Serum immunoglobulin G antibody titer to Fusobacterium nucleatum is associated with unfavorable outcome after stroke.

Stroke can be a cause of death, while in non-fatal cases it is a common cause of various disabilities resulting from associated brain damage. However, whether a specific periodontal pathogen is associated with increased risk of unfavorable outcome after stroke remains unknown. We examined risk factors for unfavorable outcome following stroke occurrence, including serum antibody titers to periodontal pathogens. The enrolled cohort included 534 patients who had experienced an acute stroke, who were divided into favorable (n = 337) and unfavorable (n = 197) outcome groups according to modified ranking scale (mRS) score determined at 3 months after onset (favorable = score 0 or 1; unfavorable = score 2-6). The associations of risk factors with unfavorable outcome, including serum titers of IgG antibodies to 16 periodontal pathogens, were examined. Logistic regression analysis showed that the initial National Institutes of Health stroke scale score [odds ratio (OR) = 1·24, 95% confidence interval (CI) = 1·18-1·31, P < 0·001] and C-reactive protein (OR = 1·29, 95% CI = 1·10-1·51, P = 0·002) were independently associated with unfavorable outcome after stroke. Following adjustment with those, detection of the antibody for Fusobacterium nucleatum ATCC 10953 in serum remained an independent predictor of unfavorable outcome (OR = 3·12, 95% CI = 1·55-6·29, P = 0·002). Determination of the antibody titer to F. nucleatum ATCC 10953 in serum may be useful as a predictor of unfavorable outcome after stroke.

The identification of raft-derived tau-associated vesicles that are incorporated into immature tangles and paired helical filaments.

AIMS: Neurofibrillary tangles (NFTs), a cardinal pathological feature of neurodegenerative disorders, such as Alzheimer's disease (AD) are primarily composed of hyper-phosphorylated tau protein. Recently, several other molecules, including flotillin-1, phosphatidylinositol-4,5-bisphosphate [PtdIns(4,5)P2] and cyclin-dependent kinase 5 (CDK5), have also been revealed as constituents of NFTs. Flotillin-1 and PtdIns(4,5)P2 are considered markers of raft microdomains, whereas CDK5 is a tau kinase. Therefore, we hypothesized that NFTs have a relationship with raft domains and the tau phosphorylation that occurs within NFTs. METHODS: We investigated six cases of AD, six cases of other neurodegenerative diseases with NFTs and three control cases. We analysed the PtdIns(4,5)P2-immunopositive material in detail, using super-resolution microscopy and electron microscopy to elucidate its pattern of expression. We also investigated the spatial relationship between the PtdIns(4,5)P2-immunopositive material and tau kinases through double immunofluorescence analysis. RESULTS: Pretangles contained either paired helical filaments (PHFs) or PtdIns(4,5)P2-immunopositive small vesicles (approximately 1 µm in diameter) with nearly identical topology to granulovacuolar degeneration (GVD) bodies. Various combinations of these vesicles and GVD bodies, the latter of which are pathological hallmarks observed within the neurons of AD patients, were found concurrently in neurons. These vesicles and GVD bodies were both immunopositive not only for PtdIns(4,5)P2, but also for several tau kinases such as glycogen synthase kinase-3ß and spleen tyrosine kinase. CONCLUSIONS: These observations suggest that clusters of raft-derived vesicles that resemble GVD bodies are substructures of pretangles other than PHFs. These tau kinase-bearing vesicles are likely involved in the modification of tau protein and in NFT formation.

The expression of CD36 in vessels with blood-brain barrier impairment in a stroke-prone hypertensive model.

AIMS: The class B scavenger receptor CD36, the receptor for oxidized low-density lipoprotein, mediates free radical production and brain injury in cerebral ischaemia. Free radical production is known to be involved in the remodelling of the cerebral vasculature of stroke-prone spontaneously hypertensive rats (SHRSP). Accordingly, we examined whether the expression of CD36 is increased in the vasculature with blood-brain barrier (BBB) impairment and collagen deposition of SHRSP. METHODS: The gene and protein expression of CD36 was examined in the vessels of the hippocampus of SHRSP with BBB impairment and those of Wistar Kyoto rats without the impairment, by real-time RT-PCR, Western blotting and immunohistochemical techniques. RESULTS: The gene and protein expression of CD36 was increased in the hippocampus of SHRSP compared with that of Wistar Kyoto rats. Confocal microscopic examination revealed CD36 immunoreactivity in perivascular microglial cells immunopositive for ED1. Immunoelectron microscopic examination revealed that the immunosignals for CD36 were located mainly in the cytoplasm of perivascular cells in vessels showing increased vascular permeability and a few in the cytoplasmic membranes of endothelial cells. CONCLUSIONS: These findings indicate that the expression of CD36 was increased in vessels with BBB impairment in the hippocampus of SHRSP and was mainly seen in the cytoplasm of perivascular microglial cells, suggesting a role of CD36 in cerebrovascular injury.

Hyperglycemia suppresses ABCA1 expression in vascular smooth muscle cells.

Hyperglycemia is a major risk factor for atherosclerotic disease. The ATP-binding cassette transporter A1 (ABCA1) functions as a pivotal regulator of lipid efflux from cells to apolipoproteins and is thus involved in lowering the risk of atherosclerosis. In this study, we have examined the glucose-mediated regulation of the ABCA1 gene expression in vascular smooth muscle cells. ABCA1 expression was examined by real-time polymerase chain reaction (PCR), Western blot analysis, and reporter gene assay. The results showed that the expression of the ABCA1 mRNA and protein decreased after the cells were treated with 22.4 mM glucose for 48 h. The transcriptional activity of the ABCA1 promoter paralleled the endogenous expression of the ABCA1 gene. Next, we used inhibitors of certain signal transduction pathways to demonstrate that the glucose-induced ABCA1 suppression is sensitive to the p38-mitogen-activated protein kinase (MAPK) inhibitors. The expression of a constitutively active form of p38-MAPK in the cells inhibited the ABCA1 promoter activity, irrespective of the presence of glucose. A dominant-negative mutant of p38-MAPK abrogated the inhibitory effect of glucose on the ABCA1 promoter activity. These results indicate that the glucose-induced suppression of ABCA1 expression is partially mediated by the activation of the p38-MAPK pathway.

The expression of P-glycoprotein is increased in vessels with blood-brain barrier impairment in a stroke-prone hypertensive model.

AIMS: We previously reported that the blood-brain barrier (BBB) function was impaired in vessels in the hippocampus in 3-month-old stroke-prone spontaneously hypertensive rats (SHRSP). In this study, we examined gene and protein expressions of P-glycoprotein, a representative efflux transporter of cerebral vessels, in the BBB-damaged hippocampal vessels of SHRSP and in the vessels of Wistar Kyoto (WKY) rats as controls, to clarify roles of the efflux transporter in the BBB-damaged vessels. METHODS: The expression of P-glycoprotein in hippocampal and cortical samples was examined by real-time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), Western blotting and immunoelectron microscopic techniques. RESULTS: Real-time RT-PCR and Western blotting analyses revealed that the gene and protein expressions of P-glycoprotein were increased in the hippocampal samples of 3-month-old SHRSP compared with hippocampal samples of 3-month-old WKY rats or with cortical samples of SHRSP. The gene expression of P-glycoprotein was also increased in the hippocampal samples of 4-week-old SHRSP. Immunoelectron microscopic examination revealed that immunosignals of P-glycoprotein were seen in the luminal and ab-luminal cytoplasmic membranes of endothelial cells and the basal lamina, that the labelling density of P-glycoprotein in the vessel wall was higher in the hippocampus of 3-month-old SHRSP than in other groups and that the immunosignals of P-glycoprotein were occasionally co-located with those of albumin. CONCLUSIONS: These findings indicate that the expression of P-glycoprotein is increased in BBB-damaged hippocampal vessels in hypertensive SHRSP compared with those in WKY rats.

Alteration in left ventricular diastolic filling and accumulation of myocardial collagen at insulin-resistant prediabetic stage of a type II diabetic rat model.

BACKGROUND: Considerable controversy exists regarding impairment of cardiac function in diabetes mellitus (DM). We investigated the serial changes in left ventricular (LV) histopathology and LV filling dynamics in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, which have been established as an animal model of type II DM. METHODS AND RESULTS: In 54 OLETF and 54 non-DM rats, body weight, blood pressure, heart rate, and transmitral pulsed Doppler examinations were performed from 5 to 47 weeks of age. An oral glucose tolerance test was performed at 10, 20, and 30 weeks of age. The hearts were excised for histopathology, including immunohistochemistry and histomorphometry of collagen, and measurement of hydroxyproline at baseline and each stage of developing DM. In the prediabetic stage (15 weeks of age), in which fast blood glucose remained normal, OLETF rats manifested mild obesity, postprandial hyperglycemia, and hyperinsulinemia, and early diastolic transmitral inflow exhibited prolonged deceleration time (OLETF, 59+/-10 ms versus non-DM, 49+/-8 ms, P<0.01) and low peak velocity (OLETF, 73+/-11 cm/s versus non-DM, 88+/-11 cm/s, P<0.01). Histopathology revealed extracellular fibrosis and abundant transforming growth factor-beta(1) receptor II in LV myocytes of OLETF rats. At 15 weeks of age, the ratio of collagen area/visual field of LV wall in OLETF rats (8.3+/-1.3%) was larger than that in non-DM rats (4.9+/-1.8%, P<0.0001), and the collagen content/dry tissue weight ratio of heart was significantly higher in OLETF (2. 0+/-0.5 mg/g) than non-DM (1.3+/-0.2 mg/g, P<0.01) rats. CONCLUSIONS: A metabolic abnormality present in the prestage of type II DM may produce LV fibrosis and alteration in cardiac function.

Angiotensin type 1 receptor blockage improves ischemic injury following transient focal cerebral ischemia.

Following cerebral ischemia, i.v. infusion of angiotensin II increases cerebral edema and mortality. Angiotensin type 1 receptor blockage should therefore improve acute cerebral ischemia. Left middle cerebral artery occlusion (120 min) followed by reperfusion was performed with the thread method under halothane anesthesia in Sprague-Dawley rats. Olmesartan (angiotensin type 1 receptor blocker; 0.01 or 0.1mumol/kg/h) was infused i.p. for 7 days following middle cerebral artery occlusion followed by reperfusion. Stroke index score, infarct volume, specific gravity, and brain angiotensin II and matrix metalloproteinases were quantified in the ischemic and non-ischemic hemispheres. Olmesartan treatment improved stroke index score, infarct volume, and cerebral edema in our cerebral ischemia model. In particular, stroke index score, infarct volume, and cerebral edema were reduced even with a low dose of olmesartan that did not decrease blood pressure. Paralleling these effects on cerebral ischemia, olmesartan treatment also reduced the reactive upregulation in brain angiotensin II, matrix metalloproteinase-2, matrix metalloproteinase-9, and membrane type 1-matrix metalloproteinase in the ischemic area. Angiotensin type 1 receptor stimulation may be one of the important factors that cause cerebral edema following cerebral ischemia, and that its inhibition may be of therapeutic advantage in cerebral ischemia.

Angiotensin-converting enzyme inhibition with enalapril slows progressive intima-media thickening of the common carotid artery in patients with non-insulin-dependent diabetes mellitus.

BACKGROUND AND PURPOSE: Whether angiotensin-converting enzyme (ACE) inhibitors have any clinically significant antiatherogenic effects in humans remains unproven. We undertook a prospective randomized clinical trial of 98 patients with non-insulin-dependent diabetes mellitus (NIDDM) to examine the efficacy of ACE inhibition with enalapril for preventing intima-media (IM) thickening of the carotid wall as measured ultrasonographically. METHODS: Ninety-eight NIDDM patients were randomly assigned either to enalapril at 10 mg/d (n=48) or to a control group (n=50); the planned duration of the trial was 2 years. All patients were seen at baseline (study entry) and 2 subsequent formal annual evaluations, in addition to standard clinical management for NIDDM. IM thickening and vascular lumen diameters were determined for all patients on the basis of baseline and 2 subsequent annual evaluations with carotid ultrasonography. We performed an intent-to-treat analysis to assess changes in IM thickening over the course of the study. RESULTS: Annual IM thickening measurements of the right and left common carotid arteries were 0.01+/-0.02 and 0.01+/-0.02 mm/y in the enalapril-treated group and 0.02+/-0.03 and 0.02+/-0.02 mm/y in the control group, respectively (P<0.05). From regression analysis, annual IM thickening was found to be predicted by enalapril use, sex, and insulin use (F(3,94)=3.86, P=0.012). When we controlled for these other variables, enalapril use reduced annual IM thickening of right and left common carotid arteries by 0.01+/-0.004 mm/y relative to the control group over the course of this study. CONCLUSIONS: Long-term treatment with an ACE inhibitor (enalapril) slows progressive IM thickening of the common carotid artery in NIDDM patients.

Rapid differential endogenous plasminogen activator expression after acute middle cerebral artery occlusion.

BACKGROUND AND PURPOSE: During focal cerebral ischemia, the microvascular matrix (ECM), which participates in microvascular integrity, is degraded and lost when neurons are injured. Loss of microvascular basal lamina antigens coincides with rapid expression of select matrix metalloproteinases (MMPs). Plasminogen activators (PAs) may also play a role in ECM degradation by the generation of plasmin or by MMP activation. METHODS: The endogenous expressions of tissue-type plasminogen activator (tPA), urokinase (uPA), and PA inhibitor-1 (PAI-1) were quantified in 10-microm frozen sections from ischemic and matched nonischemic basal ganglia and in the plasma of 34 male healthy nonhuman primates before and after middle cerebral artery occlusion (MCA:O). RESULTS: Within the ischemic basal ganglia, tissue uPA activity and antigen increased significantly within 1 hour after MCA:O (2P<0.005). tPA activity transiently decreased 2 hours after MCA:O (2P=0.01) in concert with an increase in PAI-1 antigen (2P=0.001) but otherwise did not change. The transient decrease in free tPA antigen was marked by an increase in the tPA-PAI-1 complex (2P<0.001). No significant relations to neuronal injury or intracerebral hemorrhage were discerned. CONCLUSIONS: The rapid increase in endogenous PA activity is mainly due to significant increases in uPA, but not tPA, within the ischemic basal ganglia after MCA:O. This increase and an increase in PAI-1 coincided with latent MMP-2 generation and microvascular ECM degeneration but not neuronal injury.

Duration threshold of induced hypertension on cerebral blood flow, energy metabolism, and edema after transient forebrain ischemia in gerbils.

We have investigated whether there is a duration threshold for the effects of phenylephrine-induced hypertension on CBF, brain energy metabolism, and cerebral parenchymal specific gravity (SG) following transient forebrain ischemia in gerbils. Sixty gerbils were randomly assigned to one of the four treatment groups: one control group and three groups subjected to an increase of 25 mm Hg in MABP induced by treatment, 30 min after reperfusion, with phenylephrine for 15 min, 30 min, or 60 min. The local CBF was measured continuously, and the SG was evaluated 120 min after reperfusion. Sequential changes in brain energy metabolism, as shown by the ratio of phosphocreatine to inorganic phosphate (Pi), the beta-ATP/Pi ratio, and intracellular pH, were also measured. The 15-min induced hypertension regimen was most suited to the recovery of brain energy metabolism, which was associated with an increase in local CBF and a decrease in cerebral edema. These results demonstrate that a suitable duration can be chosen to optimize the beneficial effects of phenylephrine-induced hypertension on ischemic brain injury following transient forebrain ischemia.

Effects of pravastatin sodium and simvastatin on plasma fibrinogen level and blood rheology in type II hyperlipoproteinemia.

Elevated plasma fibrinogen level is known to progress atherosclerosis and to be one of the risk factors for the occurrence of cardiovascular diseases. The objective of this study is to evaluate the changes in plasma fibrinogen level and blood rheology in patients with type II hyperlipoproteinemia before and after random administrations of HMG-CoA (3-hydroxy-e-methylglutaryl-cocarboxylase-A) reductase inhibitors, pravastatin sodium and simvastatin, and compare with results in normal subjects. Of a total of 28 patients with type II primary hyperlipoproteinemia with > 230 mg/dl fasting total plasma cholesterol, 16 patients (mean, 59.7 years old) were administered 10-15 mg/day of pravastatin sodium for an average of 10.2 weeks, and 12 patients (mean, 62.0 years old) were administered 5-10 mg/day of simvastatin for an average of 13.9 weeks. Patients were evaluated before and after drug administration and results were compared with those of 16 normal subjects of similar age (mean, 56.9 years old). Blood viscosities were measured using a cone-plate viscometer (Biorheolizer, BRL-1000, Japan). The following were measured before and after drug administration: whole blood viscosity at shear rates of 75-375 s-1, corrected blood viscosity at low (112.5 s-1) and high (225.0 s-1) shear rates for the standard hematocrit of 45%, plasma viscosity, hematocrit, total protein, serum albumin, and plasma fibrinogen. Total cholesterol level was significantly decreased (from 270 to 225, mg/dl, mean values; P < 0.0007) an average of 10.2 weeks after start of pravastatin sodium administration. In addition to the reductions of whole blood viscosity, at every shear rate examined, corrected blood viscosity, and plasma viscosity, plasma fibrinogen levels were significantly decreased (from 354 to 309 mg/dl, mean values; P < 0.0007) after start of pravastatin sodium administration. Fibrinogen level and blood rheology were not significantly changed after start of simvastatin administration despite similar significant reductions in total cholesterol level (from 260 to 207 mg/dl, mean values; P < 0.0001) to those in the case of pravastatin sodium. From the results, we conclude that administration of pravastatin sodium, but not simvastatin, reduced the plasma fibrinogen level and blood viscosities to normal levels in type II hyperlipoproteinemic patients while both drugs reduced total cholesterol level. The hydrophilicity and a small binding capacity with plasma protein of pravastatin sodium may be responsible in part for the beneficial hemorheologic effects observed in the patients with type II hyperlipoproteinemia. Further investigations should be conducted to confirm the findings observed.

Combined use of percutaneous ethanol injection and radiofrequency ablation for the effective treatment of hepatocelluar carcinoma.

Radiofrequency ablation (RFA) and percutaneous ethanol injection (PEI) therapy are currently used for the treatment of hepatocellular carcinoma (HCC). The purpose of this study was to evaluate the usefulness of combination therapy of PEI and RFA (PEI-RFA). Seventy-three patients with biopsy-proven HCC and liver cirrhosis underwent RFA after a bolus injection of ethanol into HCC. The volume of coagulated necrosis in the liver caused by PEI-RFA was estimated and compared with that by RFA alone. Coagulated necrosis areas in the liver of patients treated with PEI-RFA were significantly larger than those of patients treated with RFA alone. In PEI-RFA group, the volume of coagulated necrosis was significantly correlated with the amounts of ethanol injected into HCC. No major complications were observed during and after the PEI-RFA treatment. These results indicate that PEI-RFA is more effective than RFA alone and can make dramatic improvement of therapeutic effects in RFA therapy for HCC with fewer sessions of treatments. Therefore, PEI-RFA is considered to be a practical and promising option and may open up new avenues for the treatment of HCC.

Kinetic characterization of antibody-catalyzed insertion of a metal ion into porphyrin.

The insertion of a copper (II) ion into mesoporphyrin by a monoclonal catalytic antibody has been investigated kinetically by measuring the increase in Soret absorbance due to the production of copper (II)-mesoporphyrin. The initial rate of the reaction showed saturation kinetics as a function of the mesoporphyrin concentration, while it increased linearly with an increase in the copper (II) concentration. Based on observations, a scheme for the reaction was proposed: mesoporphyrin binds to the antibody to form a complex, and copper (II) binds to the complex to yield copper (II)-mesoporphyrin. Kinetic parameters for the respective steps were estimated, and the thermodynamic parameters were calculated. The binding of mesoporphyrin to the antibody was endothermic and entropically driven. This implies that hydrophobic interactions are an important factor in the binding. Free energy profiles for the antibody-catalyzed and uncatalyzed reactions were drawn by use of the obtained thermodynamic parameter values. The results demonstrate that the rate acceleration by, the antibody is ascribable to transition-state stabilization, and suggest that the structure of mesoporphyrin in the complex is more distorted than that of free mesoporphyrin.

Pancreatic invasion as the prognostic indicator of duodenal adenocarcinoma treated by pancreatoduodenectomy plus extended lymphadenectomy.

UNLABELLED: Pancreatoduodenectomy has become the standard procedure in resection of the duodenal adenocarcinoma, and some adjuvant therapies can be added to obtain further improvement in postoperative outcome. However, for patient selection, it is necessary to have a predictive indicator showing, if possible before laparotomy, which instances are noncurable by surgery alone or need adjuvant therapies. METHODS: A retrospective analysis was made for 24 consecutive patients whose duodenal adenocarcinoma were treated by pancreatoduodenectomy plus a wide range of lymphadenectomies without any adjuvant therapies at Osaka Medical Center for Cancer and Cardiovascular Diseases. Patient survival rates were related to macroscopic and microscopic findings and to findings obtained by preoperative imaging techniques. RESULTS: The overall survival rate was 69% at 3 years and 57% at 5 years; locoregional recurrence was the primary cause of death. Although the 5-year survival rate was 44% in patients with nodal involvement and 76% in those without, this difference did not reach statistical significance (P = .079). Instead, invasion into the pancreatic parenchyma at a macroscopic level was the most significant prognostic factor; the 5-year survival rate was 78% in the 16 patients without and 16% in the 8 patients with pancreatic invasion (P = .0047). Invasion into the pancreas correlated well with the angiographic findings; the 5-year survival rate was 25% in patients whose angiograms delineated the pancreatic invasion and 83% in patients whose angiograms did not (P = .0084). CONCLUSION: When duodenal adenocarcinoma was treated by pancreatoduodenectomy plus a wide range of lymphadenectomy, pancreatic invasion at a macroscopic level was most associated with patient survival. Pancreatic invasion was well delineated by the preoperative angiogram, which would be helpful in patient selection.

Association of plasma adrenomedullin with carotid atherosclerosis in chronic ischemic stroke.

Adrenomedullin is a potent vasodilator peptide exerting anti-atherosclerotic actions in vitro. We investigated the impact of the severity of atherosclerosis on plasma mature-adrenomedullin (m-AM) levels in 38 patients with chronic ischemic stroke. The variables of carotid artery atherosclerosis assessed using ultrasound measurement, blood pressure, and risk factors were related to m-AM levels. Severe atherosclerosis was associated with a further elevation of the increased m-AM level in patients with high systolic blood pressure. Even in patients with fewer risk factors, the presence of severe atherosclerosis was associated with an increased m-AM level. Thus, atherosclerosis elevates m-AM independent of the blood pressure level or presence of risk factors.

Thrombin inhibition attenuates neurodegeneration and cerebral edema formation following transient forebrain ischemia.

The disturbance of microcirculation following cerebral ischemia leads to an enlargement of cerebral infarct volume. Endogenous thrombin may play a role in this disturbance of microcirculation following cerebral ischemia. Therefore, the inhibition of thrombin may improve neurodegeneration and the accumulation of cerebral edema following cerebral ischemia in gerbils. The effects of thrombin inhibitor (argatroban) on cerebral ischemia were investigated in comparison with thromboxane A2 synthase inhibitor (ozagrel) and cyclooxygenase inhibitor (aspirin) following bilateral common carotid artery occlusion and reperfusion (CCA:O/R) in male Mongolian gerbils. This study consisted of three experiments: (1) morbidity and survival ratio (n=40 for each), (2) histopathology (n=12 for each), and (3) mean arterial blood pressure, local cerebral blood flow (CBF), and cerebral specific gravity (n=8 for each). Argatroban treatment improved survival ratio and stroke index, and decreased ischemically injured cell numbers in cortex and hippocampus and cerebral edema in cortex compared with aspirin and saline, in concert with the fast recovery of local CBF without reactive hyperemia following bilateral CCA:O/R. Ozagrel treatment also improved those factors compared with saline, in concert with the fast recovery of local CBF with reactive hyperemia. Aspirin treatment improved survival ratio and stroke index, and decreased ischemically injured cell numbers in cortex. Thrombin inhibition with argatroban decreases neurodegeneration and cerebral edema following bilateral CCA:O/R in gerbils.

Induced hypertension treatment to improve cerebral ischemic injury after transient forebrain ischemia.

The effect of induced hypertension treatment on cerebral ischemia is still controversial. We investigated the preferred blood pressure manipulation level and pressor agent required to reduce cerebral ischemic injury following transient forebrain ischemia induced by bilateral occlusion of the common carotid arteries in anesthetized gerbils. Following 60-min cerebral ischemia, we evaluated the preferred blood pressure manipulation level and pressor agent required to treat cerebral ischemic injury after reperfusion by examining the effects of different levels of mean arterial blood pressure (MABP), increased with phenylephrine or angiotensin II or decreased by blood withdrawal, on cerebral blood flow (CBF), survival ratio, cerebral edema, and brain energy metabolism following transient forebrain ischemia in gerbils. Mild phenylephrine-induced hypertension treatment (21+/-4 mmHg) during post-cerebral ischemia-reperfusion improved the survival ratio and reduced cerebral edema, which was also associated with an increase in local CBF and a recovery of brain energy metabolism. However, intense phenylephrine-induced hypertension, angiotensin II-induced hypertension, or hypotension worsen the survival rate and produced extra cerebral edema, that were also associated with deterioration of brain energy metabolism. These results demonstrate that a mild induced hypertension with phenylephrine (21+/-4 mmHg above the baseline level) results in reduction of the cerebral edema and improves the survival ratio and brain energy metabolism. Furthermore, angiotensin II may have neurotoxic effect to use as the pressor agent for induced hypertension after cerebral ischemia.

Nimodipine improves brain energy metabolism and blood rheology during ischemia and reperfusion in the gerbil brain.

Whether nimodipine improves cerebral blood flow (CBF) and metabolism in cerebral ischemia remains a controversial issue. We investigated the effect of nimodipine on CBF, brain energy metabolism, using a laser-Doppler flowmeter and in vivo 31phosphorus nuclear magnetic resonance (31P NMR) spectroscopy, and blood rheology during forebrain ischemia and reperfusion in gerbils. Eighty-three adult gerbils received nimodipine (1 micrograms/kg/min), or an equal volume of the vehicle, or saline, over 60 min prior to a transient forebrain ischemia for 60 min. We measured sequential changes in phosphocreatine (PCr) / inorganic phosphate (Pi) ratio, beta-ATP/Pi ratio, and intracellular pH (pHi) during ischemia and reperfusion by 31P NMR spectroscopy, and the measurement of whole blood viscosity (WBV) at 60 min after reperfusion. CBF was measured continuously throughout the study by a laser-Doppler flowmeter. During forebrain ischemia, PCr/Pi and beta-ATP/Pi ratios were higher significantly in the nimodipine-treated group (p < 0.05 and 0.01) than in the vehicle- or saline-treated groups. During reperfusion, PCr/Pi and beta-ATP/Pi ratios recovered significantly only in the nimodipine-treated group (p < 0.05 and 0.01). The WBV at high shear rate (562.5 s-1) lowered significantly in the nimodipine-treated group (p < 0.05) compared with the vehicle- or saline-treated group. CBF was higher significantly only during administration of nimodipine in the nimodipine-treated group (p < 0.01) than other groups. Nimodipine improved brain energy metabolism and blood rheology during forebrain ischemia and reperfusion in the gerbil brain.