Background and PurposeWe previously reported that L-arginine infusion increased pial vessel diameter by nitric oxidedependent mechanisms, improved regional cerebral blood flow (rCBF) distal to middle cerebral artery (MCA) occlusion, and reduced infarction volume in spontaneously hypertensive rats when administered intraperitoneally before and after MCA occlusion. In this report we extend our findings (1) by examining the time course of L-arginine on rCBF and pial vessel diameter under basal conditions and on rCBF after MCA occlusion and (2) by reproducing the protective effect of L-arginine on infarct volume when given intravenously immediately after the onset of MCA occlusion in both normotensive and hypertensive models of focal cerebral ischemia.Methods Changes in pial vessel diameter (closed cranial window) and rCBF (laser-Doppler flowmetry) were measured over time after L-arginine infusion into anesthetized Sprague-Dawley rats. rCBF was also measured distal to MCA occlusion in a brain region showing rCBF reductions in the range of 80% of baseline. The effects of infusing L-arginine (300 mg/kg for 10 minutes beginning 5 minutes after occlusion) were assessed on infarction volume in Sprague-Dawley rats after proximal MCA occlusion and in spontaneously hypertensive rats after common carotid artery plus distal MCA occlusion.
Summary: The purpose of this study was to determine the effect of selective modulation of brain temperature in the experimental settings of permanent and reversible middle cerebral artery (MCA) occlusion in Sprague Dawley rats. Three models of proximal MCA occlusion were used, in which the effect of brain-temperature mod ulations could be studied. These included (a) permanent MCA occlusion with an initial 30-min period of hypoten sion (30 or 36°C x 4 h), (b) permanent MCA occlusion alone (30, 36, or 39°C x 2 h), and (c) 2 h of reversible MCA occlusion (30, 36, or 39°C x 2 h). In the transient MCA occlusion series, intra-and postischemic cortical blood flow was assessed using a laser-Doppler flowmeter placed over the dorsolateral cortex. After a 3-day sur vival, all rats were perfusion fixed for histopathological analysis and the determination of infarct volume. In ani mals with permanent MCA occlusion plus hypotension, no significant difference in infarct volume was demon strated between the 30 and 36°C groups. In rats with per manent MCA occlusion without hypotension, significantBeneficial effects of hypothermia have been well established in the experimental settings of brain anoxia and hypoxia-ischemia (Michenfelder and Theye, 1970; Berntman et aI., 1981 ; Young et aI., 1983) and in temporary complete global cerebral ischemia (Connolly et al., 1962; Marshall et aI., 1956; Kramer et aI., 1968; Kopf et aI., 1975). Recent
380differences in infarct volume were again not demonstra ble, but an interaction between infarct area and temper ature class was shown by repeated-measures analysis, indicating that hypothermia altered the topographic pat tern of the cortical infarct. With 2 h of reversible MCA occlusion, there was a statistically significant reduction in infarct volume in the 30°C groJlP compared to 39°C rats. Although intra-and postischemic CBP were not signifi cantly different among the three temperature groups, the cortical infarct volume was positively correlated with postischemic CBP. The postischemic CBP, in turn, was positively correlated to the intraischemic brain tempera ture and was negatively correlated to CBP during the ischemic period. These findings demonstrate that moder ate manipUlations of brain temperature have a greater in fluence on the resulting cortical infarction in the setting of transient focal ischemia than in the context of permanent vascular occlusion.
An astrocytic protein S-100beta enhances the expression of inducible nitric oxide synthase in cultured astrocytes at micromolar concentrations, leading to nitric oxide-mediated death of cocultured neurons. The present study examined whether S-100beta production by reactive astrocytes accumulating within the periinfarct area was related to delayed expansion of infarct volume after permanent middle cerebral artery occlusion in the rat. After rapid increases during the initial 24 hours, the increase of infarct volume then decelerated while maintaining the increasing tendency until 168 hours in this model, attaining a significant difference compared with that at 24 hours. In the periinfarct area, the number of reactive astrocytes expressing both S-100 and glial fibrillary acidic protein, the tissue level of S-100beta as measured by the sandwich enzyme-linked immunosolvent assay method using anti-S-100beta monoclonal antibody, and the number of terminal deoxynucleotidyl transferase-mediated 2;-deoxyuridine 5;-triphosphate-biotin nick end labeling-positive cells were significantly increased preceding the delayed expansion of infarct volume. The CSF concentration of S-100beta showed a biphasic increase, presumably reflecting the immediate release from astrocytes within the ischemic core and the subsequent production in reactive astrocytes within the periinfarct area. These results show for the first time that the enhanced synthesis of S-100beta by reactive astrocytes participates in the inflammatory responses within the periinfarct area, which may be related to the occurrence of delayed infarct expansion as a major component of the cytokine network.
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