Takao Ishitsuka

Changes in local cerebral blood flow following bilateral carotid occlusion in spontaneously hypertensive and normotensive rats.

Local blood flow in the cortex and thalamus was measured by the hydrogen clearance method in spontaneously hypertensive rats (SHR) and normotensive rats (NTR) before and after bilateral carotid occlusion. There were no differences in the resting blood flow values between SHR and NTR. Following carotid occlusion cortical blood flow in SHR was markedly reduced to 17% of the resting level at 1 h and, further, to less than 10% at 3--5 h period, while in NTR it decreased only to 36--38% during 5 h occlusion. Thalamic blood flow in SHR was decreased to 39% at 1 hr and to below 20% at 3--5 h, while in NTR it remained approximately 40% of the resting level during 5 h occlusion. The blood flow reduction in either cortex or thalamus after carotid occlusion was much greater in SHR than in NTR. This difference was highly significant. The increased cerebral vascular resistance caused by persistent hypertension may play an important role in a greater reduction of blood flow in SHR after carotid occlusion. Relation of the blood flow reduction to the brain metabolism is discussed.

Stroke-prone spontaneously hypertensive rats as an experimental model of malignant hypertension

A light-microscopic study of various organs of stroke-prone spontaneously hypertensive (SHRSP) rats was performed. The rats characteristically developed fibrinoid necrosis of the wall and marked cellular thickening of the intima and media of the arterioles and small arteries of the kidney, testicle, mesentery, adrenal gland, brain, etc. Parenchymal damage of the organs, secondary to the vascular alterations took place. There were no accumulations of lipids in the vascular lesions. Though stroke has been stressed as a characteristic clinical feature of the SHRSP rats, the cerebral lesions are different from those seen in ordinary cerebrovascular disease. Furthermore, many organs are involved. The overall vascular changes in the brain and other organs are consistent with those seen in malignant hypertension; the SHRSP rat is an excellent model of this disease.

Influence of sex on cerebral ischemia following bilateral carotid occlusion in spontaneously hypertensive rats: a metabolic study.

Cerebral lactate, pyruvate and adenosine triphosphate (ATP), and acid-base balance were measured in male and female spontaneously hypertensive rats (SHR) before, and 1, 3 and 5 hours after bilateral carotid occlusion. In male SHR, cerebral lactate and the lactate/pyruvate (L/P) ratio progressively increased after occlusion, while cerebral ATP decreased. In female SHR, an increase in lactate and the L/P ratio was less marked than in male SHR. Cerebral ATP remained unchanged 5 hours after occlusion. These data suggest that bilateral carotid artery occlusion may cause more pronounced ischemic changes in the brain in male SHR than in female SHR, resulting in a greater increase in lactate with a concomitant decrease in ATP in male SHR. Results suggest that female SHR are more resistant to cerebral ischemia following bilateral carotid occlusion than male SHR. Blood pressure and gonads in the susceptibility to cerebral ischemia are discussed.

Cerebrospinal Fluid Lactate in Patients with Hepatic Encephalopathy

Cerebrospinal fluid (CSF) lactate and pyruvate concentrations were determined in 16 patients with hepatic encephalopathy before and/or after treatment. CSF lactate was significantly increased to 1.92 +/- 0.11 mmol/l in hepatic encephalopathy before the treatment in comparison to 1.40 +/- 0.05 mmol/l in control subjects. In 9 of 11 patients with moderate or stage 2 encephalopathy, CSF lactate levels were below 2 mmol/l. In contrast, in 4 of 5 patients with stage 3-4 encephalopathy, CSF lactate levels were higher than 2 mmol/l. CSF lactate was decreased with the recovery of neurological symptoms by the treatment. These findings indicate that CSF lactate levels reflect the severity of metabolic impairment of the brain. Hypocapnia was frequently observed in these encephalopathic patients, and arterial PCO2 correlated inversely with CSF lactate and linearly with CSF HCO3-, suggesting that CSF lactic acidosis contributes to hyperventilation in hepatic encephalopathy. It is concluded from present results that metabolic disorder of neuronal cells might be one of the important factors for the development of hepatic encephalopathy.

ABCD3 and ABCD3-I Scores Are Superior to ABCD2 Score in the Prediction of Short- and Long-Term Risks of Stroke After Transient Ischemic Attack

Background and Purpose— Several risk scores have been developed to predict the stroke risk after transient ischemic attack (TIA). However, the validation of these scores in different cohorts is still limited. The objective of this study was to elucidate whether these scores were able to predict short-term and long-term risks of stroke in patients with TIA. Methods— From the Fukuoka Stroke Registry, 693 patients with TIA were followed up for 3 years. Multivariable-adjusted Cox proportional hazards model was used to assess the hazard ratio of risk factors for stroke. The discriminatory ability of each risk score for incident stroke was estimated by using C-statistics and continuous net reclassification improvement. Results— The multivariable-adjusted Cox proportional hazards model revealed that dual TIA and carotid stenosis were both significant predictors for stroke after TIA, whereas abnormal diffusion-weighted image was not. ABCD3 (C-statistics 0.61) and ABCD3-I (C-statistics 0.66) scores improved the short-term predictive ability for stroke (at 7 days) compared with the ABCD2 score (C-statistics 0.54). Addition of intracranial arterial stenosis (at 3 years, continuous net reclassification improvement 30.5%; P<0.01) and exclusion of abnormal diffusion-weighted imaging (at 3 years, continuous net reclassification improvement 24.0%; P<0.05) further improved the predictive ability for stroke risk until 3 years after TIA. Conclusions— The present study demonstrates that ABCD3 and ABCD3-I scores are superior to the ABCD2 score for the prediction of subsequent stroke in patients with TIA. Addition of neuroimaging in the ABCD3 score may enable prediction of long-term stroke risk after TIA.

Massive striatal dopamine release in acute cerebral ischemia in rats.

Extracellular dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and cerebral blood flow were simultaneously determined using in vivo brain dialysis and a hydrogen clearance method in the striatum of spontaneously hypertensive rats during ischemia and after recirculation. Massive striatal dopamine release was demonstrated in acutely induced ischemic brain.

Effects of hematocrit on brain metabolism in experimentally induced cerebral ischemia in spontaneously hypertensive rats (SHR).

Brain tissue lactate, pyruvate, and adenosine triphosphate (ATP) were measured 60 min after bilateral carotid ligation in spontaneously hypertensive rats, of which hematocrit (HCT) was varied by exchanging with isovolemic homologous red cells, plasma or whole blood. Supratentorial lactate of the ischemic brain was increased more in high HCT (greater than or equal to 50%) and less in low HCT (30-39%) compared with normal HCT (40-49%). In very low HCT (less than 30%), however, lactate was increased to further extent compared with any other group of HCT (ANOVA p less than 0.0001). Lactate/pyruvate (L/P) ratio of the ischemic brain showed similar changes, namely U-shaped correlation to HCT. In contrast, supratentorial ATP was decreased more markedly in very low HCT, followed by high and normal HCT, and minimally decreased in low HCT, demonstrating an inverse U-shaped relationship to HCT. Mean arterial pressure and arterial acid-base parameters in ischemic animals did not differ among HCT groups. There were no HCT-related changes of brain metabolites in non-ischemic control rats. These findings indicate that cerebral ischemia following carotid ligation is more severe in high HCT but less in low HCT, probably due to hemodynamic effects of HCT changes. When HCT is reduced to below 30%, however, insufficient oxygen supply to the brain or anemic hypoxia may superimpose on ischemia, resulting in more markedly impairment of brain metabolism. The role of HCT as a cause of cerebral ischemia and its severity is discussed.

Sex Differences in Short-Term Outcomes After Acute Ischemic Stroke The Fukuoka Stroke Registry

Background and Purpose— Variable sex differences in clinical outcomes after stroke have been reported worldwide. This study aimed to elucidate whether sex is an independent risk factor of poor functional outcome after acute ischemic stroke. Methods— Using the database of patients with acute stroke registered in the Fukuoka Stroke Registry in Japan from 1999 to 2013, 6236 previously independent patients with first-ever ischemic stroke who were admitted within 24 hours of onset were included in this study. Baseline characteristics were assessed on admission. Study outcomes included neurological improvement, neurological deterioration, and poor functional outcome (modified Rankin Scale score, 3–6 at discharge). Logistic regression analyses were performed to evaluate the association between sex and clinical outcomes. Results— Overall, 2398 patients (38.5%) were women. Severe stroke (National Institutes of Health Stroke Scale score, ≥8) on admission was more prevalent in women than in men. The frequency of neurological improvement or deterioration during hospitalization was not different between the sexes. After adjusting for possible confounders, including age, stroke subtype and severity, risk factors, and poststroke treatments, it was found that female sex was independently associated with poor functional outcome at discharge (odds ratio, 1.30; 95% confidence interval, 1.08–1.57). There was heterogeneity of the association between sex and poor outcome according to age: women had higher risk of poor outcome than men among patients aged ≥70 years, but no clear sex difference was found in patients aged <70 years. Conclusions— Female sex was associated with the risk of poor functional outcome at discharge after acute ischemic stroke.

Effect of thromboxane synthetase inhibitor on cerebral circulation and metabolism during experimental cerebral ischemia in spontaneously hypertensive rats

The protective effect of thromboxane synthetase inhibitor, OKY-046, on brain ischemia was studied in spontaneously hypertensive rats. Cerebral ischemia was developed by bilateral carotid artery ligation (BCL) for 1 or 3 h and thereafter, circulation was restored for 15 min. OKY-046, 5 or 30 mg/kg, or saline as control was administered i.v. before BCL. Neither blood pressure nor blood gases were altered by OKY-046 or saline injection. During BCL, cerebral cortical blood flow was reduced to 25 and 15% of the resting value at 30 and 60 min, respectively, and these changes were not different among the groups. In rats with ischemia longer than 1 h, the blood flow was well preserved by OKY-046, 30 mg/kg, to 10-17% of the resting level, thus significantly higher than that (less than 5%) in non-treated rats. After 15 min recirculation, the supratentorial lactate level was lower and adenosine triphosphate (ATP) was higher in OKY-046-treated rats than in the saline-treated ischemic rats. Plasma thromboxane B2 was increased markedly in 1 h ischemic-reperfused rats without treatment and the increase was almost completely inhibited by OKY-046. In contrast, 6-keto-prostaglandin F1 alpha was increased 8.5-fold after ischemia and the increase was not affected by the treatment. OKY-046 seems to have an antiischemic effect on acutely induced cerebral ischemia. Selective inhibition of thromboxane A2 production and an inversely high level of prostaglandin I2 may be an important contribution to protection of the microcirculation during ischemia and preservation of ischemic cerebral metabolism.

Response of cortical and pial arteries to changes of arterial CO2 tension in rats — a morphometric study

Changes of the internal (d) and external diameter (D) of cerebral arteries in response to the various levels of arterial pCO2 were studied in anesthetized rats, of which brains were frozen in situ with isopentane cooled in liquid nitrogen. The parietal cortex was fixed with osmium tetroxide and stained with toluidine blue for morphometry of the cerebral arteries. In comparison with control animals (pCO2 = 41.2 mm Hg), the d/D ratio in animals with hypercapnia (pCO2 = 69.9 mm Hg) was increased by 11.7% in the pial arteries and 7.9% in the cortical arteries, indicating vasodilatation. In contrast, the d/D ratio in those with hypocapnia (pCO2 = 27.7 mm Hg) was decreased by 6.2% and 13.0%, respectively, indicating vasoconstriction. There was a significant linear correlation existing between the d/D ratio of either pial or cortical arteries and pCO2. It is concluded that the cortical arteries respond to changes of arterial pCO2 in a similar manner to the pial arteries.