The influence of hyperglycemic ischemia on tissue damage and cerebral blood flow was studied in rats subjected to short-lasting transient middle cerebral artery (MCA) occlusion. Rats were made hyperglycemic by intravenous infusion of glucose to a blood glucose level of about 20 mmol/L, and MCA occlusion was performed with the intraluminar filament technique for 15, 30, or 60 minutes, followed by 7 days of recovery. Normoglycemic animals received saline infusion. Perfusion-fixed brains were examined microscopically, and the volumes of selective neuronal necrosis and infarctions were calculated. Cerebral blood flow was measured autoradiographically at the end of 30 minutes of MCA occlusion and after 1 hour of recirculation in normoglycemic and hyperglycemic animals. In two additional groups with 30 minutes of MCA occlusion, CO2 was added to the inhaled gases to create a similar tissue acidosis as in hyperglycemic animals. In one group CBF was measured, and the second group was examined for tissue damage after 7 days. Fifteen and 30 minutes of MCA occlusion in combination with hyperglycemia produced larger infarcts and smaller amounts of selective neuronal necrosis than in rats with normal blood glucose levels, a significant difference in the total volume of ischemic damage being found after 30 minutes of MCA occlusion. After 60 minutes of occlusion, when the volume of infarction was larger, only minor differences between normoglycemic and hyperglycemic animals were found. Hypercapnic animals showed volumes of both selective neuronal necrosis and infarction that were almost identical with those observed in normoglycemic, normocapnic animals. When local CBF was measured in the ischemic core after 30 minutes of occlusion, neither the hyperglycemic nor the hypercapnic animals were found to be significantly different from the normoglycemic group. Brief focal cerebral ischemia combined with hyperglycemia leads to larger and more severe tissue damage. Our results do not support the hypothesis that the aggravated injury is caused by any disturbances in CBF. (+info)
Coronary microvascular protection with mg2+: effects on intracellular calcium regulation and vascular function.
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The use of Mg2+-supplemented hyperkalemic cardioplegia preserves microvascular function. However, the mechanism of this beneficial action remains to be elucidated. We investigated the effects of Mg2+ supplementation on the regulation of intracellular calcium concentration ([Ca2+]i) and vascular function using an in vitro microvascular model. Ferret coronary arterioles (80-150 micrometer in diameter) were studied in a pressurized (40 mmHg) no-flow, normothermic (37 degrees C) state. Simultaneous monitoring of internal luminal diameter and [Ca2+]i using fura 2 were made with microscopic image analysis. The microvessels (n = 6 each group) were divided into four groups according to the content of MgCl2 (nominally 0, 1.2, 5.0, and 25.0 mM) in a hyperkalemic cardioplegic solution ([K+] 25.0 mM). After baseline measurements, vessels were subjected to 60 min of hypoxia with hyperkalemic cardioplegia (equilibrated with 95% N2-5% CO2) containing each concentration of Mg2+ ([Mg2+]) and were then reoxygenated. During hyperkalemic cardioplegia, [Ca2+]i increased in a time-dependent manner in all groups. In the lower [Mg2+] cardioplegia groups, [Ca2+]i was significantly increased at the end of the 60-min cardioplegic period (247 +/- 44 nM and 236 +/- 49 nM in [Mg2+] 0 and 1.2 mM groups, respectively; both P < 0.05 vs. baseline) with 19.6-17.2% vascular contraction. Conversely, there was no significant [Ca2+]i increase in the higher [Mg2+] cardioplegia groups and less vascular contraction (5.4-4.1%, both P < 0.05 vs. [Mg2+] 1.2 mM group). After reperfusion, agonist (U-46619, thromboxane A2 analog)-induced vascular contraction was significantly enhanced in the lower [Mg2+] cardioplegia groups (both P < 0.05 vs. control) but was normalized in the higher [Mg2+] cardioplegia groups. Intrinsic myogenic contraction was significantly decreased in the lower [Mg2+] cardioplegia groups (both P < 0.05 vs. control) but was preserved in the higher [Mg2+] cardioplegia groups. These results suggest that supplementation of the solution with >5.0 mM [Mg2+] may prevent hyperkalemic cardioplegia-related intracellular Ca2+ overloading and preserve vascular contractile function in coronary microvessels. (+info)
Nitric oxide and hemoglobin interactions in the vasculature.
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As an endothelium-derived relaxing factor, nitric oxide (NO) maintains blood flow and O2 transport to tissues. Under normal conditions a delicate balance exists in the vascular system between endothelium-derived NO, an antioxidant, and the pro-oxidant elements of the vascular system, O-2, and peroxynitrite (a by-product of the reaction of NO and superoxide); in addition there is a balance between neurogenic tonic contraction and NO-mediated relaxation. The former balance can be disrupted in favor of peroxynitrite and hydrogen peroxide under the conditions of ischemia/reperfusion. This review suggests that NO may be beneficial, not only in terms of its new potential in improving O2 transport without accompanying significant increase in tissue blood flow, but also in its ability to suppress the prooxidative reagents of the vascular systems. These include NO-mediated inhibition of transendothelial migration by leukocyte and the antioxidative effects of NO with regard to ischemia/reperfusion; the relevance of these hypotheses to systemic administration of NO donors is discussed. (+info)
Early decrease of apurinic/apyrimidinic endonuclease expression after transient focal cerebral ischemia in mice.
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The authors examined the protein expression of apurinic/apyrimidinic endonuclease (APE/Ref-1), a multifunctional protein in the DNA base excision repair pathway, before and after transient focal ischemia in mice. Immunohistochemistry showed the nuclear expression of APE/Ref-1 in the entire region of the control brains. Nuclear immunoreactivity was decreased as early as 5 minutes after 60 minutes of ischemia in the ischemic core, which was followed by a significant reduction of APE/Ref-1-positive cells in the entire middle cerebral artery territory. Western blot analysis of the sample from the nonischemic brain showed a characteristic 37-kDa band, which was reduced after ischemia. A significant amount of DNA fragmentation was observed at 24 hours, but not at 4 hours, after ischemia. The authors' data provide the first evidence that APE/Ref-1 rapidly decreases after transient focal ischemia, and that this reduction precedes the peak of DNA fragmentation in the brain regions that are destined to show necrosis and apoptosis. Although further examination is necessary to elucidate the direct relationship between the APE/Ref-1 decrease and ischemic necrosis and apoptosis, our results suggest the possibility that rapid decrease of APE/Ref-1 and the failure of the DNA repair mechanism may contribute to necrosis or apoptosis after transient focal ischemia. (+info)
Pinealectomy aggravates and melatonin administration attenuates brain damage in focal ischemia.
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Large infarcts develop in pinealectomized rats subjected to middle cerebral artery occlusion, which was attributed to loss of antioxidant action of melatonin. However, melatonin also has vascular actions, and pinealectomy may induce hypertension. The authors investigated (1) whether hemodynamic factors contribute to infarct development in pinealectomized rats, (2) whether melatonin administration can reverse the unfavorable effect of pinealectomy on infarct formation, and (3) whether melatonin can reduce the infarct volume in nonpinealectomized rats subjected to focal transient ischemia (2 hours middle cerebral artery occlusion, 22 hours reperfusion). Rats were pinealectomized 3 months before ischemia to eliminate any possible action of pinealectomy-induced hypertension on stroke. Blood pressure and regional CBF values during ischemia and reperfusion were not significantly different between pinealectomized and sham-operated rats, suggesting that pinealectomy-induced increase in infarct was not related to hemodynamic factors. The infarct volume resumed to the level of sham-operated rats on melatonin administration. Injection of melatonin (4 mg/kg) before both ischemia and reperfusion reduced infarct volume by 40% and significantly improved neurologic deficit scores in pinealectomized as well as sham-operated rats subjected to middle cerebral artery occlusion. These data suggest that physiologic melatonin release as well as exogenously given melatonin has a neuroprotective action in focal cerebral ischemia. (+info)
Effect of diaspirin cross-linked hemoglobin on normal and postischemic microcirculation of the rat pancreas.
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Microcirculatory alterations with reduced nutritive supply to the pancreas could be the cause of hyperamylasemia, which occurs in some patients receiving the vasoactive oxygen carrier diaspirin cross-linked hemoglobin (DCLHb) in clinical studies. Therefore, the effects of DCLHb on rat pancreas microcirculation were evaluated. Anesthetized Sprague-Dawley rats received one of the following treatments during baseline conditions (n = 7 rats/group): 10% hydroxyethyl starch (HAES) (0.4 ml/kg), DCLHb (400 mg/kg), or DCLHb (1,400 mg/kg). After 1 h of complete, reversible pancreatic ischemia, other animals received 10% HAES (0.4 ml/kg) or DCLHb (400 mg/kg) during the onset of reperfusion. The number of red blood cell-perfused capillaries (functional capillary density, FCD) and the level of leukocyte adherence in postcapillary venules in the pancreas were assessed by means of intravital microscopy during 2 h after treatment. In the nonischemic groups, FCD was 18% greater after DCLHb (1,400 mg/kg) than after 10% HAES treatment without any increase in leukocyte adherence. In the inschemia-reperfusion (I/R) 10% HAES group, FCD was significantly (P < 0.05) lowered, leukocyte adherence enhanced, and mean arterial pressure (MAP) reduced by 31% compared with nonischemic animals. DCLHb treatment in the I/R group resulted in a slight increase in FCD, a significant (P < 0.05) reduction of leukocyte adherence, and a complete restoration of MAP compared with the animals of the I/R control group. Thus our data provide no evidence for a detrimental effect on the pancreatic microcirculation or an enhanced risk of postischemic pancreatitis by DCLHb. (+info)
Ischaemia and reperfusion during open abdominal aortic aneurysm surgery induce extensive thrombin generation and activity.
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OBJECTIVES: does open surgery for abdominal aortic aneurysm (AAA) influence coagulation? METHODS: in 23 patients operated on for AAA, cubital blood was sampled pre-, intra- and postoperatively. Femoral blood was also sampled intraoperatively. RESULTS: preoperatively, prothrombin fragment 1+2 (F1+2), thrombin-antithrombin complex (TAT) and soluble fibrin (SF) were elevated in AAA patients. During aortic clamping all parameters increased significantly in cubital blood (p<0.01) as well as in femoral blood (p<0.001) and after aortic declamping F1+2 and TAT increased further. F1+2, TAT and SF were significantly higher in femoral than cubital blood. Postoperatively F1+2 and TAT returned to preoperative values, while SF still had a significantly higher level than preoperatively (p<0.001). Blood loss showed co-variation with F1+2 increase in femoral blood after aortic declamping (p<0.05). CONCLUSIONS: these data indicate that the coagulation system was strongly activated by the occurrence of an AAA. During AAA surgery a further extensive activation was seen. The activity was still high, but on decline, one week postoperatively. Ischaemia and reperfusion of the lower part of the body were the major stimuli for thrombin generation and activity. (+info)
Decompressive craniectomy, reperfusion, or a combination for early treatment of acute "malignant" cerebral hemispheric stroke in rats? Potential mechanisms studied by MRI.
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BACKGROUND AND PURPOSE: Both early reperfusion and decompressive craniectomy have proved beneficial in the treatment of large space-occupying "malignant" hemispheric stroke. The aim of this study was to directly compare the benefit of reperfusion with that of craniectomy and to study the effects of combined treatment in a rat model of focal cerebral ischemia. METHODS: Cerebral ischemia was introduced in 28 rats. Four groups were investigated: (1) no treatment, (2) decompressive craniectomy, (3) reperfusion, and (4) reperfusion and craniectomy as treatment at 1 hour after middle cerebral artery occlusion. Perfusion- and diffusion-weighted MRI were performed serially from 0.5 to 6 hours after middle cerebral artery occlusion. RESULTS: The 6-hour DWI-derived hemispheric lesion volumes in the reperfusion group (10.2+/-3.9%), the craniectomy group (23.0+/-6.4%), and the combination group (21.8+/-12.4) were significantly smaller than that in the control group (44.1+/-5.4%) (P<0.05). Reperfusion, craniectomy, and combined treatment led to higher perfusion in the cortex compared with the control group, whereas only reperfused animals achieved significantly higher perfusion in the basal ganglia. In 5 animals, combined reperfusion and decompressive craniectomy resulted in an early contrast media enhancement. CONCLUSIONS: Early reperfusion and craniectomy were shown to be effective in decreasing infarction volume by improving cerebral perfusion. Reperfusion remains the best therapy in malignant hemispheric stroke. Combined treatment yields no additional benefit compared with single treatment, probably because of early blood-brain barrier breakdown. (+info)