Effect of hypocapnia on cerebral oxygen metabolism and blood flow in ischemic cerebrovascular disorders

Effects of hypocapnia on cerebral oxygen consumption (CMRO2) and blood flow (CBF) in cerebral ischemia were studied in 19 patients. The CMRO2 did not change significantly during hypocapnia within the whole group of patients, because 10 out of 19 cases showed a decrease (p less than 0.001) and other 9 showed an increase (p less than 0.01) of CMRO2 during hypocapnia. The first 10 showed higher resting CMRO2 (p less than 0.001) and arteriovenous differences of oxygen content (AVDO2; p less than 0.02) than the other 9. However, the resting CBF and CO2 reactivity to hypocapnia were not different between them, and clinical situations were also similar. A dissociation between flow and metabolism was suggested in the first 10 with rather preserved CMRO2, while reduced metabolic demands were suggested in the other 9. Different responses of CMRO2 to hypocapnia are expected in cerebral ischemia, i.e. in cases with rather preserved CMRO2 it decreases despite an AVDO2 increase, suggesting a capability of CMRO2 to respond to CBF reduction, while it increases in cases with more decreased CMRO2, as the AVDO2 increase exceeds the CBF reduction to maintain the decreased CMRO2 for a further CBF reduction. The vascular CO2 reactivity, therefore, might be maintained to be constant between these patients.     

Cerebrovascular and metabolic changes during the delayed vasospasm following experimental subarachnoid hemorrhage in baboons, and treatment with a calcium antagonist

A model has been designed in baboons for simulating the clinical situation during the late phase of vasospasm in patients with subarachnoid hemorrhage (SAH). A total amount of 14-33 ml autologous blood was injected into the cisternal system on 3 occasions in the course of 4 days. Neurological symptoms were seen, and the mortality rate was 29%. Angiography 3 days after the last injection showed arterial vasoconstriction amounting to 23% in the vertebro-basilar system, and 11% (right) and 18% (left) in the carotid system. Cerebral blood flow (CBF) measured by the intra-arterial 133Xe technique and the cerebral metabolic rate of oxygen (CMRO2) were reduced by 18% and 11%, respectively. The hypercapnic CBF response was significantly impaired, from a mean of 3.90 ml/100 g/min to 1.72 ml/100 g/min of flow increase for each mm Hg elevation of paCO2. Autoregulation, tested by administration of angiotensin II, was also significantly affected as evidenced by a pressure-dependent increment of CBF during hypertension in 5 out of 7 animals tested. The impaired autoregulation was reflected in the autoregulatory index, which in the whole group increased from 0.06 ml/100 g/min for each mm Hg increase in MABP in the pre-SAH animals to 0.29 ml/100 g/min per mm Hg post-SAH. Treatment with the calcium antagonist, nimodipine (0.5 microgram/kg/min i.v. during 45 min), enhanced CBF significantly by 17% before experimental SAH, whereas after SAH the effect was slight and did not reach statistical significance; CMRO2 was not significantly affected in either group. Intravenous nimodipine combined with hypertension resulted in a marked increase in the autoregulatory index to 1.58 ml/100 g/min per mm Hg in pre-SAH animals and a less pronounced increment to 0.58 ml/100 g/min per mm Hg following experimental SAH. The beneficial effect of nimodipine reported in SAH patients is therefore, in view of our findings, more likely due primarily to a protective mechanism at the cellular level than to an influence on the vascular bed.     

The effects of hyponatraemia and subarachnoid haemorrhage on the cerebral vasomotor responses of the rabbit

Impairment of cerebral autoregulation and development of hyponatraemia are both implicated in the pathogenesis of delayed cerebral ischaemia and infarction following subarachnoid haemorrhage (SAH) but the pathophysiology and interactions involved are not fully understood. We have studied the effects of hyponatraemia and SAH on the cerebral vasomotor responses of the rabbit. Cerebrovascular reactivity to hypercapnia and cerebral autoregulation to trimetaphan-induced hypotension were determined in normal and hyponatraemic rabbits before and 6 days after experimental SAH produced by two intracisternal injections of autologous blood. Hyponatraemia (mean plasma sodium of 119 mM) was induced gradually over 48 h by administration of Desmopressin and intraperitoneal 5% dextrose. Sham animals received normal saline. The cerebrovascular reactivity (% change +/- SD in cortical CBF/mm Hg PaCO2, measured by hydrogen clearance) of hyponatraemic (4.8 +/- 3.0%) and SAH (1.3 +/- 2.0%) animals was significantly less (p less than 0.05) than control (11.6 +/- 4.0%) and sham (8 +/- 2.0%) animals, whereas the reactivity of hyponatraemic-SAH animals was preserved (9.8 +/- 6.0%). Hyponatraemia and SAH alone each significantly impaired CBF autoregulation but their combined effects were not additive. Systemic hyponatraemia impairs normal cerebral vasomotor responses but does not augment the effects of experimental SAH in the rabbit.     

Cerebrovascular effects of prostaglandin inhibitors in the gerbil

Autoregulation of cerebral blood flow (CBF) to mean arterial blood pressure (MABP) of 40-50 mm Hg has been demonstrated in the spontaneously breathing gerbil anaesthetised with barbiturate (60 mg/kg). CO2 reactivity has also been assessed at 2.8% change CBF/mm Hg change in arterial PCO2. In six animals pretreated with indomethacin (3 mg/kg), autoregulation was preserved although the resting CBF was significantly reduced, but CO2 reactivity was completely abolished. 1-n-Butyl imidazole, a specific thromboxane synthetase inhibitor, was used in six other animals (3 mg/kg), and this abolished CO2 reactivity while preserving autoregulation; the effect of this agent has not been described previously. Both drugs inhibit different pathways of prostaglandin metabolism and may interfere with normal CO2 reactivity in several ways. Two explanations are that prostaglandins constitute the final common pathway in effecting cerebrovascular response to CO2 or, alternatively, that the free radicals and ionic fluxes generated during prostaglandin metabolism are a coincidental source of the hydrogen ion changes required.     

Changes in cerebral blood flow and metabolism following intraarterial or local administration of nimodipine, before and after experimental subarachnoid hemorrhage in baboons

Experimental subarachnoid hemorrhage (SAH) was induced in baboons by repeated injections of autologous blood into cisterna chiasmatis and cisterna magna, a total of 14-33 ml being injected over 3-4 days. Cerebral blood flow (CBF; 133xenon clearance) and cerebral metabolic rate of oxygen (CMRO2) were measured before, and 7 days after, the first blood injection. The effect of the calcium channel blocker, nimodipine, used in a commercially available form for clinical application, was studied following continuous i.a. infusion (0.1 microgram X kg-1 X min-1) for an interval of 45 min, and also 20 and 60 min after intrathecal administration of 1 microgram X kg-1. During the infusion experiments, CBF was increased by 25-30% both before and after the cisternal blood injection. CMRO2 was also enhanced, but much less. Nimodipine in doses given did not alter systemic blood pressure. Following intrathecal application, CBF and CMRO2 slightly increased at 20 min only before experimental SAH.     

Haemodynamic and metabolic disturbances in the acute stage of subarachnoid haemorrhage demonstrated by PET

OBJECTIVE: To investigate the occurrence of early haemodynamic and metabolic changes in the acute stage of subarachnoid haemorrhage (SAH). MATERIAL AND METHODS: Eleven SAH patients were studied. Regional cerebral blood flow (CBF), cerebral metabolic rate of oxygen (CMRO2) and oxygen extraction ratio (OER) were measured with positron emission tomography (PET) 22-53 h after haemorrhage, utilizing 15O-labelled water bolus and the 15O-inhalation technique. Ten volumes of interest (VOIs) representing vascular territories were outlined in each patient according to a standardized procedure. The occurrence of irreversible ischaemia, penumbra, oligaemia, hyperperfusion and normal haemodynamics according to PET criteria was investigated. These pathophysiological categories were related to final tissue outcome as determined by follow-up computed tomography (CT). RESULTS: All five tissue subtypes were represented in the vascular region VOIs; oligaemia was the predominant pathophysiological pattern. When global changes were analysed, blood flow was reduced in three, oxygen metabolism was reduced in four, and OER was increased in four of seven unsedated patients, respectively. The sedated patients all had markedly reduced CBF and CMRO2 and OER in the high or supranormal range. CONCLUSION: Haemodynamic and metabolic disturbances proved to be common after SAH. These abnormalities probably reflect the primary brain injury caused by the initial haemorrhage. The impact of secondary insults such as acute hydrocephalus, brain oedema, vasospasm, seizures, hypotension and hypoxaemia are likely to be dependent on the degree of primary injury, which can be assessed by PET.     

The role of adenosine in the vascular adaptation of neonatal cerebral blood flow during hypotension

This study investigated the potential role of adenosine in cerebral blood flow (CBF) regulation in the neonate during moderate and severe hypotension. Experiments were done in anesthetized, 1- to 3-day-old piglets. Regional CBF (determined by radiolabeled microsphere technique) and cerebral metabolic rate for O2 (CMRO2) were measured (a) during normotension and (b) during a 3-min period of moderate (58 +/- 9 mm Hg) or severe (36 +/- 7 mm Hg) hypotension produced by the inflation of a balloon catheter placed in the aortic root. Measurements of CBF and CMRO2 were performed successively after intracerebroventricular (i.c.v.) injections of vehicle (n = 17), the adenosine receptor blocker 8-phenyltheophylline (8-PT, 10 micrograms, n = 14), and the A2-receptor agonist 5'-N-(ethylcarboxamide)adenosine (NECA, 2 ng, n = 8). After i.c.v. administration of vehicle, none of the parameters studied was significantly altered by moderate hypotension, but severe hypotension decreased the total CBF (mean +/- SD) from 86 +/- 24 to 40 +/- 15 ml min-1 100 g-1 and CMRO2 from 3.2 +/- 0.8 to 1.8 +/- 1.0 ml min-1 100 g-1 (p less than 0.05). Administration of 8-PT did not alter these parameters during normotension, but significantly decreased CBF during moderate hypotension compared to postvehicle values (53 +/- 11 versus 81 +/- 12 ml min-1 100 g-1, p less than 0.05). This loss of autoregulation was completely reversed by NECA. During severe hypotension, 8-PT altered the CBF redistribution towards the brainstem.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cerebrovascular effects of sodium nitroprusside in the anaesthetized baboon: a positron emission tomographic study.

The effects of sodium nitroprusside (SNP), a potent hypotensive agent, on cerebral blood flow (CBF) have been extensively studied in clinical and experimental situations but the results remain controversial. Whereas its properties would predict a dilatation of cerebral blood vessels, most studies report either no change or a decrease in CBF. The aim of this study was to investigate the effects of SNP on CBF, cerebral blood volume (CBV), and cerebral oxygen metabolism (CMRO2), by means of positron emission tomography in the anaesthetized baboon. Measurements were performed during normotension (mean arterial pressure (MABP): 97+/-16 mm Hg) and repeated following SNP-induced hypotension (MABP: 44+/-9 mm Hg). Sodium nitroprusside led to an increase in CBF and CBV (+30% and +37%, respectively, P<0.05), whereas no change in CMRO2 was noted. Linear regression analysis of CBF values as a function of MABP confirmed that CBF increases when MABP is reduced by SNP. The comparison between these cerebrovascular changes and those found during trimetaphan-induced hypotension in our previously published studies further argues for a direct dilatatory effect of SNP on cerebral blood vessels.     

Vascular reactivity in the primate brain after acute cryogenic injury.

The effects of an acute cryogenic injury on cerebral flow (CBF) and cerebral vascular reactivity were studied in 12 anaesthetised, ventilated baboons. Autoregulation, defined in this study as intact with a greater than 20% change in cerebrovascular resistance in response to a change in cerebral perfusion pressure, was tested before the lesion by arterial hypotension. Intact autoregulation was found in half the animals, but all animals showed an increase in CBF with hypercarbia. The cryogenic lesion was followed by a marked rise in intracranial pressure, and a fall in CBF which was only partly related to the status of autoregulation beforehand. After injury, arterial hypertension caused an increase in cerebrovascular resistance of more than 20% in half the animals. This response was not related to the presence of autoregulation before the lesion, and was accompanied by a greater impairment of the cerebrovascular response to carbon dioxide, more severe brain oedema, and lower cerebral oxygen consumption, than in the remaining baboons which had a pressure passive response to arterial hypertension. This study confirms that the failure of CBF to increase with arterial hypertension may indicate severe brain damage rather than intact physiological autoregulation.     

Effects of cerebrovascular autoregulation and CO2 reactivity in experimental localized brainstem infarction

Using the previously reported method of experimental localized brainstem infarct in dogs, we designed this study to elucidate sequential changes of regional cerebral blood flow (rCBF) in three separate regions of the central nervous system: the cerebral cortex, thalamus, and midbrain. The data obtained were referred to in subsequent investigations of cerebrovascular autoregulation and vasomotor reactivity to CO2. Localized brainstem infarct was produced by permanently occluding the perforators of the posterior cerebral arteries between the bilateral origins of the posterior communicating arteries. The hydrogen clearance method was applied to measure rCBF. Cerebrovascular autoregulation and CO2 reactivity were assessed in three regions 1, 3, and 5 h after vascular occlusion, respectively. Vascular occlusion resulted in a decrease of rCBF that was 65% in the midbrain and close to 30%-40% in the thalamus. However, no significant change was seen in the cerebral cortex even 5 h after vascular occlusion. Induced hypertension impaired autoregulation in the thalamus, while it was preserved in the cerebral cortex. Induced hypotension did not alter autoregulation in any of the three regions. A marked loss of CO2 reactivity was observed in the ischemic brainstem, although it was well preserved in the cerebral cortex. The results suggest that noradrenergic fibers originating from the cervical sympathetic ganglia play a main role in the cerebrovascular autoregulation in the cerebral cortex, while noradrenergic fibers possibly originating from the autonomic centers in the brainstem are responsible in the thalamus; that the noradrenergic neuron probably is not involved in the maintenance of cerebral blood flow during hypotension; and that the effect of CO2 is mediated by its direct effect on the arteriolar wall in the central nervous system.     

Effects of graded hyperventilation on cerebral blood flow autoregulation in experimental subarachnoid hemorrhage.

An impaired CBF autoregulation can be restored by hyperventilation at a PaCO2 level of about 2.9 to 4.1 kPa (22 to 31 mm Hg). However, it is uncertain whether the restoring effect can take place at lesser degrees of hypocapnia. In the current study, CBF autoregulation was studied at four PaCO2 levels: 5.33 kPa (40 mm Hg, normoventilation), 4.67 kPa (35 mm Hg, slight hyperventilation), 4.00 kPa (30 mm Hg, moderate hyperventilation), and 3.33 kPa (25 mm Hg, profound hyperventilation). At each PaCO2 level, eight rats 2 days after experimental subarachnoid hemorrhage (SAH) and eight sham-operated controls were studied. The CBF was measured by the intracarotid 133Xe method. The CBF autoregulation was found to be intact in all controls but completely disturbed in the normoventilated SAH rats. However, by slight hyperventilation, CBF autoregulation was restored in seven of eight SAH rats with a decline in CBF of 10%. The CBF autoregulation was found intact in all of the moderately or profoundly hyperventilated SAH rats, whereas the decline in CBF was 21% and 28%, respectively. In conclusion, hyperventilation to a PaCO2 level between 4.00 and 4.67 kPa (30 to 35 mm Hg) appears to be sufficient for reestablishing an impaired autoregulation after SAH.     

Cerebral blood flow, cerebral oxygen metabolism, cerebral glucose metabolism, and tissue pH in human acute cerebral infarction using positron emission tomography

It is necessary for treatment and deciding prognosis to make clear about changes of cerebral blood flow and metabolism in acute cerebral infarction. This preliminary PET study was designed to investigate physiological and biochemical changes in acute cerebral infarction by positron emission tomography (PET). PET studies were performed in six patients with acute cerebral infarction within 48 hours after onset of stroke using continuous inhalation of C15O2 for cerebral blood flow (CBF), 15O2 for cerebral metabolic rate for oxygen (CMRO2), 11CO for cerebral blood volume, the intravenous injection of 11C-dimethyloxazolidinedione for tissue pH and the intravenous injection of 18F-fluorodeoxyglucose for cerebral metabolic rate for glucose (CMRGlu). Metabolic coupling index (MCI) image was made from CBF image and CMRGlu image to investigate relation between CBF and CMRGlu. Also oxygen glucose index (OGI) image was made from CMRO2 image and CMRGlu image to investigate relation between CMRO2 and CMRGlu. Preliminary results demonstrate that reduction of CBF, CMRO2, and CMRGlu in the affected cortex except for reperfusion case. Increase of OER was recognized four of six cases. Patterns of MCI and OGI in the cortex which CMRO2 value is less than 65 mumol/100 g/min were different from those in the cortex which CMRO2 value is more than 65. MCI of the affected cortex (CMRO2 less than 65) decreased relative to that of the cortex (CMRO2 greater than or equal to 65). OGI of the affected cortex (CMRO2 less than 65) significantly decreased in comparison with that of the cortex (CMRO2 greater than or equal to 65).(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of orthostatic hypotension on cerebral blood flow and middle cerebral artery velocity in autonomic failure, with observations on the action of ephedrine.

Cerebral blood flow (CBF) and middle cerebral artery velocity (MCAv) have been measured using 133xenon washout and transcranial Doppler in ten patients with autonomic failure. Four pure autonomic failure and four multiple system atrophy patients behaved similarly: tilting them sufficiently to induce significant orthostatic hypotension without causing syncopal symptoms led to a significant fall in their mean MCAv, but no change in their mean CBF. These findings suggest that cerebral autoregulation is preserved in autonomic failure, orthostatic hypotension resulting in a reactive vasodilatation which lowers MCAv, reduces vascular resistance, and maintains CBF. Ephedrine helped to correct the orthostatic hypotension, but had no direct effect on CBF. Two siblings with orthostatic hypotension secondary to dopamine-beta-hydroxylase deficiency also had preserved cerebral autoregulation, but ephedrine led to paradoxical hypotension in these patients.     

Cerebral blood flow and CO2 reactivity in patients with transient ischemic attack]

To elucidate the changes in cerebral blood flow (CBF) and CO2 reactivity in patients with transient ischemic attack (TIA), 10 patients with TIA and 5 healthy adults (controls) underwent two consecutive CBF measurements (i.e. the first measurement during room air inhalation and the second measurement during 5%CO2 inhalation). Hemispheric mean CBF was determined by each CBF measurement using 133Xenon inhalation method. CO2 reactivity was evaluated by analysing delta CBF (= mean CBF during hypercapnea-mean CBF at rest) and delta CBF/delta PaCO2. The resting mean CBF values in the bilateral hemispheres (i.e. both of the affected and unaffected hemispheres) were significantly lower in TIA patients than controls (p less than 0.05). Inhalation of 5%CO2 significantly increased mean CBF in TIA patients bilaterally, however the mean CBF value during hypercapnea was again significantly lower in TIA patients than controls (p less than 0.05). CO2 reactivity in TIA patients was not significantly different from controls (p greater than 0.05). The result demonstrated that TIA patients have a chronic and global cerebral oligemia with normal CO2 reactivity. The chronic and global cerebral oligemia may develop a transient ischemic neurological symptom by being superimposed with local decrease of CBF.     

Cerebral blood flow and metabolism following subarachnoid haemorrhage: effect of subarachnoid blood

The amount of effused blood following a subarachnoid haemorrhage (SAH) was estimated in 48 patients by cerebral computerized tomographic scanning. The cerebral oxygen consumption (CMRO2) was calculated as arteriovenous difference for oxygen multiplied by mean cerebral blood flow measured by the 133-Xe inhalation technique. A significant negative correlation was observed between CMRO2 and amount of subarachnoid blood, with additional reduction in CMRO2 in case of ventricular bleeding. Cerebral blood flow on admission, opposed to CMRO2, showed no correlation to amount of blood on CT scan. A correlation was observed for blood flow measured at day 5 and further on, indicating a restored coupling between flow and metabolism. The clinical (Hunt) grade on admission and the outcome correlated to the amount of blood. These observations suggest that the acute reduction in CMRO2 following a SAH is mainly determined by the amount of blood escaping during the aneurysm rupture, and that the cerebral blood flow level a few days after SAH mainly is determined by the initial reduction in oxygen uptake.     

Vascular responses in cerebrovascular "Moyamoya" disease--evaluated by positron emission tomography

We investigated cerebral blood flow and metabolism, and cerebral vascular response in 9 patients with cerebrovascular Moyamoya disease or unilateral Moyamoya phenomenon using positron emission tomography (PET). The subjects consisted of 5 men and 4 women, and were from 9 to 60 years old. Five patients had bilateral occlusion in the carotid fork with Moyamoya vessels (fulfilled the criteria of cerebrovascular Moyamoya disease), and four patients had unilateral Moyamoya phenomenon. The PET scanner used was the HEADTOME III, of which spatial resolution in clinical use was 10 mm full width at half-maximum (FWHM) in the image plane. Cerebral blood flow (CBF), cerebral metabolic rate of oxygen (CMRO2), cerebral oxygen extraction fraction (OEF), and cerebral blood volume (CBV) were measured in resting state by the 15O-labelled gases steady state method in every patient and 22 normal controls (17 men and 5 women, and from 26 to 64 years old). Consecutively cerebral vascular responses were measured by H215O autoradiographic method in resting state, hypercapnia, hypocapnia, and hypertension. Forced hypercapnia, hypocapnia, and hypertension were achieved by 7% CO2 inhalation, hyperventilation, and venous infusion of angiotensin II, respectively. CMRO2 of the whole brain was significantly lower in patients than in normal controls (p less than 0.05), and CBV of the lentiform nucleus significantly increased in patients (p less than 0.01). This reflected Moyamoya vessels in the basal ganglionic regions. In 3 of 5 patients with bilateral Moyamoya vessels, CBF and CMRO2 in the symptomatic cerebral hemisphere were lower than that in the nonsymptomatic hemisphere.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effects of nimodipine on cerebral blood flow and metabolism

Nimodipine, a calcium entry blocker, was administered in increasing doses of 0.1-3.0 micrograms kg-1 min-1 to six dogs after they had recovered consciousness from a surgical preparation that was conducted under general anesthesia and while they were under the influence of total spinal anesthesia. CBF was measured with a sagittal sinus outflow technique and CMRO2 was calculated as the product of CBF and the arteriovenous O2 difference. Nimodipine did not influence either CBF or CMRO2. There was a decrease in the cortical pyruvate level at the end of the study, but no significant change in phosphocreatine, ATP, lactate, or energy charge when compared with six control dogs. It has previously been reported that nimodipine increases the CBF in global ischemia with a potentially beneficial effect on the neurological outcome. With no effect on normal CBF or metabolism, this suggests that nimodipine may be useful in a variety of ischemic situations without fear of either a steal phenomenon or untoward effects on intracranial pressure.     

Positron emission tomography in minor ischemic stroke using oxygen-15 steady-state technique

A study with positron emission tomography (PET) was performed on 10 patients with ischemic stroke and mild disability. The patients underwent cerebral angiography, x-ray computed tomography (CT) scan and regional cerebral measurements of CBF, CMRO2, oxygen extraction ratio (OER), and cerebral blood volume (CBV). Only minor arterial involvement was detected by angiography. In all patients, PET images of functional defects were more extensive than the corresponding CT hypodensity, and there were statistically significant reductions in CBF, CMRO2, and CBF/CBV ratio as compared with control subjects. Half of the regions analyzed in the affected hemisphere demonstrated a disruption of the normal coupling between CBF and CMRO2 as reflected by OER values significantly higher or lower than those of the corresponding region of the contralateral hemisphere. The pathophysiological pattern of high OER combined with a reduction in CBF proportionally greater than the reduction in CMRO2 was particularly indicative of regional chronic hemodynamic compromise in these patients.     

Evidence that 20-HETE contributes to the development of acute and delayed cerebral vasospasm

Recent studies have indicated that arachidonic acid (AA) is metabolized by the cytochrome P450 4A (CYP4A) enzymes in cerebral arteries to produce 20-hydroxyeicosatetraenoic acid (20-HETE) and that this compound has effects on cerebral vascular tone that mimic those seen following subarachnoid hemorrhage (SAH). In this regard, 20-HETE is a potent constrictor of cerebral arteries that decreases the open state probability of Ca(2+)-activated K(+) channels through activation of protein kinase C (PKC). It increases the sensitivity of the contractile apparatus to Ca(2+) by activating PKC and rho kinase. The formation of 20-HETE is stimulated by angiotensin II (AII), endothelin, adenosine triphosphate (ATP) and serotonin, and inhibited by NO, CO and superoxide radicals. Inhibitors of the formation of 20-HETE block the myogenic response of cerebral arterioles to elevations in transmural pressure in vitro and autoregulation of cerebral blood flow (CBF) in vivo. 20-HETE also plays an important role in modulating the cerebral vascular responses to vasodilators (NO and CO) and vasoconstrictors (AII, endothelin, serotonin). Recent studies have indicated that the levels of 20-HETE in cerebrospinal fluid (CSF) increase in rats, dogs and human patients following SAH and that inhibitors of the synthesis of 20-HETE prevent the acute fall in CBF in rats and reverse delayed vasospasm in both dogs and rats. This review examines the evidence that an elevation in the production of 20-HETE contributes to the initial fall in CBF following SAH and the later development of delayed vasospasm.     

Nimodipine pretreatment improves cerebral blood flow and reduces brain edema in conscious rats subjected to focal cerebral ischemia

The effect of nimodipine pretreatment on CBF and brain edema was studied in conscious rats subjected to 2.5 h of focal cortical ischemia. An infusion of nimodipine (2 micrograms/kg/min i.v.) or its vehicle, polyethylene glycol 400, was begun 2 h before the ischemic interval and was continued throughout the survival period. Under brief halothane anesthesia, the animals' right middle cerebral and common carotid arteries were permanently occluded, and 2.5 h later, they underwent a quantitative CBF study ([14C]iodoantipyrine autoradiography followed by Quantimet 970 image analysis). Nimodipine treatment improved blood flow to the middle cerebral artery territory without evidence of a "vascular steal" and reduced the volume of the ischemic core (cortex with CBF of less than 25 ml/100 g/min) and accompanying edema by approximately 50% when compared with controls (p = 0.006 and 0.0004, respectively). Mild hypotension induced by nimodipine did not aggravate the ischemic insult. The ischemic core volumes, however, were 50-75% smaller than the 24-h infarct volumes generated in a similar paradigm that demonstrated 20-30% infarct reduction with continuous nimodipine treatment. These results suggest that nimodipine pretreatment attenuates the severity of early focal cerebral ischemia, but that with persistent ischemia, cortex surrounding the ischemic core undergoes progressive infarction and the early benefit of nimodipine treatment is only partly preserved.