The purpose of the present study was to clarify the role and site of the L-arginine-nitric oxide (NO) system in cerebrovascular regulation using the cranial window method. Twenty-six cats were anesthesized by intraperitoneal injection of a-chloralose and urethane. A cranial window with small tubes was placed in the skull for monitoring the pial vessels by means of a videocamera system and for the superfusion of reagents. Intralingual arterial injection (n=10) of 10 mg/kg (40 μmol/kg) N^G-monomethyl-L-arginine (L-NMMA), an inhibitor of nitric oxide synthase, significantly increased the mean arterial blood pressure (MABP ; 9.313.9%, P <0.05); it also decreased the diameter of pial arteries larger than 100μm (Al ; 8.99.7%, P < 0.05), those smaller than 100, um (A2 ; 6.511.9%, P <0.05), and pial veins (V ; 5.99.0%, P <0.05). The effects on MABP and pial vessel diameter elicited by L-NMMA were significantly antagonized by the administration of 120 μmol/kg L-arginine, but not by D-arginine at the same dose. Superfusion of 1 mM L-NMMA onto the brain surface (n=16) significantly reduced the diameter of larger pial arteries (Al; 9.819.4%, P <0.05) and smaller pial arteries (A2; 18.136.7%, P <0.05) without significant changes in MABP and the diameter of pial veins.
Both intraluminal and abluminal administration of L-NMMA significantly constricted the pial arteries. The response of the larger pial arteries to abluminal administration of L-NMMA was less marked when compared with that of the smaller arteries. It is concluded that the endothelial L-arginine-NO system plays an important role in maintaining the basal vascular tone of feline pial vessels.

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An examination was made of the role of component substances of the cerebrospinal fluid (CSF) such as platelet-derived growth factor (PDGF) in the development of proliferative angiopathy, one of the characteristic organic changes of cerebral vessels caused by subarachnoid hemorrhage (SAH). Experimental SAH was induced by a transorbital tear of the right middle cerebral artery (MCA) in 16 cats. Significant luminal narrowing and wall thickening due to proliferative organic changes were observed in the right MCA in 10 case with SAH. Such changes were minimal in 6 cats in which tissue plasminogen activator was administered intrathecally at 24 hours after SAH. PDGF (either the A or B dimer; 1 jig) was injected into the cisterna magna in 20 other cats. Organic changes equivalent to those noted in the cats with SAH were observed especially in cats receiving intrathecal PDGF B dimer. Immunohistochemically, PDGF was detected on the outer side of the MCA within 2 days after SAH. These findings suggest that bioactive substances capable of eliciting organic changes are released into the CSF in SAH. Furthermore, in particular PDGF (possibly the B chain) may play an important role in the development of organic changes in the vessel wall following SAH. From the clinical standpoint, intrathecal fibrinolysis may be effective for preventing the organic changes.

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In this report, we describe our initial experience with three-dimensional CT angiography (3D-CTA) in the evaluation of intracerebral lesions. The purpose of the study was to assess the detection of lesions of the intracranial vasculature by 3D-CTA and to compare the results obtained with those of both digital subtraction angiography (DSA) and magnetic resonance angiography (MRA). Six patients including 4 with intracranial aneurysms and 2 with stenosis of the vertebral artery and basilar artery were investigated with 3D-CTA and DSA, and also underwent MRA. 3D-CTA is a rapid non-invasive method for visualizing the intracranial vasculature. In this study, aneurysms measuring 3 mm or larger were demonstrated by 3D-CTA as well as MRA. All of the aneurysms observed with both 3D-CTA and MRA were seen equally well by both techniques. 3D-CTA has several properties that afford it unadvantage over MRA. 3D-CTA acquistion takes only 20 sec to perform, so that lesions can be imaged without motion artifacts. The 3D-CTA image reflects the volume of contrast material in a structure and is independent of flow rate. Cases with either larger aneurysms or stenosis were seen better with 3D-CTA, owing to the development of flow-related or motion artifacts on MRA. On the other hand, MRA was considered to be superior to 3D-CTA in some cases, in which calcium in the vessel wall or skull base obscured the anatomy of the aneurysms on images obtained by 3D-CTA represents a promising non-invasive method is concluded that 3D-CTA represents a promising non-invasive method for imaging the intracranial vasculature and is comperable with MRA techniques in demonstrating intracranial lesions.

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To investigate the involvement of glutamate receptor in the pathophysiology of cerebral ischemic injury, we examined the expression of N-methyl-D-aspartate (NMDA) -type glutamate receptor (NMDAR1) mRNA on neurons and glial cells in the hippocampus after transient global cerebral ischemia. The ischemia was produced in 56 adult Mongolian gerbils by occluding both carotid arteries for 2 or 5 min. In situ hybridization histochemistry with oligonucleotide probes for NMDAR1 mRNA and immunocytochemistry using antibody against glial fibrillary acidic protein were performed. After 5 min of ischemia, a time-dependent decrease in hybridizing with the probes was observed in CAl pyramidal neurons. On the other hand, NMDAR1 mRNA-positive glial cells were increased in number throughout the lacunosum moleculare layer. The positive cells appeared to migrate in the CAl pyramidal layer at 7 days following 5 min of ischemia. The intensity of hybridization in the CA1 pyramidal neurons was not changed following 2 min of ischemia, but the intensity in the glial cells was elevated at 3 and 7 days following the ischemic insult. These results suggest that the neuronal NMDA receptor is down-regulated and the glial one is up-requlated after lethal ischemic insult. Glial NMDA receptor may play an important role in both the development of delayed neuronal death and in the acqusition of ischemic tolerance by neurons.

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Left atrial diameter and left ventricular dysfunction are predictors of thromboembolism in patients with nonvalvular atrial fibrillation (NVAF). To screen high-risk patients for the primary prevention of thromboembolism, we measured various hemostatic molecular markers [thrombin-antithrombin III complex (TAT), fibrinopeptide A (FPA), plasmin-α₂plasmin-inhibitor complex, D-dimer, βthromboglobulin (β-TG) and platelet factor 4 (PF4)] and examined the correlations between the markers and cardiac output, ejection fraction, left atrial diameter (LAD) by transthoracic echocardiography, and systolic and diastolic blood pressure in NVAF patients. The hemostatic molecular markers were also investigated in 46 age-matched controls without atherosclerotic vascular diseases. The NVAF group had significantly higher concentrations of TAT, FPA, β-TG and PF₄ than the control group. TAT was significantly correlated to LAD. These findings suggest that TAT may be a useful indicator for predicting the occurrence of embolization in NVAF.

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To assess the incidence of stroke in subjects with silent brain infarction (SB1) which were found by health screening of the brain using MRI, we performed a follow-up study by questionaire in 582 subjects without stroke and 28 with minor stroke. The incidence of SBI was found to be 15.7%, Development of stroke was observed in 4 of 467 subjects without SBI (0.86%), 6 of 87 with SBI (6.9%), and 3 of 28 patients with minor stroke (10.7%). Periventricular hyperintensity was not related to the development of stroke. There were 8 patients with brain infarction and 2 with brain hemorrhage. Hypertension and older age were significantly related to the development of stroke. Multivariate analysis demonstrated that the subjects with SBI formed a significantly high risk group for stroke.

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Patients with hypertensive intracerebral hemorrhage (ICH) who suffered recurrence at different sites were investigated. Overall, recurrence of ICH was noted in 29 (5.8%) of 500 patients with ICH who were admitted to our department of neurosurgery over a period of 10 years. These patients comprised 18 men and 11 women. The incidence of recurrence was slightly higher in men. The average age at the time of recurrence was about 64 years old. The site involved was the ipsilateral cerebral hemisphere in 7 patients, the contralateral cerebral hemisphere in 16 patients (56%), and the supratentorial and infratentorial regions in 6 patients. The recurrence of hypertensive intracerebral hemorrhage thus showed a tendency to occur in the contralateral cerebral hemisphere. The time interval between the initial hemorrhage and recurrence was 3 years or more in over half of the patients (52%). The grade of activities of daily living following recurrence became worse than after the initial hemorrhage, and the functional prognosis was very poor. Assessments of the risk factors for recurrence revealed that a medical history of hypertension, hypoalbuminemia and/or hypoproteinemia, and hypocholesterolemia were present a the time of recurrence or hospital admission in 22 patients (76%), 13 patients (45%), and 6 patients (21%), respectively. However, the incidence of recurrence showed no difference in relation to the performance of neurosurgery after the initial hemorrhage. Based on these results, it can be concluded that not only blood pressure control but also sufficient nutritional management and prolonged follow-up are required to prevent recurrence of ICH.

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Six hundred and fifteen patients with aneurysmal subarachnoid hemorrhage, under the age of 70 years, who were consecutively adrmitted to Kagawa Prefectural Central Hospital from July 1972 to June 1994, were reviewed. The changes in treatment protocol durng this peroid included the institution of early surgery instead of delayed surgery and the development of a variety of modalities for the treatment of cerebral vasospasm. This resulted in an increased rate of patients who actually underwent direct aneurysmal clipping. The outcome evaluated at 6 months after the first hemorrhage was significantly improved during this period, especially in patients with Hunt and Kosnik grade III (p <0.05 x²). Patients classified as showing good recovery (Glasgow outcome scale) increased from 6.3% to 61.3%. Mortality decreased from 28.3% to 9.7%. Early surgery eliminated fatal rebleeding and vasospasm while awaiting scheduled surgery. Advanced operative procedures and perioperative management improved the outcome of patients who underwent surgery. The major problem with the current protocol is preoperative rebleeding at the acute stage, and further progress on this subject is considered mandatory.

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We investigated whether or not there are differences in the effects of phenylephrine-induced hypertension, with changes in its duration and extent, on the CBF, brain energy metabolism and brain parenchymal specific gravity following transient forebrain ischemia in gerbils. Gerbils were randomly assigned to one of the following 6 treatment groups : 15 mild-HT group (n=14); 25 mmHg increase in MABP by treatment with phenylephrine for 15 min, 30 mild-HT group (n=14); for 30 min, 60 mild-HT group (n= 14); for 60 min, 15 severe-HT group (n=14); 45 mmHg increase in MABP for 15 min, hypotension group (n=14); 30 mmHg decrease in MABP by exsanguination for 15 min at 30 min after reperfusion, and control group (n=14), without phenylephrine treatment. The CBF was measured continuously and the brain specific gravity was evaluated at 120 min after reperfusion. The sequential changes in brain energy metabolism, as indicated by the PCr/Pi ratio, β-ATP/Pi ratio and pHi, were also determined and were found to return to the preischemic level at 120 min after reperfusion. The recovery in brain energy metabolism was more rapid in the 15 mild-HT group, and the brain specific gravity was also greater in this group. The 15-min mild induced hypertension regime was most suited to the recovery of the brain energy metabolism which was associated with an increased CBF and without exacerbation of brain edema. In contrast, the 30- and 60-min mild induced hypertension and 15-min sevee induced hypertension regimes worsened the recovery of the brain energy metabolism and exacerbated brain edema. These findings clearly demonstrate differences in the beneficial effects of phenylephrine-induced hypertension, with changes in its duration and extent, on ischemic brain injury following transient forebrain ischemia.

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This study was undertaken to clarify the etiology of Binswanger's disease based on the relationships between vascular lesions and white-matter changes characterizing the disease. We focussed on the extracranial carotid artery and peripheral artery of the lower limbs in Binswanger's disease, and evaluated the carotid ultrasonographic findings and the ankle pressure index (API) as compared to those in control groups. The mean age of our 21 patients with Binswanger's disease (Binswanger group) was 79.9 years (5 males and 16 females). The diagnosis was made from the clinical features and computed tomography (CT) findings, which showed diffuse low-density areas of white matter in the bilateral hemispheres, compatible with the clinical criteria of Binswanger's disease as proposed by Bennett et al. The controls consisted of 3 groups : 67 patients with lacunar infarction (perforating group), 52 patients with cortical infarction (cortical group), and 70 individuals without cerebrovascular disease examined on CT (non-CVD group). Patients with atrial fibrillation were excluded from the study. The extracranial carotidlesions, examined by 7.5-MHz B-mode ultrasonography, included occlusions and plaques. Plaque was defined as a thickened intima-media complex of 2.1 mm or more, and was divided into two types according to the ratio of the plaque length to thickness : nodular plaques (< 3) and mural plaques (≥ 3). Intravenous digital subtraction angiography was also performed in some patients. Moreover, the API, expressed as the ratio of the ankle pressure to brachial pressure determined by 5-MHz Doppler ultrasound, was studied and a low API (<0.9) was considered to indicate obstructive changes in the legs. In the Binswanger group, carotid lesions were frequently observed in 16 patients, who included 2 patients with carotid occlusion and 16 patients with plaque alone. In particular, the incidence of bilateral carotid lesions was 71% in the Binswanger group, which was significantly higher than that in the perforating (28%), cortical (44%), and non-CVD (23%) groups. Most of the lesions comprised nodular plaques as observed in half of the carotid arteries, although the plaques in the Binswanger group were thinner than those in the cortical group. A low API, seen in 43% of the Binswanger group, tended to be frequent, when compared to that in the non-CVD group.
In conclusion, a high incidence of atherosclerotic lesions in both the extracranial carotid artery and peripheral artery of the lower limbs in Binswanger's disease indicated that severe athero- and arteriosclerosis had already developed in this disease. Although in a few cases the carotid lesions could have contributed to the white-matter changes, plaques were considered to frequently accompany arteriolar changes in the white matter, which proved difficult to detect clinically. The causes of the white-matter changes, were therefore small-vessel disease, with or without large-vessel disease, but the carotid lesions could have promoted the small-vessel damage and the white-matter changes in some manner (decreased “Windkessel” function).

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During a recent 6-year period, the incidence of aneurysmal subarachnoid hemorrhage was in investigated in the Shimokita area of Aomori Prefecture with a population of 91, 199. A total of 99 patients with aneurysmal subarachnoid hemorrhage were hospitalized, and the annual incidence of aneurysmal subarachuoid hemorrhage was 21.7 per 100, 000 population. The age-adjusted annual incidence using Japan census data for 1990 was 21.0 per 100, 000 population. The age-specific annual incidences ranged from 36 to 44 per 100, 000 population at the age of 40-79 years in men. However, in women, the age-specific annual incidences became higher with increasing age, and revealed a peak, which amounted to 75 per 100, 000 population, in the seventh or later decade of life.

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A non-hypertensive 43-year-old woman suddenly suffered from right hemiplegia, sensory disturbance and headache. On admission, she showed coma and tetraplegia. A chest X-ray revealed pulmonary edema, and her arterial b lood gases demonstrated severe hypoxemia. She was treated with artificial ventilation. A brain CT scan disclosed pontine hemorrhage rupturing into the fourth ventricle. Her echocardiogram displayed no abnormality. The pulmonary edema was improved by the next day, and her chest X-ray became normal on the 3rd day. This case was diagnosed as neurogenic pulmonary edema secondary to potine hemorrhage. We speculate that elevation of the intraventricular pressure and oppression of the medulla oblongata caused neurogonic pulmonary edema. Hypoxemia with pontine hemorrhage should be considered for not only neurogenic hypoventilation but also neurogonic pulmonary edema, and adequate respiratory management must be carried out.

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