after head injury. The ischemic burden represented by this "traumatic penumbra" is poorly detected by bedside clinical monitors and has significant associations with outcome.     

Regional cerebral blood flow autoregulation in normotensive and spontaneously hypertensive rats--effects of sympathetic denervation

The present study was designed to investigate the effect of acute sympathetic denervation on the regional cerebral blood flow (CBF) autoregulation during acute elevation of blood pressure in spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY). CBF to the parietal cortex and thalamus was measured by the hydrogen clearance method and, to test autoregulation, systemic arterial blood pressure was elevated by intravenous infusion of phenylephrine. Superior cervical ganglia were removed on both sides to interrupt sympathetic innervation in the deeper structures of the brain. Acute bilateral sympathetic denervation did not alter the resting blood pressure or CBF in either SHR or WKY. In innervated SHR, resting mean arterial pressure (MAP) was 165 +/- 5 mm Hg (mean +/- SEM) and the upper limit of autoregulation in the cortex was 210 +/- 3 mm Hg, which was significantly lower than that in the thalamus (229 +/- 3 mm Hg, p less than 0.02). In bilaterally denervated SHR, the upper limits were lowered to 193 +/- 4 mm Hg in the cortex (p less than 0.02 vs. innervated SHR) and to 207 +/- 5 mm Hg in the thalamus (p less than 0.02 vs. innervated). In WKY, resting MAP was approximately 55 mm Hg lower than that in SHR. Acute denervation reduced the upper limits from 142 +/- 3 mm Hg to 130 +/- 4 in the cortex (p less than 0.05) and from 158 +/- 4 to 145 +/- 4 in the thalamus (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Protective effect of the 20-HETE inhibitor HET0016 on brain damage after temporary focal ischemia.

Cytochrome P450 metabolism of arachidonic acid produces the potent vasoconstrictive metabolite, 20-hydroxyeicosatetraenoic acid (20-HETE). Recent studies have implicated 20-HETE as a vasoconstrictive mediator in hemorrhagic stroke. The purpose of this study was to determine the effect of the 20-HETE inhibitor, HET0016, on lesion volume and cerebral blood flow (CBF) after temporary middle cerebral artery occlusion (MCAO) in rats. Plasma pharmacokinetics and tissue concentrations of HET0016 were determined after a 10 mg/kg intraperitoneal dose. Separate rats were treated with HET0016 or vehicle before 90 mins of MCAO. Lesion volume was assessed by 2,3,5-triphenyl-tetrazolium-chloride and cerebral flow was determined using laser Doppler flow. The effect of MCAO on in vitro microsomal formation of mono-oxygenated arachidonic acid metabolites was also determined. Results show that HET0016 has a short biologic half-life, distributes into the brain, and is associated with a 79.6% reduction in 20-HETE concentration in the cortex. Lesion volume was greatly reduced in HET0016-treated (9.1%+/-4.9%) versus vehicle-treated (57.4%+/-9.8%; n=6; P<0.001) rats. An attenuation of the observed decrease in CBF was observed in HET0016-treated (180 mins 89.2%+/-6.2%; 240 mins 88.1%+/-5.7% of baseline flow) versus vehicle control (180 mins 57.6%+/-19.0%; 240 mins 53.8%+/-20.0% of baseline flow; n=6; P<0.05). Brain cortical microsomal formation rate of 20-HETE was also reduced at 24 h in the ipsilateral hemisphere after MCAO. These data support a significant role for 20-HETE in the pathogenesis of ischemic stroke.     

Effects of cortical spreading depression on cortical blood flow, impedance, DC potential, and infarct size in a rat venous infarct model

A cortical venous infarction model has been evaluated as to the degree of regional flow reduction and by studying effects of cortical spreading depression (CSD). Two adjacent cortical veins were occluded photochemically with rose bengal and fiberoptic illumination. Seven rats served to demonstrate effects on regional cortical blood flow using laser Doppler scanning. In 36 rats local CBF, DC potential, and brain tissue impedance were measured continuously for 75 min after vein occlusion. No, 3, or 10 CSD waves were induced by potassium chloride injection during the initial 75 min. Rats were compared for spontaneous CSDs; baseline local CBF, CBF, and impedance response to CSD; and infarct volume. Seventy-five minutes after vein occlusion regional cortical flow in a 3.5x7-mm window was reduced to 34.3+/-13.2%. At 45% of the 840 measured locations in 7 rats flow was <40% baseline and at 27.3% <30%, indicating a widespread penumbra territory. During the initial 75 min 2.1+/-1.1 spontaneous CSDs were observed. There was a positive correlation between the number of spontaneous CSDs seen acutely and infarction volume after 5 days. Moreover, brain injury was significantly increased in the group with 10 KCl-induced CSDs. A reduced 1CBF response and an overshooting tissue impedance change during CSD were predictors of ischemic damage. This study demonstrates a CSD-related growth of the venous infarct. Second, the data indicate that flow after two-vein occlusion resembles that seen under penumbra conditions, allowing for studies of damage mechanisms responsible for infarct growth.     

Estrogen receptor antagonist ICI182,780 exacerbates ischemic injury in female mouse.

Recent findings in animals emphasize that experimental ischemic brain damage can be strikingly reduced by estrogen: however, the neuroprotective mechanisms are not well understood. It was hypothesized that estrogen signaling via cognate estrogen receptors (ERs) within the vasculature is an important aspect of cerebral ischemic protection in the female brain, in part by amplifying intraischemic cerebral blood flow (CBF). In the present study, the hypothesis that chronic treatment with the pure ER antagonist ICI182,780 (ICI) would increase ischemic brain damage by a blood flow-mediated mechanism was investigated. Adult C57B1/6J mice were pretreated with either subcutaneous ICI (100 microg/day) or oil/ethanol vehicle for 1 week before 2 hours of middle cerebral artery occlusion (MCAO) and 22 hours of reperfusion. End-ischemic regional CBF was evaluated in additional cohorts using [14C]iodoantipyrine autoradiography. Infarction volume as measured by cresyl violet histology was greater in the striatum of ICI-treated females (70 +/- 3% of contralateral striatum vs. 40 +/- 12% in vehicle-treated females). Cortical injury was not enhanced relative to control animals (39 +/- 6% of contralateral cortex in ICI group vs. 27 +/- 8% in vehicle-treated group). Physiologic variables and ischemic reduction of the ipsilateral cortical laser-Doppler flow signal were similar between groups. Further, ICI treatment did not alter end-ischemic cortical or striatal CBF. The deleterious effect of ICI was limited to females, as there were no differences in stroke damage or CBF between male treatment groups. These data suggest that estrogen inhibits ischemic brain injury in striatum of the female by receptor-mediated mechanisms that are not linked to preservation of intraischemic CBF.