Abstract—Activation of the mammalian target of rapamycin (mTOR) leads to cell growth and survival. We tested the hypothesis that inhibition of mTOR would increase infarct size and decrease microregional O2 supply/consumption balance after cerebral ischemia–reperfusion. This was tested in isoflurane-anesthetized rats with middle cerebral artery blockade for 1 h and reperfusion for 2 h with and without rapamycin (20 mg/kg once daily for two days prior to ischemia). Regional cerebral blood flow was determined using a C14-iodoantipyrine autoradiographic technique. Regional small-vessel arterial and venous oxygen saturations were determined microspectrophotometrically. The control ischemic-reperfused cortex had a similar blood flow and O2 consumption to the contralateral cortex. However, microregional O2 supply/consumption balance was significantly reduced in the ischemic-reperfused cortex. Rapamycin significantly increased cerebral O2 consumption and further reduced O2 supply/consumption balance in the reperfused area. This was associated with an increased cortical infarct size (13.5 ± 0.8% control vs. 21.5 ± 0.9% rapamycin). We also found that ischemia–reperfusion increased AKT and S6K1 phosphorylation, while rapamycin decreased this phosphorylation in both the control and ischemic-reperfused cortex. This suggests that mTOR is important for not only cell survival, but also for the control of oxygen balance after cerebral ischemia–reperfusion.

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Background and Purpose-After cerebral vessel blockage, local blood flow and O 2 consumption becomes lower and oxygen extraction increases. With reperfusion, blood flow is partially restored. We examined the effects of ischemia-reperfusion on the heterogeneity of local venous oxygen saturation in rats in order to determine the pattern of microregional O 2 supply/consumption balance in reperfusion. Methods-The middle cerebral artery was blocked for 1 hour using the internal carotid approach in 1 group (n=9) and was then reperfused for 2 hours in another group (n=9) of isoflurane-anesthetized rats. Regional cerebral blood flow was determined using a C 14 -iodoantipyrine autoradiographic technique. Regional small vessel arterial and venous oxygen saturations were determined microspectrophotometrically. Results-After 1 hour of ischemia, local cerebral blood flow (92±10 versus 50±10 mL/min per 100 g) and O 2 consumption (4.5±0.6 versus 2.7±0.5 mL O 2 /min per 100 g) decreased compared with the contralateral cortex. Oxygen extraction increased (4.7±0.2 versus 5.4±0.3 mL O 2 /100 mL) and the variation in small vein (20-60 μm) O 2 saturation as determined by its coefficient of variation (=100×SD/mean) increased (5.5 versus 10.5). With 2 hours of reperfusion, the blood flow decrement was reduced and O 2 consumption returned to the value in the contralateral cortex. Oxygen extraction remained elevated in the ischemic-reperfused area and the coefficient of variation of small vein O 2 saturation increased further (17.3). Conclusions-These

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We studied serious renal disease in Egypt by registering all 155 patients coming to the nephrology service at the University of Cairo during a period of 62 days in 1993. The patients presented with severe uremic symptoms. Admission creatinine and urea levels were high, 804 mumol/l and 64 mmol/l. Fifteen percent of the patients died; 115 underwent dialysis. Sixty patients presented with chronic renal failure; 53 with acute renal failure, but 24 of these were later found to have end-stage renal failure. Of 29 patients with true acute renal failure, 11 (38%) had pre-renal failure and 7 (24%) post-renal failure. Twenty-one patients were followed up after transplantation and chronic dialysis, another 17 had nephrotic syndrome, 3 hypertension, and one had asymptomatic urinary abnormalities. The most common specific etiology for chronic end-stage renal failure was diabetes mellitus type II in the older patients; second most common was Schistosoma in the younger ones. Most diabetic patients came from the city. All but one Schistosoma patient came from rural Egypt. In the 22 patients who underwent renal biopsy the most common diagnosis was mesangio capillary glomerulonephritis. The prevalence of acute renal failure, particularly iatrogenic-toxic, is increasing.

This study was performed to investigate whether WIN 55,212-2 (WIN), a cannabinoid receptor agonist, could attenuate blood-brain barrier (BBB) disruption in focal cerebral ischemia in rats and whether the CB₁ receptor antagonist rimonabant could prevent this attenuation. A total of 0.3 or 1 mg/kg of WIN was injected intravenously before and after permanent middle cerebral artery (MCA) occlusion. Some animals were pretreated with rimonabant 2 mg/kg i.p. before receiving 0.3 mg/kg of WIN. At 1 h after MCA occlusion, BBB permeability was determined by measuring the transfer coefficient (K_i) of ¹⁴C-α-aminoisobutyric acid and the volume of dextran distribution. With MCA occlusion, K_i increased in the ischemic cortex (IC) in all of the experimental groups. However, the K_i of the IC of the WIN 0.3 and 1 mg/kg groups was lower (–46 and –42%, respectively, p < 0.05) than that of the control group. With rimonabant pretreatment, the K_i of the IC became higher (+88%, p < 0.05) than with WIN 0.3 mg/kg alone and similar to that of the control rats. The difference in the volume of dextran distribution between the IC and the contralateral cortex was significant in the control but not in the WIN-treated rats. With rimonabant pretreatment, however, the difference became significant. Our data demonstrated that WIN could attenuate BBB disruption in focal cerebral ischemia and this attenuation could be prevented with rimonabant. Our data suggest an involvement of CB₁ receptors in the regulation of BBB disruption in the early stage of stroke.

We performed this study to determine how pretreatment of the ovariectomized rats with 17beta-estradiol could affect blood-brain barrier disruption caused by the vascular endothelial growth factor (VEGF), an important mediator of vascular permeability. Ovariectomized female rats aged twelve to fourteen weeks were used in the study. A 500 micro g 17beta-estradiol 21-day release pellet was implanted in the 17beta-estradiol group, and a vehicle pellet was implanted in the control group 21 days before the experiments. We performed three craniotomies under isoflurane anesthesia to expose cerebral cortices. Normal saline, 10 (- 10)M and 10 (- 9)M VEGF patches were applied on each hole for 30 min. The transfer coefficient (Ki) of (14)C-alpha-amino isobutyric acid and volume of (3)H-dextran (70,000 dalton) distribution were determined to measure the degree of BBB disruption. Ki was increased by 108 % and 138 % with 10 (- 10)M and 10 (- 9)M VEGF respectively after VEGF application in the control group (p < 0.01). However, there was no significant increase in the Ki with the VEGF application in the 17beta-estradiol group, and their values were significantly lower than the corresponding data of the control group (10 (- 10)M: - 55 %, 10 (- 9)M: - 52 %, p <0.05). The volume of dextran distribution in the control group increased by 47 % with VEGF 10 (- 9)M (p < 0.05), whereas there was no significant change in the volume of dextran distribution with VEGF application in the 17beta-estradiol group and the volume was lower than the corresponding volume of the vehicle-treated control group (10 (- 10)M: - 34 %, 10 (- 9)M: -32 %, p < 0.05). In conclusion, our study demonstrated that chronic 17beta-estradiol treatment prevented BBB disruption induced by the VEGF in the ovariectomized rats.

Objectives Return of regional cerebral blood flow (rCBF) in focal cerebral ischaemia may not ensure proper distribution of blood flow to meet metabolic demand. This study was performed to determine how inhibition of neuronal nitric oxide synthase (NOS) during ischaemia-reperfusion would affect microregional O supply/consumption balances and their variation. Methods Twenty minutes before middle cerebral artery (MCA) occlusion, a NOS inhibitor 7-nitroindazole (7-NI) 50 mg/kg ip (7-NI group) or vehicle (control group) was administered. At 1 hour of ischaemia and 2 hours of reperfusion, rCBF, the size of cortical infarct and arteriolar and venular O saturations (20-60 μm in diameter) using cryomicrospectrophotometry were determined. Results Ischaemia-reperfusion decreased the average venular O saturation and the ratio of O supply/consumption. But, 7-NI treatment improved the average O supply/consumption ratio and venular O saturation (57.6 ± 1.3 vs 52.0 ± 3.8%) in ischaemia-reperfusion. The heterogeneity of venular O saturations reported as coefficient of variation (CV = 100 × SD/mean) was much smaller in the 7-NI than the control group (8.8 vs 15.5). The number of veins with low O saturation ( < 50%) was also smaller with the 7-NI (4/70) than the control group (18/70). The size of cortical infarct was smaller with 7-NI treatment. Discussion Our data suggest that inhibition of neuronal NOS by 7-NI improved microregional O balance in the ischaemic-reperfused cortex (IR-C). The improvement in microregional O balance could be one of the contributing factors to the reduced size of cortical infarct.