Reperfusion after cerebral ischemia: influence of duration of ischemia

The influence of the duration of ischemia on the pattern of cerebral blood flow in recirculation was studied in anesthetised rats. Severe incomplete cerebral ischemia (mean ischemic flow = 5.8 +/- 0.4 ml/100 g/min) was produced by four-vessel occlusion and recirculation permitted after 15, 30 or 60 minutes ischemia. All three groups showed an immediate hyperemia followed by hypoperfusion. Hyperemia was maximal following 15 minutes ischemia and least pronounced following 60 minutes ischemia (p = 0.0249). Hypoperfusion started most quickly following 15 minutes ischemia and was delayed following 60 minutes ischemia (p less than 0.001). In established hypoperfusion there was no difference in flow between the three groups. The possible mechanisms of these changes in flow are discussed.     

Monoclonal leukocyte antibody does not decrease the injury of transient focal cerebral ischemia in cats.

BACKGROUND AND PURPOSE: We tested the hypothesis that inhibition of leukocyte function by administration of monoclonal antibody 60.3 (MoAb 60.3) improves electrophysiological recovery and decreases injury volume following transient focal cerebral ischemia in cats. METHODS: Halothane-anesthetized cats underwent 90 minutes of left middle cerebral artery and bilateral common carotid artery occlusion followed by 180 minutes of reperfusion. Cats were assigned to receive either 2 mg/kg MoAb 60.3 (n = 8) directed at the CDw18 leukocyte antigen complex or an equal volume of diluent (sterile saline; n = 10) at 45 minutes of ischemia in a blinded fashion. RESULTS: Blood flow to the left temporoparietal cortex decreased to less than 5 ml/min/100 g with ischemia, but was minimally affected on the right side. Postischemic hyperemia occurred in the left caudate nucleus, whereas blood flow in other brain regions returned to control. No region demonstrated delayed hypoperfusion, and there were no differences between groups. Somatosensory evoked potential recorded over the left cortex was ablated during ischemia and recovered to less than 10% of baseline amplitude at 180 minutes of reperfusion in both groups. Left hemispheric injury volume, as assessed by 2,3,5-triphenyltetrazolium chloride staining, was not affected by drug treatment (mean +/- SE values: MoAb 60.3, 37 +/- 5%; placebo, 38 +/- 7% of hemisphere). CONCLUSIONS: Inhibition of leukocyte function with MoAb 60.3 does not afford protection from severe focal ischemia and reperfusion in cats.     

Tirilazad mesylate does not improve early cerebral metabolic recovery following compression ischemia in dogs.

BACKGROUND AND PURPOSE: Tirilazad mesylate (U74006F) has been reported to improve recovery following cerebral ischemia. We conducted a randomized blinded study to determine if the drug would improve immediate metabolic recovery after complete cerebral compression ischemia. METHODS: Mongrel dogs were anesthetized with pentobarbital and fentanyl and treated with either vehicle (citrate buffer, n = 8) or tirilazad (1.5 mg/kg i.v. plus 0.18 mg/kg/hr, n = 8). Normothermic complete cerebral compression ischemia was produced for 12 minutes by lateral ventricular fluid infusion to raise intracranial pressure above systolic arterial pressure. Cerebral high-energy phosphate concentrations and intracellular pH were measured by phosphorus magnetic resonance spectroscopy. Cerebral blood flow was measured with radiolabeled microspheres, and oxygen consumption was calculated from sagittal sinus blood samples. Somatosensory evoked potentials were measured throughout the experiment. RESULTS: During ischemia, both groups demonstrated complete loss of high-energy phosphates and a fall in intracellular pH (vehicle, 5.76 +/- 0.23; tirilazad, 5.79 +/- 0.26; mean +/- SEM). At 180 minutes of reperfusion, there were no differences between groups in recovery of intracellular pH (vehicle, 6.89 +/- 0.07; tirilazad, 6.88 +/- 0.18), phosphocreatine concentration (vehicle, 89 +/- 16%; tirilazad, 94 +/- 24% of baseline value), oxygen consumption (vehicle, 2.6 +/- 0.2 ml/min/100 g; tirilazad, 1.8 +/- 0.5 ml/min/100 g), or somatosensory evoked potential amplitude (vehicle, 11 +/- 6%; tirilazad, 7 +/- 4% of baseline value). Forebrain blood flow fell below baseline levels at 180 minutes of reperfusion in the tirilazad-treated animals but not in the vehicle-treated dogs (vehicle, 28 +/- 4 ml/min/100 g; tirilazad, 18 +/- 5 ml/min/100 g). CONCLUSIONS: We conclude that tirilazad pretreatment does not improve immediate metabolic recovery 3 hours following 12 minutes of normothermic complete ischemia produced by cerebral compression.     

Chronic trigeminal ganglionectomy or topical capsaicin application to pial vessels attenuates postocclusive cortical hyperemia but does not influence postischemic hypoperfusion.

Marked hyperemia accompanies reperfusion after ischemia in the brain, and may account for the propensity of cerebral hemorrhage to follow embolic stroke or carotid endarterectomy, and for the morbidity that follows head injury or the ligation of large arteriovenous malformations. To evaluate the contribution of trigeminal sensory fibers to the hyperemic response, CBF was determined in 12 symmetrical brain regions, using microspheres with up to five different isotopic labels, in four groups of cats. Measurements were made at 15-min intervals for up to 2 h of reperfusion after global cerebral ischemia induced by four-vessel occlusion combined with systemic hypotension of either 10- or 20-min duration. In normal animals, hyperemia in cortical gray matter 30 min after reperfusion was significantly greater after 20 min (n = 10) than after 10 min (n = 7) of ischemia (312 ml/100 g/min versus 245 ml/100 g/min; p less than 0.01). CBF returned to preischemic levels approximately 45 min after reperfusion and was reduced to approximately 65% of basal CBF for the remaining 75 min. In cats subjected to chronic trigeminal ganglionectomy (n = 15), postocclusive hyperemia in cortical gray matter was attenuated by up to 48% on the denervated side (249 versus 150 ml/100 g/min; p less than 0.01) after 10 min of ischemia. This effect was maximal in the middle cerebral artery (MCA) territory, and was confined to regions known to receive a trigeminal innervation. In these animals, substance P (SP) levels in the MCA were reduced by 64% (p less than 0.01), and the density of nerve fibers containing calcitonin gene-related peptide (but not vasoactive intestinal polypeptide or neuropeptide Y) was decreased markedly on the lesioned side. Topical application of capsaicin (100 nM; 50 microliters) to the middle or posterior temporal branch of the MCA 10-14 days before ischemia decreased SP levels by 36%. Postocclusive hyperemia in cortical gray matter was attenuated throughout the ipsilateral hemisphere by up to 58%, but the cerebral vascular response to hypercapnia (PaCO2 = 60 mm Hg) was unimpaired. The duration of hyperemia and the severity of the delayed hypoperfusion were not influenced by trigeminalectomy, capsaicin application, or the intravenous administration of ATP. These data demonstrate the importance of neurogenic mechanisms in the development of postischemic hyperperfusion, and suggest the potential utility of strategies aimed at blocking axon reflex-like mechanisms to reduce severe cortical hyperemia.     

Polyethylene glycol-conjugated superoxide dismutase fails to augment brain superoxide dismutase activity in piglets

We studied the effect of intravenously administered polyethylene glycol-conjugated superoxide dismutase (8,000 units/kg) on brain superoxide dismutase activity in 44 1-2-week-old piglets in the absence and presence of global cerebral ischemia and reperfusion. Four groups (n = 6 each) of piglets not exposed to ischemia were studied. Enzyme administration increased plasma superoxide dismutase activity from less than 5 to 142 +/- 8 units/ml (mean +/- SEM) without increasing brain activity (e.g., activities in the caudate were 7.9 +/- 0.5 and 8.1 +/- 0.4 units/mg protein) for up to 2 hours following administration. Four additional groups (n = 5 each) of piglets were given either enzyme or polyethylene glycol 5 minutes prior to 10 minutes of global cerebral ischemia induced by aortic cross-clamping followed by either 5 or 45 minutes of reperfusion. Enzyme administration increased plasma superoxide dismutase activity from less than 5 to 144 +/- 5 units/ml but failed to increase brain activity even after 45 minutes of reperfusion (e.g., activities in the caudate were 8.5 +/- 0.3 and 8.6 +/- 0.6 units/mg protein). We conclude that intravenous polyethylene glycol-conjugated superoxide dismutase does not increase superoxide dismutase activity in the brain despite global ischemia and reperfusion.     

Effects of U74006F on multifocal cerebral blood flow and metabolism after cardiac arrest in dogs

Lipid peroxidation reactions during reperfusion after cardiac arrest may contribute to postischemic cerebral hypoperfusion, which in turn can contribute to permanent neurological dysfunction. We designed this study to determine whether the aminosteroid U74006F, a putative inhibitor of lipid peroxidation, mitigates cerebral multifocal hypoperfusion after cardiac arrest. We used our established dog model of ventricular fibrillation cardiac arrest (no blood flow) of 12.5 minutes, reperfusion by cardiopulmonary bypass of less than or equal to 5 minutes, and control of extracerebral variables during 4 hours postarrest. Cerebral blood flow was monitored by the stable xenon computed tomography method. Changes in cerebral oxygen consumption were obtained from mean blood flow values of coronal slices and the cerebral arteriovenous (sagittal sinus) oxygen content difference. A treatment group (n = 5) received U74006F starting with reperfusion (1.5 mg/kg i.a. plus 1.5 mg/kg i.v.) and three additional (graded) doses over 4 hours (total dose 4.5, 7.5, or 14.5 mg/kg). The U74006F-treated group showed the same postarrest transient hyperemia and protracted hypoperfusion in terms of global (computed tomography slice), regional, and local (multifocal) cerebral blood flow values and the same global cerebral oxygen consumption pattern as a concurrent control group (n = 5). At 1-4 hours postarrest, in both groups there was mismatching of global cerebral oxygen consumption, which reached baseline values, in relation to global cerebral blood flow and oxygen delivery, which remained at 50% of baseline. We conclude that treatment with U74006F after prolonged cardiac arrest causes no deleterious side effects and does not seem to alter multifocal postarrest cerebral blood flow and oxygen consumption.     

Recirculation in the rat brain following incomplete ischemia

The objective of this study was to characterize local cerebral blood flow (CBF) in the recirculation period following incomplete forebrain ischemia. Specifically, we wished to determine whether perfusion defects developed in the immediate recirculation period, to study how initial hyperemia and delayed hypoperfusion at the local level were related to the severity of the preceding ischemia, and to find out whether reflow was influenced by the nutritional state of the animals. To that end, forebrain ischemia of 15 min duration was induced in fed and fasted ventilated rats under 70% N2O. Local CBF was measured with an autoradiographic technique at the end of ischemia, as well as at 5 and 60 min following the start of recirculation. Control experiments were performed to examine the influence of ischemia on cerebral metabolic state in fed and fasted animals. The ischemia reduced CBF to excessively low values (less than 5% of control) in many forebrain structures, including the cerebral cortices, caudoputamen, and hippocampus. In spite of this, perfusion defects failed to appear after 5 min of recirculation. Instead, moderate to marked hyperemia was present in all previously ischemic structures. After 60 min of recirculation, pronounced hypoperfusion developed. The magnitude of the initial hyperemia was poorly related to the severity of the preceding ischemia, but the latter partly determined the degree of delayed hypoperfusion. Thus, little or no hypoperfusion developed in structures whose flow rates exceeded 30-40% of control during ischemia. Fasted animals had a better preserved flow to many structures than did fed animals, indicating that the detrimental effect of feeding (or glucose infusion) is also reflected in lower perfusion rates.     

Conjugated superoxide dismutase reduces extent of caudate injury after transient focal ischemia in cats.

We tested the efficacy of preischemic and postischemic systemic treatment with 30,000 units polyethylene glycol-conjugated superoxide dismutase in a reperfusion model of focal cerebral ischemia. Forty-one anesthetized cats underwent 2 hours' occlusion of the left middle cerebral artery and both common carotid arteries followed by 4 hours of reperfusion. Cats were blindly assigned to one of three groups: treatment with vehicle (10% polyethylene glycol in saline, n = 17), pretreatment with drug 3 hours before ischemia (n = 12), and posttreatment with drug at the time of reperfusion (n = 12). Size of the ischemic injury was calculated from 2,3,5-triphenyltetrazolium chloride staining. Injury in the caudate nucleus was significantly reduced with pretreatment (28 +/- 6% of ipsilateral caudate volume, mean +/- SEM) compared with the vehicle (56 +/- 8%). Posttreatment did not significantly ameliorate caudate injury (46 +/- 10%). Between the first and second hours of ischemia ipsilateral caudate blood flow determined using microspheres increased significantly from 11 +/- 4 to 16 +/- 5 ml/min/100 g with pretreatment, but blood flow remained constant throughout ischemia with vehicle (8 +/- 2 ml/min/100 g) and posttreatment (10 +/- 3 ml/min/100 g). The size of cortical injury (vehicle, 17 +/- 5%; pretreatment, 11 +/- 3%; posttreatment, 17 +/- 5% of hemispheric volume) did not differ significantly among groups. Somatosensory evoked potential recovery did not differ among groups. We conclude that pretreatment with conjugated superoxide dismutase can ameliorate the extent of injury in an end-artery region, such as the caudate nucleus, in a reperfusion model of focal ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)     

Incomplete versus complete cerebral ischemia: improved outcome with a minimal blood flow

It has been reported that incomplete cerebral ischemia with cerebral blood flow less than 10% of control may be more damaging than an equal period of complete ischemia. In this study, the effects of severe, incomplete cerebral ischemia on neurological outcome and cerebral metabolism were studied in dogs anesthetized with nitrous oxide. The results were compared with those of a previous study concerned with the effects of complete ischemia. Dogs could sustain only 8 to 9 minutes of complete ischemia with return of normal neurological function, whereas maintenance of a cerebral blood flow rate less than 10% of control extended this limit to 10 6o 12 minutes. Following a 10-minute exposure, only dogs undergoing incomplete ischemia regained a normal cerebral oxygen consumption within 90 minutes; similarly, animals subjected to incomplete ischemia enjoyed a faster return of EEG activity than dogs exposed to complete ischemia of the same duration. Cerebral metabolite levels did not prove to be a good index of return of neurological function. Within periods of cerebral ischemia in which meaningful neurological recovery might be expected, we conclude that some blood flow is better than no flow.     

Opioids and the prostanoid system in the control of cerebral blood flow in hypotensive piglets

The interaction between opioid and prostanoid mechanisms in the control of cerebral hemodynamics was investigated in the conscious hypotensive piglet. Radiomicrospheres were used to determine regional cerebral blood flow (rCBF) in piglets pretreated with the opioid receptor antagonist, naloxone, or its vehicle, saline, during normotension, hypotension, and after the administration of indomethacin, a cyclooxygenase inhibitor, during hypotension. Hemorrhage (30 ml/kg) decreased systemic arterial pressure from 68 +/- 12 to 40 +/- 10 mm Hg but did not decrease blood flow to any brain region. Indomethacin treatment (5 mg/kg) of hypotensive piglets decreased blood flow to all brain regions within 20 min; this decrease in CBF resulted from increases in cerebral vascular resistance of 65 and 281% at 20 and 40 min after treatment, respectively. In hypotensive piglets, cerebral oxygen consumption was reduced from 2.62 +/- 0.71 to 0.53 +/- 0.27 ml 100 g-1 min-1 and to 0.11 +/- 0.04 ml 100 g-1 min-1 at 20 and 40 min following indomethacin, respectively. Treatment with naloxone (1 mg/kg) had no effect on rCBF, calculated cerebral vascular resistance, or cerebral oxygen consumption of normotensive or hypotensive piglets. However, decreases in CBF and oxygen consumption and increases in cerebral vascular resistance upon treatment of hypotensive piglets with indomethacin were attenuated in animals pretreated with naloxone. These data indicate that the removal of prostanoid modulation of an opioid-mediated constrictor influence on the cerebral circulation is a potential mechanism for the increase in cerebral vascular resistance that follows indomethacin treatment of hypotensive piglets.     

Cerebral blood flow and neuronal damage during progressive cerebral ischemia in gerbils

A combined autoradiographic and immunohistochemical method was used to correlate the extent of focal cerebral ischemia and morphologic ischemic damage following unilateral carotid occlusion in 16 gerbils for 5-30 minutes. Immunohistochemical lesions detectable by the reaction for microtubule-associated proteins 1 and 2 were visible in the subiculum-CA1 and CA2 regions of the hippocampus and layer III/IV of the cerebral cortex after 5 minutes of ischemia (n = 4). Local blood flow was promptly reduced but still heterogeneous after 10 minutes of ischemia (n = 4); local blood flow in immunohistochemical lesions was less than 5 ml/100 g/min except in highly vulnerable regions, where flow values of 5-15 ml/100 g/min were observed. After 15 minutes of ischemia (n = 4) local blood flow in less vulnerable regions including the thalamus and caudoputamen also declined to less than 5 ml/100 g/min, and immunohistochemical lesions became visible in those regions after 30 minutes of ischemia (n = 4). On the other hand, many brain regions tolerated local blood flow of less than 5 ml/100 g/min without ischemic damage. The present study demonstrates that selective tissue vulnerability during progressive cerebral ischemia depends on the degree of hypoperfusion and on factors inherent to neurons in various brain regions.     

Nicardipine increases cerebral blood flow but does not improve neurologic recovery in a canine model of complete cerebral ischemia

The effects of the calcium entry blocker nicardipine on CBF, CMRO2, and neurologic outcome following 10 min of complete cerebral ischemia were examined in dogs. In CBF and CMRO2 studies, the CBF in the untreated group (seven dogs) and the nicardipine group (seven dogs; 20 micrograms kg-1 at 30 min postischemia and a subsequent infusion of 2 micrograms kg-1 min-1 for 90 min) initially increased to 300-400% and then returned to preischemic values at 30 min postischemia. Thereafter the CBF in the untreated group significantly decreased to 50% of preischemic values for the following 90-min period (hypoperfusion), while the CBF in the nicardipine group did not differ from preischemic values. The CMRO2 in both groups decreased to approximately 50-80% of preischemic values after 15 min postischemia and did not differ between the groups throughout the study. In neurologic outcome studies, 18 dogs were divided into three groups (of six dogs each): untreated; saline infusion only, posttreated; nicardipine as in CBF and CMRO2 studies, pretreated; nicardipine 20 micrograms kg-1 at 2 min preischemia and a subsequent infusion of 2 micrograms kg-1 min-1 from immediately postischemia to 120 min postischemia. Nicardipine treatment initiated either before or after ischemia failed to improve neurologic outcome at 48 h postischemia. Thus, the increase of postischemic global CBF by nicardipine is not accompanied by neurologic recovery in a canine model of complete cerebral ischemia.     

Fetal cerebral blood flow and metabolism during oligemia and early postoligemic reperfusion

The early time period following ischemia may be of pathogenetic importance in hypoxic-ischemic brain injury. Global cerebral oligemia was induced in ten late gestation fetal sheep by inflation of a balloon occluder around the brachiocephalic artery. Cerebral blood flow, oxygen, glucose, and lactate net flux, and oxygen delivery were measured by the Fick principle following 1 h of oligemia and at 5, 30, and 60 min of postoligemic reperfusion. During oligemia, cerebral blood flow decreased by 74 +/- 10% (mean +/- SD) and oxygen consumption decreased by 34 +/- 24%. The glucose:oxygen quotient was elevated throughout the oligemic period. In the early (5 min) reperfusion period, blood flow and oxygen delivery were not different from control but oxygen consumption was persistently depressed by 27 +/- 32%; fractional extraction of oxygen was 0.38 +/- 0.10 during control and 0.24 +/- 0.09 during early reperfusion. The venous oxygen tension increased modestly from 15.2 +/- 2.4 to 18.0 +/- 1.7 mm Hg; the postoligemic venous pO2 was limited by the lack of reactive hyperemia combined with the low arterial pO2 of the intrauterine environment. Postoligemic carbohydrate fluxes could not be differentiated from control possibly due to blood-brain barrier limitations. These factors may be related to the relative resistance of the fetal brain to hypoxic-ischemic injury.     

Anesthetic modulation of cerebral hemodynamic and evoked responses to transient middle cerebral artery occlusion in cats

We measured cerebral blood flow and somatosensory evoked potentials during transient focal cerebral ischemia in cats to compare the effects of four commonly used anesthetic regimens: ketamine/fentanyl/N2O (fentanyl), pentobarbital, ketamine/alpha-chloralose (alpha-chloralose), and ketamine/halothane/N2O (halothane). Six cats in each group were subjected to 60 minutes of left middle cerebral artery occlusion followed by 120 minutes of reperfusion. Although the amplitude of the initial somatosensory evoked potential wave complex was highest in the alpha-chloralose group (58.6 +/- 16.5 microV) and smallest in the halothane group (27.5 +/- 5.7 microV), amplitude fell by 75% in all groups upon occlusion. Baseline cerebral blood flow varied substantially between groups (e.g., in the right intersylvian gyrus: fentanyl, 96 +/- 12; pentobarbital, 30 +/- 5; alpha-chloralose, 24 +/- 3; and halothane, 76 +/- 11 ml/min/100 g). Occlusion decreased cerebral blood flow to subcortical (e.g., left caudate) structures in all groups (fentanyl, 29 +/- 11%; pentobabital, 45 +/- 12%; alpha-chloralose, 27 +/- 13%; and halothane, 18 +/- 5% of baseline). Postischemic hyperemia occurred in the cortical regions of cats anesthetized with pentobarbital or alpha-chloralose that had reduced cerebral blood flows during occlusion but not in cats anesthetized with fentanyl (cerebral blood flow during occlusion not different from that of cats anesthetized with pentobarbital or alpha-chloralose) or halothane. After 120 minutes of reperfusion, cerebral blood flow had returned to baseline values in all groups. Recovery of cerebral blood flow and somatosensory evoked potential amplitude at that time did not differ among groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cerebral vasoconstriction in response to hypocapnia is maintained after ischemia/reperfusion injury in newborn pigs.

BACKGROUND AND PURPOSE: Hypocapnic cerebral vasoconstriction is used therapeutically to reduce elevated intracranial pressure caused by cerebral edema. Because cerebral ischemia/reperfusion injury causes a selective loss of prostanoid-dependent responses, including vasodilation to hypercapnia, we designed these experiments to examine the effect of ischemia/reperfusion on hypocapnic cerebral vasoconstriction. METHODS: Microvascular responses were studied in 10 newborn pigs (closed cranial window) in response to hyperventilation-induced hypocapnia (PaCO2, 22 +/- 2 mm Hg) both before and 45 minutes after 20 minutes of global cerebral ischemia. Responses to hypercapnia (PaCO2, 63 +/- 3 mm Hg), topical isoproterenol (10(-7) M), and norepinephrine (10(-4) M) were also studied before and after ischemia in the same animals for comparison. RESULTS: Before ischemia/reperfusion, pial arterioles vasoconstricted to hypocapnia (-17 +/- 2%) and norepinephrine (-35 +/- 4%) and vasodilated to CO2 (37 +/- 7%) and isoproterenol (25 +/- 2%). After ischemia/reperfusion, the constriction of pial arterioles to hypocapnia (-19 +/- 2%) was similar to that before ischemia. This is in contrast to the loss of dilation to hypercapnia. Dilation to isoproterenol and constriction to norepinephrine were not affected by ischemia. CONCLUSIONS: Hypocapnic cerebral vasoconstriction is maintained after ischemia/reperfusion. Since prostanoid-dependent responses, such as hypercapnic dilation, are lost following cerebral ischemia, these data suggest that hypocapnic constriction is not dependent on an intact prostanoid system and that cerebral vascular responses to CO2 involve multiple mechanisms, depending on whether CO2 is increasing or decreasing from baseline.     

Blood flow and metabolism during and after repeated partial brain ischemia in neonatal piglets.

BACKGROUND AND PURPOSE: Our investigation sought to determine whether neonatal brain ischemic vascular and metabolic effects were altered by repeated episodes of ischemia. METHODS: We studied twelve piglets using in vivo magnetic resonance spectroscopy to obtain multiple, simultaneous measurements of cerebral blood flow and phosphorylated metabolites from the same tissue volume. The relationship between cerebral blood flow and energy metabolism was examined over a range of reduced cerebral blood flow (90-10% of control). Three episodes of partial ischemia were studied, each lasting 10 minutes and separated by 45 minutes. RESULTS: During each interval of ischemia, plots of the percent reduction in cerebral blood flow versus the percent change in phosphorylated metabolites (phosphocreatine, inorganic phosphorus) or unit change in intracellular pH did not differ in slope and intercept. The relationship between beta-ATP and cerebral blood flow during repeated ischemia revealed similar slopes, but a lower intercept during the third interval of ischemia (p = 0.029). After ischemia, cerebral blood flow was reduced as a function of the severity of the preceding ischemia. After each interval of ischemia, phosphocreatine and intracellular pH were unchanged from preischemic values. Inorganic phosphorus remained elevated after ischemia (117 +/- 16 and 118 +/- 11% of control, p less than 0.005, following the first and second intervals of ischemia), and beta-ATP was restored to progressively lower values (92 +/- 10 and 83 +/- 11% of control, p less than 0.025). Calculated free ADP decreased after ischemia and correlated with the postischemic level of beta-ATP (r = 0.63, p = 0.001). CONCLUSIONS: These results demonstrate that the relationship between cerebral blood flow and metabolism was reasonably preserved during repeated partial ischemia. However, following ischemia, alterations occurred in both cerebral blood flow and metabolism. These alterations may reflect a relative inhibition of ATP production by metabolic regulators such as ADP on either glycolysis or oxidative phosphorylation or both.     

MK-801 attenuates capillary bed compression and hypoperfusion following incomplete focal cerebral ischemia

The effects of the N-methyl-D-aspartate (NMDA) antagonist MK-801 on capillary beds and CBF following 1 h of transient incomplete focal cerebral ischemia were studied by examining 133Xe CBF, capillary diameter, and area of perfused vasculature. Capillary diameter increased from a control of 5.24 +/- 0.37 to 8.62 +/- 0.57 microns (p less than 0.001) and area of perfused vasculature from 20,943 +/- 1,151 to 30,442 +/- 1,691 microns2/x 10 magnification field (p less than 0.001) with MK-801 1.0 mg/kg administered 30 min prior to ischemia. After flow restoration in control animals, there was a relative hypoperfusion with eventual normalization of CBF over 60 min. Alternatively, in MK-801 1.0 mg/kg animals, there was rapid normalization of CBF upon flow restoration without the postischemic hypoperfusion observed in controls. On histological analysis, there was consistently less neuronal edema in MK-801-treated animals. These results support the hypothesis that hypoperfusion following incomplete focal cerebral ischemia may be due in part to NMDA-mediated cellular edema with subsequent extravascular capillary bed compression.     

Adenosine release and changes in pial arteriolar diameter during transient cerebral ischemia and reperfusion

We utilized the closed cranial window technique in the anesthetized rat to determine changes in CSF concentrations of adenosine, inosine, and hypoxanthine and pial arteriolar diameter during transient (20 min) forebrain ischemia and reperfusion. After mock CSF under the cranial window was allowed to equilibrate with cerebral interstitial fluid, endogenous adenosine concentration was found to be 0.16 +/- 0.05 microM, while inosine and hypoxanthine were 0.35 +/- 0.17 and 1.23 +/- 0.47 microM, respectively. The concentration of adenosine in CSF increased 4.2-fold during ischemia and 13.8-fold during the first 5 min of reperfusion. Inosine and hypoxanthine concentrations were also significantly increased during ischemia and reperfusion. After 1 h of reperfusion, CSF adenosine and inosine levels had decreased from peak value but remained significantly above preischemic values. In contrast, hypoxanthine remained at peak concentrations even after 60 min of reperfusion. Preischemic arteriolar diameter was 42.6 +/- 11.3 microns and was not significantly changed after 20 min of ischemia. However, during the first 5 min of reperfusion, arteriolar diameter increased significantly (p less than 0.05), coincident with peak adenosine concentrations. By 60 min of reperfusion, arteriolar diameter had returned to baseline. These results indicate that during the postischemic period, adenine nucleosides and hypoxanthine in CSF are elevated and could affect reperfusion.     

Cerebral and cerebellar blood flow autoregulations in acutely induced cerebral ischemia in spontaneously hypertensive rats--transtentorial remote effect

Autoregulation of cerebral (CBF) and cerebellar blood flow (CeBF) was studied before, during and after acutely induced cerebral ischemia in spontaneously hypertensive rats. Cerebral ischemia of the supratentorial portion was induced for one hour by bilateral carotid artery ligation (BCL). The animals were artificially ventilated and the blood flow was measured with a hydrogen clearance technique. To test the autoregulation, the blood pressure was stepwise lowered by bleeding and maintained at a new level, i.e. 15% or 30% lower than the baseline values before, during and after cerebral ischemia. At the preischemic state, CBF and CeBF were 52.1 +/- 6.2 and 58.9 +/- 4.6 ml/100 g/min (mean +/- SEM), of which autoregulations were normally preserved. Following BCL, CBF was markedly decreased to about 10% of control value while CeBF was minimally reduced to 46.9 +/- 8.6 ml/100 g/min (80%). At the ischemic state, CBF became almost zero flow during hypotension. CeBF was also reduced to 74% and further to 58% of the resting value by 15% and 30% decrease in the blood pressure, respectively, indicating impaired CeBF autoregulation. At the 30 min post-ischemic state, CBF was recovered to 48.0 +/- 4.9 and CeBF to 53.9 +/- 5.4 ml/100 g/min. Autoregulation of CBF was still abolished, whereas CeBF was kept constant by 15% fall of blood pressure and slightly reduced to 84% by 30% hypotension, indicating almost recovery of CeBF autoregulation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Postischemic alterations of complex spike cell discharges and evoked potentials in rat hippocampal CA1 region

Postischemic alterations of spontaneous discharges of complex spike cells (CS cells) and evoked potential in the rat hippocampal CA1 region were studied. Following 5 min of ischemia, CS cell discharge reappeared approximately 5 min after reperfusion and the frequency remained low, reaching a final value of 66.1 +/- 16.0% (n = 11) of preischemic frequency 2 h later. However, only one of 7 CS cells subjected to 20 min of ischemia exhibited discharges 2 h later. In the group with 5 min of ischemia, we obtained CS cell discharges from all rats at both 1 and 2 days after ischemia, with cluster frequencies indistinguishable from preischemic levels. In the group with 20 min of ischemia, discharges were noted in 7 neurons of 11 rats after 1 day, and in only 2 neurons of 8 rats after 2 days: their mean frequencies were lower than preischemic levels. In experiments of evoked potentials, the mean percentages of amplitudes of the post-synaptic potential (psp) 2 h after 3, 5 and 20 min of ischemia were 98.0 +/- 10.7 (n = 8), 70.7 +/- 8.22 (n = 9) and 45.1 +/- 6.34% (n = 7) of preischemic amplitudes, respectively. These results suggest that the functional deterioration of spike generation, as well as synaptic transmission, starts during transient ischemia and/or at the early stage of reperfusion.