Effects of profound anemia on brain tissue oxygen tension, carbon dioxide tension, and pH in rabbits.

This study sought to determine the maximum tolerable limit of anemia for the brain during halothane anesthesia. Using a multiparameter sensor, we continuously monitored brain tissue oxygen tension (PO2), carbon dioxide tension (PCO2), and pH during profound hemodilution and subsequent transfusion. Twelve New Zealand White rabbits were anesthetized, intubated, and mechanically ventilated at a fraction of inspired oxygen (FiO2) of 21% to produce an arterial carbon dioxide tension (PaCO2) of 35 to 40 mm Hg. The femoral artery was cannulated to continuously monitor arterial blood pressure and to intermittently measure arterial blood gases. The electroencephalogram (EEG) was recorded throughout the course of the study. A fiberoptic sensor was inserted into the brain for the continuous measurement of brain PO2, PCO2, pH, and temperature. Cerebral blood flow (CBF) was measured by the hydrogen clearance method. Severe anemia was induced by repeatedly withdrawing 50-mL aliquots of blood and infusing an equal volume of 6% hetastarch. This procedure was performed four times for each rabbit. After the forth blood draw and fluid infusion, a total of 60 mL of packed red blood cells were transfused. Upon completion of the hemodilution, the hemoglobin concentration was 2.4 +/- 0.3 g/dL (mean +/- SEM). Brain tissue PO2 decreased from 27 +/- 3 mm Hg to a minimum of 12 +/- 2 mm Hg. Brain tissue pH also decreased from 7.22 +/- 0.03 to 7.12 +/- 0.05 and returned to the baseline value with transfusion. Brain PCO2 did not change significantly during the experiment. Cerebral blood flow increased from 37 +/- 3 to 66 +/- 15 mL x 100 g(-1) x min(-1) during hemodilution and returned to baseline after infusion of red blood cells. There was some loss of EEG amplitude and the calculated cerebral metabolic rate (CMRO2) decreased from 4.3 +/- 0.6 to 1.9 +/- 0.3 mL x 100 g(-1) x min(-1) at the most profound level of anemia. This is the first report of which the authors are aware of continuous monitoring of brain tissue pH, PCO2, and PO2 during profound hemodilution and transfusion. Hemodilution results in a decrease in brain tissue PO2. Increases in CBF and oxygen extraction can only partially compensate for the decreased oxygen carrying capacity of the blood. Decreases in brain tissue PO2, pH, CMRO2, and a loss of EEG amplitude suggest that the maximum tolerable limit of hemodilution was achieved in this study.

Effects of adenosine agonists and an antagonist on excitatory transmitter release from the ischemic rabbit hippocampus.

The purpose of this study was to determine the effects of adenosine agonists and an antagonist on ischemia-induced extracellular glutamate concentrations in an animal model of transient cerebral ischemia using in vivo cerebral microdialysis. Fifty New Zealand white rabbits were randomly assigned to one of five groups (normothermia, hypothermia, cyclopentyladenosine (CPA), theophylline, or propentofylline). Microdialysis probes were stereotactically placed in the dorsal hippocampus. Twenty minutes before the onset of ischemia, either 1 mg/kg CPA, 5 mg/kg propentofylline, or 20 mg/kg theophylline were administered intravenously. Esophageal temperature was maintained at 38 degrees C, except in the hypothermic animals, which were cooled to 30 degrees C throughout the entire experiment. Two 12-min periods of cerebral ischemia, separated by a 105-min interval of reperfusion, were produced by inflating a neck tourniquet. High-performance liquid chromatography was used to determine the glutamate concentration in the microdialysate. There were no significant increases in glutamate concentrations during the first ischemic period in any of the five groups. During the second ischemic episode, glutamate concentrations in the normothermic group peaked at levels approximately three times higher than the initial values. A similar pattern of changes in glutamate concentrations was observed in the CPA, propentofylline, and theophylline groups. In the hypothermic group, the concentrations of glutamate remained at baseline levels during the entire experiment. Contrary to expectations, neither the adenosine agonists (CPA, propentofylline) nor the antagonist (theophylline) had any effect on extracellular glutamate concentrations in the peri-ischemic period. Although adenosine and its analogs may be cerebroprotective agents, their mechanism of action is not fully understood. The data derived from this study indicates that the acute administration of such agents had no effect on ischemia-induced glutamate release within the hippocampus under these experimental conditions. Based on these results, further work is needed to compare in vivo versus in vitro experimental results in acute and long-term treatment studies with adenosine receptor agonists and antagonists.

Monitoring brain PO2, PCO2, and pH during graded levels of hypoxemia in rabbits.

Brain ischemia and hypoxia are of concern when they occur following traumatic brain injury because they frequently result in potentially preventable secondary brain damage. In this study, we examined the ability of an implantable catheter (Paratrend 7; Diametrics Medical, St. Paul, MN) to continuously measure brain tissue pH, PCO2, and PO2 during graded levels of hypoxia. Values obtained from this catheter were compared with simultaneous measurements of arterial and sagittal sinus blood. As expected, there was a good correlation between the changes in pH, PCO2, and PO2 in brain tissue and sagittal sinus blood. Brain tissue PO2 was numerically lower than sagittal sinus blood at all inspired levels of oxygen. These data suggest that the Paratrend 7 may be useful in monitoring brain tissue oxygen tension in patients at risk for regional cerebral ischemia and hypoxia.

In vivo comparison of the effects of inhibition of MAO-A versus MAO-B on striatal L-DOPA and dopamine metabolism.

Utilizing the cerebral microdialysis technique, we have compared in vivo the effects of selective MAO-A, MAO-B, and nonselective MAO inhibitors on striatal extracellular levels of dopamine (DA) and DA metabolites (DOPAC and HVA). The measurements were made in rats both under basal conditions and following L-DOPA administration. Extracellular levels of dopamine were enhanced and DA metabolite levels strongly inhibited both under basal conditions and following L-DOPA administration by pretreatment with the nonselective MAO inhibitor pargyline and the MAO-A selective inhibitors clorgyline and Ro 41-1049. The MAO-B inhibitor deprenyl had no effect on basal DA, HVA, or DOPAC levels. Nevertheless, deprenyl significantly increased DA and decreased DOPAC levels following exogenous L-DOPA administration, a finding compatible with a significant glial metabolism of DA formed from exogenous L-DOPA. We conclude that DA metabolism under basal conditions is primarily mediated by MAO-A. In contrast, both MAO-A and MAO-B mediate DA formation when L-DOPA is administered exogenously. The efficacy of newer, reversible agents which lack the "cheese effect" such as Ro 41-1049 are comparable to the irreversible MAO-A inhibitor clorgyline. The possible relevance of these findings for the treatment of Parkinson's disease is discussed.

Effect of etomidate on in vivo ischemia-induced dopamine release in the corpus striatum of the rat: a study using cerebral microdialysis.

Dopamine (DA) is released in large quantities into the corpus striatum during cerebral ischemia and may exacerbate tissue damage. Using cerebral microdialysis, we studied the effect of etomidate on in vivo ischemia-induced DA release in rat corpus striatum. Reversible cerebral ischemia was induced by using carotid ligatures and hypovolemic hypotension, and monitored with laser Doppler flowmetry. After baseline measurements, 20 normothermic, anesthetized rats were subjected to three separate periods of cerebral ischemia, interrupted by 45- to 75-min periods of reperfusion. The rats were randomized into two groups. All rats received 400 mg/kg of intraperitoneal chloral hydrate for induction of anesthesia. In Group I (n = 10) anesthesia was maintained using additional intraperitoneal chloral hydrate 100 mg/kg every 2 h. Group II received etomidate 0.6 mg/kg 10 min before the first episode of cerebral ischemia, followed by an infusion of 60 micrograms.kg-1 x min-1. Before each subsequent period of induced ischemia, an additional dose of etomidate (0.6 mg/kg) was administered. DA levels were approximately 350 times above baseline in Group I during the three ischemic episodes (IS1, IS2, and IS3). In Group II, ischemia-induced DA release was significantly attenuated (by 79%) during IS1, IS2, and IS3 compared to Group I (P < 0.01). DA levels did not significantly change in magnitude during the three ischemic episodes in either group.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of isoflurane and halothane on in vivo ischemia-induced dopamine release in the corpus striatum of the rat. A study using cerebral microdialysis.

BACKGROUND: Dopamine is released in large quantities into the corpus striatum during cerebral ischemia and may exacerbate tissue damage. METHODS: Using cerebral microdialysis, the effect of isoflurane on in vivo ischemia-induced dopamine release was studied in rat corpus striatum. Reversible cerebral ischemia was induced using carotid ligatures and induced hypovolemia and was monitored with laser-Doppler flowmetry. Following baseline measurements, 28 normothermic, anesthetized rats were subjected to cerebral ischemia followed by reperfusion. The rats were divided into four groups. Group 1 (n = 10) was anesthetized using chloral hydrate. Groups 2 and 3 received 1.5% end-tidal isoflurane. In group 2 (n = 6), hypotension was left untreated during the reperfusion period, and in group 3 (n = 6), mean arterial pressure was maintained using phenylephrine. Group 4 (n = 6) received 1-1.2% end-tidal halothane. RESULTS: Compared with pre-ischemic levels, large quantities of dopamine (350 x baseline levels) were released in group 1 animals during cerebral ischemia. Compared with group 1, ischemia-induced dopamine release was significantly reduced in group 2 (by 58%) and in group 3 (by 56%), but not in group 4. Group 2 animals were uniformly hypotensive during reperfusion and continued to release substantial amounts of dopamine (8 x baseline levels). In groups 1, 3, and 4, dopamine release decreased to near baseline levels during reperfusion. In group 3, dopamine metabolite production was significantly increased during ischemia, suggesting that enzymatic function and neuronal reuptake of dopamine was preserved. CONCLUSIONS: Isoflurane, compared with chloral hydrate and halothane, inhibits the release of the neurotransmitter dopamine during cerebral ischemia.

Low and high dose bromocriptine have different effects on striatal dopamine release: an in vivo study.

We wished to determine if low and high doses of bromocriptine produce distinct patterns of dopamine release and metabolism. Accordingly, we administered bromocriptine (0, 2.5, 5, and 10 mg/kg, IP) to rats and monitored extracellular concentrations of dopamine and dopamine metabolites in the corpus striatum with the technique of cerebral microdialysis. Extracellular dopamine levels increased following administration of 2.5 and 5 mg/kg bromocriptine. In contrast, dopamine levels decreased following 10 mg/kg bromocriptine. Dopamine metabolite levels decreased 45 minutes following all doses of bromocriptine. Bromocriptine administration had no effect on the levels of 5HIAA, the major serotonin metabolite. These findings with high dose bromocriptine fit the predicted profile of a dopamine D2 receptor agonist. The delayed decrease in dopamine metabolites at all bromocriptine doses is consistent with the known dopamine synthesis inhibiting action of bromocriptine. In contrast, the increased dopamine release observed following low and medium doses of bromocriptine is not readily explainable by current theories of bromocriptine action which predict decreased dopamine release and therefore decreased striatal extracellular dopamine levels with both high and low-doses of bromocriptine. Our findings indicate that bromocriptine has a complex pharmacological action that extends beyond simple agonism at dopamine D2 receptors.

Effect of repeated electroconvulsive shock on striatal L-dopa and dopamine metabolism: an in vivo study.

A course of treatments with electroconvulsive shock (ECS) has been reported to reestablish L-dopa efficacy in patients with advanced Parkinson's disease. We wished to determine if ECS could modify L-dopa and dopamine metabolism in an animal model of Parkinson's disease. Therefore, we administered repeated ECS (8 ECS at 48 hr intervals) to rats with partial destruction of the nigrostriatal dopamine pathway and used the cerebral microdialysis technique to monitor extracellular concentrations of dopamine and dopamine metabolites (DOPAC and HVA) in the corpus striatum. The control group of animals received sham-ECS treatments. Basal dopamine levels were decreased by 20% in animals receiving repeated-ECS versus sham-ECS. DOPAC levels, on the other hand, were increased by 84% in animals receiving repeated-ECS. HVA levels were equal in the two groups. Following L-dopa administration, dopamine and HVA levels increased equally in control animals and animals which had previously received repeated-ECS. DOPAC concentrations were uniformly greater in rats receiving repeated-ECS. When ECS was administered acutely, dopamine levels increased 390% and returned to baseline values in 75 minutes, DOPAC and HVA were unchanged, and 5HIAA levels decreased 30%. We conclude that 1) acute ECS administration produces a transient, marked release of striatal dopamine and 2) repeated ECS can reset the level of basal dopamine release, a finding compatible with ECS-induced dopamine receptor supersensitivity, and 3) neither single nor repeated administration of ECS has a major effect on the formation of dopamine or HVA from exogenously administered L-dopa although there was a strong tendency for increased DOPAC formation. ECS may exert its putative antiparkinsonian effect by enhancing dopamine receptor sensitivity.

Catechol-O-methyltransferase inhibition increases striatal L-dopa and dopamine: an in vivo study in rats.

We administered Ro 40-7592, an inhibitor of the enzyme catechol-O-methyltransferase (COMT) that crosses the blood-brain barrier, to rats and monitored extracellular catecholamine levels in the corpus striatum before and after the intraperitoneal administration of a bolus of l-dopa. Acute administration of Ro 40-7592 increased basal levels of l-dopa and dihydroxyphenylacetic acid (DOPAC) and decreased basal homovanillic acid (HVA) levels, but did not affect basal dopamine levels. In rats treated with Ro 40-7592, l-dopa administration produced a greater increase in striatal levels of l-dopa, dopamine, and DOPAC than it did in controls, while HVA formation was attenuated. We conclude that inhibition of COMT activity promotes central dopamine synthesis and release following administration of pharmacologic doses of l-dopa.

Changes in body temperature markedly affect striatal dopamine release and metabolism: an in vivo study.

Dopamine release and metabolism in the corpus striatum increased markedly when the core body temperature of anesthetized rats was increased from 35 degrees to 41 degrees C while temperatures below 34 degrees were associated with a marked attenuation of dopamine release. These observations may have clinical relevance in cases where alterations in body temperature are associated with extrapyramidal dysfunction.

Effect of dietary protein on striatal dopamine formation following L-dopa administration: an in vivo study.

We varied the diet of rats and monitored extracellular levels of dopamine in the striatum. Following L-dopa administration, the increase in striatal dopamine levels was attenuated by 78% in rats that had consumed a high protein diet as opposed to a low protein diet. Similarly, the increase in striatal dopamine levels was attenuated by 61% in rats that had just eaten a protein-containing meal as compared to fasting animals. These findings demonstrate that dietary protein strongly affects brain dopamine formation from exogenous L-dopa.

Effect of long-term L-dopa administration on striatal extracellular dopamine release.

When L-dopa was administered acutely to rats, the increase in the extracellular level of dopamine in the corpus striatum was attenuated by 43% in animals that had received L-dopa daily for 60 days as compared with animals receiving placebo. These findings indicate that chronic treatment with L-dopa impairs striatal dopamine formation or release.

Effect of yohimbine on brain monoamines: an in vivo study.

Following the administration of yohimbine, an alpha 2-adrenoreceptor antagonist, the levels of norepinephrine (NE), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5HIAA) increased significantly in the lateral ventricular fluid of rats. These increases were abolished when animals were pretreated with alpha-methyl-para-tyrosine or reserpine. Dopamine (DA) was not detected in ventricular fluid either before or after yohimbine administration. Yohimbine administration did, however, increase intracellular DA levels in the corpus striatum. These findings indicate that yohimbine promotes NE and DA release in the brain and suggest that it also modifies the activity of the serotonin system.

Attenuation of the early anterior negativity of median nerve somatosensory evoked potential in the MPTP-treated monkey.

Median nerve somatosensory evoked potentials (SEP) were recorded in 7 Cynomolgus monkeys, before and after the administration of N-Methyl 1,4 Phenyl 1,2,3,6 tetrahydropiridine (MPTP), a neurotoxin which induces a parkinsonian syndrome in primates. Following MPTP administration, the amplitude of the negative component recorded at 15 ms over the frontal derivations (N15) decreased by 70% or more. This amplitude reduction was not modified by administration of dopamine precursors. These findings shed light on recent findings in human parkinsonian patients.

Ischemia in the dorsal hippocampus is associated with acute extracellular release of dopamine and norepinephrine.

The cerebral dialysis technique was employed to monitor extracellular concentrations of dopamine (DA), norepinephrine (NE), dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) in the dorsal hippocampus of gerbils before and after cerebral ischemia induced by carotid artery occlusion. Extracellular concentrations of DA and NE in the dorsal hippocampus increased from baseline levels of less than 35 fmol/collection interval to 180 and 200 fmol/collection, respectively, within 36 minutes following carotid artery ligation (n = 8 animals). Extracellular concentrations of the DA metabolites, DOPAC and HVA, did not change significantly following carotid artery ligation. These data demonstrate that ischemia in the dorsal hippocampus is associated with a mared release of DA and NE. This release may contribute to the selective vulnerability of the dorsal hippocampus to neuronal damage during ischemia.

Striatal L-dopa metabolism studied in vivo in rats with nigrostriatal lesions.

We have used cerebral dialysis to monitor striatal metabolism of exogenously administered L-dopa (L-dihydroxyphenylalanine) in rats with unilateral lesions of the substantia nigra. The concentration of extracellular dopamine (DA) increased in both striata following L-dopa administration but the increase was markedly attenuated in the lesioned striatum. The formation of dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), the major DA metabolites, was also reduced in the lesioned striata following L-dopa administration; however, the reduction was not as great as was that of DA formation. A significant metabolism of exogenous L-dopa to 3-O-methyldopa occurred in both striata. L-dopa administration transiently increased extracellular levels of 5-hydroxyindoleacetic acid (5 HIAA) in both the lesioned and intact striata. These results suggest that the striatum with a reduction in DA nerve terminals is deficient both in the capacity to synthesize DA and in the storage mechanisms necessary to protect the newly synthesized DA from oxidative metabolism.