J. Hamar

Acute improvement in histological outcome by MK-801 following focal cerebral ischemia and reperfusion in the cat independent of blood flow changes.

The present study reports on the acute effects of MK-801 on the histopathological outcome and blood flow changes during focal cerebral ischemia and reperfusion. In addition, acute changes in the EEG and blood pressure are also reported. In 16 halothane-anesthetized cats, the left middle cerebral artery (MCA) was occluded for 2 h followed by 4 h of reperfusion. Thirty minutes after the onset of ischemia, eight animals were treated with 1 mg/kg of MK-801, while eight animals received saline. Blood flow from the peripheral MCA territory was measured with H2 clearance. There was a comparable reduction in blood flow (down to 20% of control) in the ischemic gyri of the two groups followed by a partial recovery after recirculation. There was a similar decrease in the EEG amplitude over the ischemic central MCA territory in the treated and the untreated group. Treatment with MK-801 induced a burst suppression in the EEG and a transient drop (11.4 ± 6.5 mm Hg) in the mean arterial pressure. The volume of early ischemic damage decreased by one-third in the MK-801-treated group compared to the untreated one, both in the total hemisphere (from 29 ± 10 to 20 ± 5%) and in the hemispheric cortex (range 36 ± 8 to 24 ± 13%). A major fraction of this improvement was localized to the middle and posterior parietal (mainly perifocal) regions of the MCA territory. These results show that in our model, MK-801 improves histopathological outcome despite the lack of apparent effect on the cortical blood flow, and an adverse effect on the systemic blood pressure. This is the first report that describes data on a reproducible model of reperfusion after temporary occlusion of the MCA in a cat, extending the findings of the Glasgow group, who observed similar neuroprotection in models of permanent MCA occlusion.

Effect of phenoxybenzamine on cerebral blood flow and metabolism in the baboon during hemorrhagic shock.

Experiments were performed on 2 groups of baboons anesthetized with Sernylan. One group served as control and the other was premedicated with 5 mg/kg phenoxybenzamine (PBZ). A 2-step hypovolemic shock model was used followed by retransfusion of the shed blood. Cerebral blood flow was measured by the 188Xe clearance method. Arterial and cerebral venous samples were taken and analyzed for blood gases as well as glucose and lactate content. The cerebral metabolic rates of oxygen, glucose, and lactate were calculated. In addition, the effect of CO2 inhalation was studied before shock was induced. PBZ produced no effect on either CBF or the flow response to CO2 prior to bleeding. PBZ pretreatment prevented the fall in cerebral blood flow and CMRO2 produced by systemic hypotension due to bleeding. Lactic acid showed no evidence of change either in production or uptake by the brain during the experimental procedure. The cerebral metabolic pathway of glucose, however, seemed to be affected by PBZ both before and during shock.

Prolonged effects of MK-801 in the cat during focal cerebral ischemia and recovery: Survival, EEG activity and histopathology

Previously we reported an improvement in histological outcome in cats treated with MK-801 shortly after the induction of temporary middle cerebral artery occlusion, and examined after 2 h of ischemia followed by 4 h of reperfusion. This study investigates the prolonged effects of the same drug treatment. Focal cerebral ischemia was produced in 34 cats by temporary occlusion of the left middle cerebral artery for 2 h. Stroke severity was determined using the ratio of the EEG amplitude from the ipsilateral to that of the contralateral hemisphere. Thirty minutes after the onset of ischemia, cats were treated i.v. with either 1 mg/kg MK-801 or saline. Electrocortical activity of the animals who survived were followed for 6 days postocclusion at which point they were sacrificed for histopathological analysis. Twelve of the animals died during recovery, of which 4 were MK-801 treated, and 8 were saline controls. The EEG ratios in the non-surviving animals were more depressed than in the animals that survived, whereas the depression in the EEG amplitude in both the treated and the control surviving animals was equal. Among the survivors no reduction in infarct size with MK-801 treatment was observed. Thus treatment with MK-801 in the middle cerebral artery occlusion model in the cat leads to a significant increase in the rate of survival (P < 0.05), but no prolonged improvement in late histopathology, in contrast with acute histological findings using this model. MK-801 treatment may be shifting the stroke model towards the survival of animals with larger infarcts. Histological recovery during prolonged reperfusion may eliminate the early neuroprotective effects seen with MK-801 treatment.

Effect of ischemia and reperfusion on λ of the lumped constant of the [14C]deoxyglucose technique

We measured the parameter λ, which is the ratio of the distribution spaces of 2-deoxy-d-glucose (DG) and glucose in the brain, in a model of focal cerebral ischemia in the cat. λ is the parameter in the lumped constant of the [14C]DG technique most susceptible to changes in ischemia. Cats were subjected to occlusion of the middle cerebral artery for a period of 2 h. During the last 60 min of occlusion, [14C]DG was infused in a programmed fashion so as to obtain a stable arterial blood [14C]DG concentration. The brain was funnel-frozen to preserve tissue metabolites and the frozen brain was sampled regionally (4 to 7-mg samples) for local concentrations of glucose, ATP, phosphocreatine (PCr), and lactate. In a separate series of cats, the infusion of [14C]DG was started after 2 h of occlusion and 3 h of recirculation. In both series, λ declined slightly for increased levels of tissue glucose and increased appreciably as tissue glucose decreased. A similar relationship was observed between λ and ATP and PCr, although the correlation was not as clear. Since λ, and hence the lumped constant, increases in ischemia as well as in postischemic tissue, it is important to measure tissue glucose concentration if quantitative values of local cerebral glucose metabolism are desired in this condition.

Acute effect of scalding injury on blood flow in muscle and subcutaneous tissue in the paw of the anaesthetized dog.

Blood flow in muscle and subcutaneous tissue was studied before and after a scalding injury of the dog paw. The hydrogen clearance technique was used in anaesthetized dogs. As scalding of the paw resulted in an increased blood pressure and muscular movements, animals were given a muscle relaxant and ventilated artificially. Before scalding injury the blood flow was 29.8 and 19.7 ml per min per 100 g in muscular and subcutaneous tissue, respectively. After immersion of the paw for 10 sec in water of 100 degrees C the blood flow transiently increased and later decreased. No major changes were found in the contralateral paw. The decrease was most pronounced (50%) in subcutaneous tissue. In the acute situation the impeded circulation in the burn oedema may protect the organism from potentially harmful substances formed in the injured tissue.

Immunoglobulin enriched colostral milk reduces gut-derived endotoxemia in a rat hemorrhage model

AbstractBackground: Several studies indicate that a breakdown of mucosal barrier is often a major cause of endotoxemia and septic complications after hemorrhagic/traumatic insults. The aim of this study was to investigate, whether enteral administration of an immunoglobulin enriched colostral milk preparation (ICM) is able to affect endotoxemia as well as survival in a hemorrhagic shock model in rats. Materials and Methods: Rats were orally pre-treated with either 5 ml of 0.9% saline (CON) or ICM (3 g/kg body weight) once a day for 5 days (ICM). Laboratory control animals were not treated (LAB-CON). On day 6, intestinal endotoxin contents were assessed. In a separate set of animals treated similarly, hemorrhage was induced on the 6th day by bleeding the animals to a mean arterial pressure of 30–35 mm Hg for 3 h followed by resuscitation over 1 h. Results: Pre-treatment with ICM significantly reduced intraluminal endotoxin contents in the duodenum when compared with CON (0.43 ± 0.27 vs.. 1.03 ± 0.67 EU/mg contents; p = 0.03). Hemorrhage for 3 h resulted in a significant rise in plasma endotoxin concentrations in CON animals compared with LAB-CON (0.30 ± 0.20 vs. 0.06 ± 0.04 EU/ml). ICM pre-treatment attenuated plasma endotoxin levels after hemorrhage(0.11 ± 0.12 EU/ml). The 6-day-survival rate after hemorrhage tended to be higher in the ICM pre-treated animals when compared with CON (66.7% vs. 40%). Conclusion: A passive immunization of the gut together with the reduction of the intraluminal endotoxin contents by enteral administration of immunoglobulin-enriched preparations might prove to be a prophylactic approach towards preventing gut-derived endotoxemia after hemorrhagic/traumatic insults.