Biomedical subjects

R J Traystman

Publications and source records attributed to R J Traystman.

At least 109 records · Page 6Linked to original sources

PubMed1997

Role of leukocytes in cerebral autoregulation and hyperemia in bacterial meningitis in rabbits.

The effect of leukocytes on regional cerebral blood flow (rCBF) and cerebrovascular autoregulation in experimental meningitis was determined in rabbits. Four groups of animals were studied. Cerebrospinal fluid (CSF) leukocyte migration was prevented in two groups by pretreatment with 1.5 mg/kg of IB4, a monoclonal antibody directed against CD11/18 leukocyte adhesion receptors. Intracisternal inoculation was performed with saline (control and control-IB4 groups) or Haemophilus influenzae type b (Hib and Hib-IB4 groups). Eighteen hours later, rCBF was determined with radiolabeled microspheres. Autoregulation was assessed by graded hemorrhagic hypotension. Compared with untreated meningitis (Hib group), IB4-pretreated meningitis (Hib-IB4 group) was associated with a reduced CSF leukocyte count (1,980 +/- 880 vs. 200 +/- 110 cells/microliter; P < 0.05) and an elevated CSF colony count (2.87 +/- 0.08 vs. 5.63 +/- 0.72 log10colony-forming units/ml; P < 0.05). Compared with control, baseline CBF was elevated in both untreated and IB4-pretreated meningitis (51 +/- 2, 54 +/- 2, 66 +/- 5, and 102 +/- 17 ml.100 g-1.min-1 in control, control-IB4, Hib, and Hib-IB4 groups, respectively). The degree of hyperemia in meningitis was related to the CSF colony count, with a high CBF occurring in animals with high colony counts. During hypotension, CBF remained at or above baseline in the Hib group and both control groups, indicating preservation of cerebrovascular autoregulation in untreated Hib meningitis. In the Hib-IB4 group, the elevated baseline CBF was not maintained during hypotension, falling to 51% of baseline at a cerebral perfusion pressure of 30 mmHg and indicating impairment of cerebrovascular autoregulation. These results suggest that CSF leukocytes are not primarily responsible for the hyperemic response in Hib meningitis. Cerebral hyperemia may be induced either directly by bacterial components or indirectly by components of the inflammatory cascade that precede CSF leukocyte migration.

Animals↗

PubMed1997

NO contributes to neurohypophysial but not other regional cerebral fluorocarbon-induced hyperemia in cats.

The large increase in cerebral blood flow (CBF) after fluorocarbon (FC)-exchange transfusion is thought to be caused by low oxygen content, decreased viscosity, or direct vasodilatory effect of the FC perfusate. The aim of this study was to determine whether nitric oxide (NO)-mediated vasorelaxation is increased in FC-perfused hemoglobin (Hb)-free cats because NO is not scavenged by Hb. We measured regional CBF with radiolabeled microspheres in three groups of anesthetized mechanically ventilated cats. The first group [FC + N(omega)-nitro-L-arginine methyl ester (L-NAME), n = 7] underwent a complete FC-exchange transfusion with FC-43 and subsequent nitric oxide synthase (NOS) inhibition with L-NAME (10 mg/kg i.v.) followed by L-arginine (100 mg/kg i.v.). A second group (FC + saline; n = 6) underwent an identical protocol, but NOS was not antagonized (saline i.v.). In a third group (blood + L-NAME; n = 7), cats were not FC exchanged but NOS was inhibited. In a separate cohort of four FC-perfused cats, NOS activity in brain tissue samples was reduced to 26% of control after NOS inhibition. FC-exchange transfusion nearly doubled hemispheric blood flow in both FC-exchanged groups, whereas it was constant in the blood + L-NAME group. These increases in regional CBF (hemispheres, brain stem, cerebellum, thalamus, and white matter) were not reversed by inhibition of NOS, except in the neurohypophysis, where L-NAME reduced blood flow to levels comparable to values in the blood + L-NAME group. In summary, increases in regional CBF after total FC-exchange transfusion are not caused by a lack of NO scavenging, with the exception of neurohypophysis. These findings suggest an increased vasorelaxation in neurohypophysis of FC-perfused and Hb-free cats caused by unscavenged NO, but this mechanism does not play a major role in FC-related CBF increases in the rest of the cerebral circulation.

Animals↗

PubMed1997

Ultrasound evaluation of piglet diaphragm function before and after fatigue.

Clinically, a noninvasive measure of diaphragm function is needed. The purpose of this study is to determine whether ultrasonography can be used to 1) quantify diaphragm function and 2) identify fatigue in a piglet model. Five piglets were anesthetized with pentobarbital sodium and halothane and studied during the following conditions: 1) baseline (spontaneous breathing); 2) baseline + CO2 [inhaled CO2 to increase arterial PCO2 to 50-60 Torr (6.6-8 kPa)]; 3) fatigue + CO2 (fatigue induced with 30 min of phrenic nerve pacing); and 4) recovery + CO2 (recovery after 1 h of mechanical ventilation). Ultrasound measurements of the posterior diaphragm were made (inspiratory mean velocity) in the transverse plane. Images were obtained from the midline, just inferior to the xiphoid process, and perpendicular to the abdomen. M-mode measures were made of the right posterior hemidiaphragm in the plane just lateral to the inferior vena cava. Abdominal and esophageal pressures were measured and transdiaphragmatic pressure (Pdi) was calculated during spontaneous (Sp) and paced (Pace) breaths. Arterial blood gases were also measured. Pdi(Sp) and Pdi(Pace) during baseline + CO2 were 8 +/- 0.7 and 49 +/- 11 cmH2O, respectively, and decreased to 6 +/- 1.0 and 27 +/- 7 cmH2O, respectively, during fatigue + CO2. Mean inspiratory velocity also decreased from 13 +/- 2 to 8 +/- 1 cm/s during these conditions. All variables returned to baseline during recovery + CO2. Ultrasonography can be used to quantify diaphragm function and identify piglet diaphragm fatigue.

Abdominal Muscles↗

PubMed1997

Parallel antioxidant and antiexcitotoxic therapy improves outcome after incomplete global cerebral ischemia in dogs.

BACKGROUND AND PURPOSE: We have previously shown that incomplete global cerebral ischemia complicated by dense acidosis produces a profound secondary deterioration of energy metabolism and cerebral blood flow. Antioxidant treatment only partially averts this deterioration, suggesting that parallel or sequential mechanisms are involved in cerebral ischemic injury. We tested the hypothesis that a novel competitive N-methyl-D-aspartate (NMDA) receptor antagonist GPI 3000 (GPI) ameliorates metabolic injury and that the effectiveness of the iron-chelator and antioxidant deferoxamine (DFO) is augmented by combined therapy with GPI after incomplete global cerebral ischemia. METHODS: Anesthetized dogs were treated with 30 minutes of global incomplete cerebral ischemia. Preischemic plasma glucose was raised to approximately 500 mg/dL to exaggerate lactic acidosis. Brain ATP, phosphocreatine, and pH were measured by 31P MR spectroscopy for 180 minutes of reperfusion. Neurophysiological outcomes were assessed by evoked potential monitoring. Five groups were treated with either saline; 75 mg/kg DFO preischemia plus 75 mg/kg at reperfusion onset, followed by 27.5 mg/kg per hour for the remainder of reperfusion (DFO group); 25 mg/kg GPI pretreatment, followed by 5 mg/kg per hour (GPI-pre group); 25 mg/kg GPI at reperfusion, followed by 5 mg/kg per hour (GPI-post group); or DFO and GPI-pre at the same doses (Combined group). RESULTS: Ischemic cerebral blood flow (microspheres: 5 to 8 mL/min per 100 g) was similar among the groups. End-ischemic pHi was also similar; 5.9 in saline, 6.1 in DFO, 6.2 in GPI-pre, 6.2 in Combined, and 6.1 in GPI-post groups. Progressive hypoperfusion was observed in all groups except Combined during reperfusion. Metabolic recovery was improved relative to saline in all drug-treated groups. Phosphocreatine recovery was improved in Combined compared with DFO and GPI-pre groups. Somatosensory evoked potential recovery was not observed in the saline group and incomplete in all treatment groups. At 60 and 90 minutes of reperfusion, DFO, GPI-pre, and Combined groups demonstrated improved recovery relative to the saline group. CONCLUSIONS: Pretreatment and posttreatment with GPI ameliorated postischemic metabolic failure, suggesting that NMDA-mediated mechanisms are more important in global cerebral ischemia complicated by dense, acidosis than early studies indicated. Combined treatment with GPI and DFO improved cerebral blood flow during reperfusion and one indicator of energy recovery. These data support the hypothesis that parallel therapy aimed at antioxidant and antiexcitotoxic mechanisms of ischemic brain injury augment recovery compared with the individual agents.

Amino Acids↗

PubMed1997

Neither L-arginine nor L-NAME affects neurological outcome after global ischemia in cats.

BACKGROUND AND PURPOSE: We attempted to determine whether N-nitro-L-arginine methyl ester (L-NAME) would improve neurological outcome and whether L-arginine (L-ARG) would worsen neurological outcome after transient global ischemia. METHODS: Halothane-anesthetized cats (n = 6 for each group) were treated with intravenous saline, L-NAME (5 mg/kg or 10 mg/kg), or L-arginine (300 mg/kg) 30 minutes before 10 minutes of ischemia (temporary ligation of the left subclavian and brachiocephalic arteries with hemorrhagic hypotension to 50 mm Hg). At 30 minutes of reperfusion, cats in the L-ARG group were administered an additional 300 mg/kg dose of intravenous L-arginine. RESULTS: Time (mean +/- SE) to isoelectric electroencephalography was similar among groups (saline, 26 +/- 11 seconds; L-NAME-5, 15 +/- 4 seconds; L-NAME-10, 36 +/- 27 seconds; and L-ARG, 22 +/- 7 seconds). At 72 hours, reperfusion pathological injury was severe and neurological deficit score (mean, range) was similar among groups (saline, 38[11 to 70]; L-NAME-5, 52 [40 to 73]; L-NAME-10, 47 [23 to 70]; and L-ARG, 40 [0 to 79]). CONCLUSIONS: Nitric oxide is not important in the mechanism of brain injury after global ischemia in cats.

Animals↗

PubMed1997

Intravenous basic fibroblast growth factor decreases brain injury resulting from focal ischemia in cats.

BACKGROUND AND PURPOSE: We tested the hypothesis that intravenous administration of basic fibroblast growth factor (bFGF) during 4 hours of permanent focal ischemia would affect acute brain injury. METHODS: Halothane-anesthetized cats underwent left middle cerebral artery (MCA) occlusion for 4 hours. Control cats received diluent (n = 14). Experimental cats were treated with bFGF at a rate of 5 (n = 13), 50 (n = 13), or 250 microg/kg per hour (n = 9) intravenously beginning 60 minutes after initiation of ischemia and continuing until the end of the protocol. RESULTS: As measured by the microsphere method, blood flow to ipsilateral caudate nucleus and ipsilateral inferior temporal cortex was decreased similarly during ischemia, before drug administration, in all groups. Likewise, there was no difference in blood flow to ipsilateral caudate nucleus or inferior temporal cortex as a result of bFGF administration during MCA occlusion. Triphenyltetrazolium-determined injury volume of the ipsilateral cerebral cortex (control, 40+/-7%; bFGF 5 microg/kg per hour, 22+/-5%; bFGF 50 microg/kg per hour, 26+/-7%; bFGF 255 microg/kg per hour, 23+/-6% of ipsilateral cerebral cortex; mean+/-SEM) was less in cats treated with bFGF. There was no difference among groups in injury volume to caudate nucleus (control, 29+/-8%; bFGF 5 microg/kg per hour, 29+/-8%; bFGF 50 microg/kg per hour, 21+/-7%; bFGF 250 microg/kg per hour, 32+/-7% of ipsilateral caudate nucleus). Somatosensory evoked potential amplitude decreased similarly (to <20% of baseline amplitude in all groups) during MCA occlusion and was not altered by bFGF administration. CONCLUSIONS; These data indicate that systemic administration of bFGF ameliorates acute injury in the cerebral cortex without increasing blood flow during focal ischemia in cats. Because bFGF afforded protection when administered after the onset of ischemia, bFGF may provide its beneficial effect by limiting progression of injury in ischemic border regions.

Animals↗

PubMed1997

Characterization of ionotropic glutamate receptor-mediated nitric oxide production in vivo in rats.

BACKGROUND AND PURPOSE: Glutamate receptor activation can stimulate nitric oxide (NO) production and possibly play a role in long-term potentiation and excitotoxic-mediated injury. We studied the differential effect of agonist-induced activation of ion channel-linked N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor subtypes on NO production in vivo in rat hippocampus. We also studied whether dantrolene, a ryanodine calcium channel inhibitor previously shown to attenuate metabotropic glutamate receptor stimulation of NO production, also attenuated ionotropic glutamate receptor-mediated stimulation of NO production. METHODS: Microdialysis probes were placed bilaterally into the CA3 region of the hippocampus of pentobarbital-anesthetized adult Sprague-Dawley rats and were perfused for 5 hours with artificial cerebrospinal fluid (CSF) containing 3 mumol/L [14C]L-arginine. Recovery of [14C]L-citrulline in the effluent was used as a marker of NO production. In 13 groups of rats, increases in [14C]L-citrulline recovery were compared between right- and left-sided probes perfused with no additional drugs versus combinations of NMDA, AMPA, the NO synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME), the non-competitive glutamate receptor blocker MK-801, the AMPA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), and dantrolene. RESULTS: Recovery of [14C]L-citrulline during perfusion with artificial CSF progressively increased to 272 +/- 73 fmol/min (+/-SEM) over 5 hours. Contralateral perfusion with 1 mmol/L L-NAME inhibited [14C]L-citrulline recovery. Perfusion with 1 mmol/L MK-801 or 1 mmol/L CNQX reduced [14C]L-citrulline recovery compared with contralateral perfusion with CSF alone. Perfusion with 1 mmol/L NMDA enhanced [14C]L-citrulline recovery, and this enhancement was attenuated by L-NAME, MK-801, and CNQX but not by dantrolene. Perfusion with 1 mmol/L AMPA enhanced [14C]L-citrulline recovery, and this enhancement was also attenuated by L-NAME, MK-801, and CNQX but not by dantrolene. CONCLUSIONS: Through an indirect method of assessing NO production in vivo, results with MK-801 and CNQX indicate that NMDA and AMPA receptor activation contribute to basal NO production in the rat hippocampus. Enhanced NO production with NMDA and AMPA agonists appears to involve a complex neuronal interaction because the effect of NMDA was attenuated by both MK-801 and CNQX and because the effect of AMPA was attenuated by both CNQX and MK-801. In contrast to metabotropic glutamate receptor activation, release of calcium from intracellular ryanodine calcium channels does not appear to be a prominent mediator of ionotropic glutamate receptor stimulation of NO production.

6-Cyano-7-nitroquinoxaline-2,3-dione↗

PubMed1997

Ecgonine methyl ester, a major cocaine metabolite, causes cerebral vasodilation in neonatal sheep.

Maternal cocaine abuse has been associated with fetal and neonatal neurologic abnormalities, including hemorrhagic cerebral infarctions, but the mechanisms for cocaine's cerebral effects are unknown. We previously showed that acute cocaine injection causes cerebral vasodilation in cats and immature sheep; others have shown that cocaine causes cerebral vasoconstriction in piglets and in pressurized neonatal sheep arteries. Although methodologic and species differences may explain these conflicting results, we tested another possibility; that is, that ecgonine methyl ester (EME), a major cocaine metabolite in sheep, causes cerebral vasodilation and may account, in part, for cocaine's vascular effects. We studied the cerebral effects of a single i.v. injection of EME (2.5 mg/kg) in eight chronically catheterized, unanesthetized neonatal sheep (4 +/- 2 d old). We measured cerebral hemisphere blood flow (CBF) using radiolabeled microspheres, mean arterial pressure, heart rate, and arteriovenous oxygen content, and we calculated cerebral oxygen consumption (CMRo2) and cerebrovascular resistance at baseline and 0.5, 2, 5, and 60 min after EME injection. EME injection had no systemic effects, including no changes in mean arterial pressure, heart rate, or arterial blood gases. Within 0.5 min of injection, EME caused a 21% decrease in cerebrovascular resistance, which remained decreased for 60 min. CBF increased by 20% at 0.5, 2, and 5 min. Blood flow to brain regions other than the cerebral hemispheres paralleled changes in CBF, with cerebellar flow remaining increased at 60 min. There was no change in CMRo2. There was a small, but physiologically insignificant, decrease in arterial oxygen content. We conclude that EME causes cerebral vasodilation in neonatal sheep and may account, in part, for cocaine's cerebral vascular effects.

Animals↗

PubMed1997

Newborn cerebrovascular responses after first trimester moderate maternal ethanol exposure in sheep.

Fetal alcohol syndrome is one of the leading causes of mental retardation in the United States, but the pathogenesis of the associated brain damage is unknown. We tested the hypothesis that neonatal cerebrovascular responses to CO2 and/or hypoxia may be altered by moderate chronic maternal ethanol exposure early in gestation. We studied 26 newborn lambs (1-4 d old). Their mothers had received daily i.v. infusions of either ethanol (1 g/kg; ethanol concentration = 167 +/- 3 mg/dL; mean +/- SEM) or a similar volume of saline for 3 wk during the first trimester. In nine lambs, we studied cerebral responses to CO2 (saline, n = 4; ethanol, n = 5) and in 17 lambs, cerebral responses to hypoxia (saline, n = 7; ethanol, n = 10). Cerebrovascular responses to CO2 were not different between the groups. However, the cerebral vasodilatory response to hypoxemia was significantly attenuated in the ethanol lambs, such that cerebral O2 delivery was not maintained. During severe hypoxia (arterial PO2 = 30 mm Hg), cerebral blood flow increased 106 +/- 23% (mean +/- SEM) above baseline in the saline-treated group, but increased only 32 +/- 15% above baseline in the ethanol-treated group (p < 0.02). Similarly, cerebrovascular resistance in the saline group decreased 52 +/- 6% from baseline, but decreased only 16 +/- 11% in the ethanol group (p < 0.02). We conclude that moderate maternal ethanol infusion early in pregnancy attenuates neonatal hypoxic, but not CO2, cerebrovascular responsivity.

Alcoholism↗

PubMed1996

Nitric oxide synthase 1 and nitric oxide synthase 3 protein expression is regionally and temporally regulated in fetal brain.

Two constitutively expressed isoforms of nitric oxide synthase (NOS) have been identified, Nos1 and Nos3. Nos1 was originally identified in neuronal cells and Nos3 in endothelial cells. Because the biochemical activity of NOS is developmentally regulated, we tested the hypothesis that protein expression is also developmentally regulated. Antibodies to Nos1 and Nos3 were evaluated for specificity by immunoblotting and then used for immunohistochemistry. In fetal and adult sheep brain homogenates, Nos1 antibodies identified one immunoreactive band of proteins at 155 kDa. The Nos3 antibody detected one immunoreactive band at 145 kDa that comigrated with a reactive band in endothelial cell lystates. Immunoblots of developing neocortex demonstrated that Nos1 was enriched at early gestational ages, whereas Nos3 expression was relatively constant throughout development. By immunohistochemistry, distinct isoform-specific patterns of immunoreactivity were detected. At 60 days, Nos1 immunoreactivity is primarily localized in neuropil, but by midgestation, nonpyramidal neurons are labeled in the cortical plate. Developing neurites are Nos1-positive at 60 and 71 days, decreasing in abundance by 93 days. By 93 days the striatum is fully populated by Nos1-expressing nonprincipal neurons. In hippocampus and subthalamic nucleus, Nos1 immunoreactivity is greatest at 60 and 71 days gestation, decreasing thereafter. Immunoreactivity for Nos3 delineates cerebrovasculature maturation from a primarily radial to a highly complex branching arrangement. Hindbrain structures achieve mature organization of the cerebrovasculature before forebrain. We conclude that constitutive NOS protein expression is developmentally regulated and that distinct isoforms of NOS are regulated differentially during brain development. Expression of Nos3 parallels maturation of the cerebrovasculature, whereas the transient, region- and cell type-dependent enrichment of Nos1 in the developing brain may indicate a temporally and spatially restricted role for this enzyme in the maturation of specific neuronal populations.

Animals↗

PubMed1996

Inhibition of glutamine synthetase reduces ammonia-induced astrocyte swelling in rat.

Astrocyte hypertrophy and swelling occur in a variety of pathophysiological conditions, including diseases associated with hyperammonemia. Ammonia is rapidly incorporated into glutamine by glutamine synthetase localized in astrocytes. We tested the hypotheses that (1) 6 h of hyperammonemia (500-600 microM) is adequate for producing astrocyte enlargement, and (2) astrocyte enlargement is attenuated by inhibition of glutamine synthetase with methionine sulfoximine. Pentobarbital-anesthetized rats received an intravenous infusion of either sodium or ammonium acetate after intraperitoneal pretreatment with vehicle, methionine sulfoximine (0.8 mmol/kg) or buthionine sulfoximine (4 mmol/kg), an analogue that does not inhibit glutamine synthetase. Hyperammonemia produced enlarged cortical astrocytes characterized by (1) decreased electron density of cytoplasmic matrix in perikaryon, processes and perivascular endfeet, (2) increased circumference of nuclear membrane, (3) increased numbers of mitochondria and rough and smooth endoplasmic reticulum in perikarya and large processes, and (4) less compact bundles of intermediate filaments. Pretreatment with methionine sulfoximine, but not buthionine sulfoximine, attenuated the decrease in cytoplasmic density and the increase in nuclear circumference; most perivascular endfeet remained as dense as occurred with sodium acetate infusion. However, increased numbers of organelles in expanded perikarya and large processes occurred after methionine sulfoximine treatment with and without ammonium acetate infusion. In separate groups of rats, hyperammonemia produced an increase in cortical tissue water content which was inhibited by methionine sulfoximine, but not buthionine sulfoximine. We conclude that clinically-relevant levels of hyperammonemia can cause astrocyte enlargement within 6 h in vivo characterized by both watery cytoplasm and increased organelles indicative of a cellular metabolic stress and altered astrocyte function. The watery cytoplasm component of astrocyte enlargement depends on glutamine synthesis rather than on ammonium ions per se, and is possibly caused by the osmotic effect accumulated glutamine.

Ammonia↗

PubMed1996

Effects of traumatic brain injury on the cholinergic system in the rat.

Rats subjected to a mild to moderate fluid percussion injury exhibit memory deficits that are similar to rats that have received lesions of the septohippocampal system. Because the cholinergic system plays a major role in septohippocampal function, we studied the kinetics of the synthetic enzyme for acetylcholine, choline acetyltransferase (ChAT), at 1 h, 24 h, or 5 days after a fluid percussion injury. Decreases in ChAT activity were found in the dorsal hippocampus (25%), frontal (32%), and temporal (23%) cortices 1 h after injury. In the parietal cortex, a greater than 50% increase in ChAT activity was observed at all time intervals assessed. At 5 days after TBI, there was an 18% increase in ChAT activity in the medial septal area. These data provide evidence that a mild to moderate fluid percussion injury produces changes in the cholinergic system in brain areas related to memory.

Analysis of Variance↗

PubMed1996

Intensity of halothane- and hypercapnia-induced cerebral hyperemia is strain-dependent in rats.

Cerebrovascular responses to physiologic and pharmacologic stimuli vary between laboratories using different strains of the same species. We tested whether the cerebral blood flow (CBF) response to 1% halothane or hypercapnia is strain-dependent in rats. Age-matched adult male (n = 14 of each strain) Wistar, Wistar-Kyoto (WKY), and spontaneously hypertensive rats (SHR) were anesthetized with pentobarbital and mechanically ventilated. Under baseline conditions blood flow to cerebrum (microspheres) in WKY (66 +/- 5 mL.min-1.100 g-1) was less than (P < 0.05) in Wistar (88 +/- 5 mL.min-1.100g-1) and SHR (83 +/- 5 mL.min-1.100 g-1). Blood flow to brainstem was greater (P < 0.05) in Wistar (106 +/- 8 mL. min-1.100 g-1) than in WKY (71 +/- 5 mL.min-1. 100 g-1) and SHR (84 +/- 4 mL.min-1.100 g-1). In the halothane protocol (n = 8 each strain), administration of 1% halothane, during normocapnia, increased blood flow to the cerebrum in WKY (64 +/- 6 to 120 +/- 12 mL.min-1.100 g-1, P < 0.05) and SHR (78 +/- 6 to 115 +/- 8 mL.min-1.100 g-1, P < 0.05) but not Wistar rats (88 +/- 8 to 102 +/- 5 mL.min-1.100 g-1, not significant). Discontinuing halothane caused blood flow to return to baseline values. In the hypercapnia protocol (n = 6 each strain), exposure to 3% CO2 (to achieve a PaCO2 of 50-55 mm Hg) and 6% CO2 (to achieve a PaCO2 of 60-70 mm Hg) caused blood flow to the cerebrum to increase in Wistar (87 +/- 11 to 112 +/- 15 to 162 +/- 23) to similar amount as observed in WKY (69 +/- 7 to 115 +/- 13 to 162 +/- 23 mL.min-1. 100 g-1) but less than that observed in SHR (89 +/- 7 to 174 +/- 24 to 237 +/- 28 mL.min-1.100 g-1). These data demonstrate that the cerebral hyperemic response to vasodilator stimuli is strain-dependent in rats.

Anesthetics, Inhalation↗

PubMed1996

Enhanced recovery of brain electrical activity by adenosine 3',5'-cyclic monophosphate following complete global cerebral ischemia in dogs.

OBJECTIVE: To test the hypothesis that adenosine 3',5'-cyclic monophosphate (cAMP) or dibutyl-cAMP (a more lipid-soluble, less rapidly metabolized analog of cAMP) would improve recovery of cerebral electrical activity and metabolic function after transient global cerebral ischemia by improving cerebral blood flow during the reperfusion period. DESIGN: Randomized, controlled, prospective study. SETTING: University research laboratory. SUBJECTS: Twenty-five male beagle dogs. INTERVENTIONS: Nine control dogs received saline (20-mL/kg bolus and 0.01 mL/kg/min) intravenously, beginning 25 mins before 12 mins of cerebral global ischemia (by aortic occlusion). The dogs in the experimental groups received either cAMP (40 mg/kg 25 mins before ischemia and 0.2 mg/kg/min throughout reperfusion, n = 7), or dibutyl-cAMP (6 mg/kg 25 mins before ischemia and 3 mg/kg at 60, 90, and 120 mins of reperfusion, n = 9). MEASUREMENTS AND MAIN RESULTS: Total and regional cerebral blood flow, cerebral oxygen consumption, and somatosensory evoked potentials were measured during 180 mins of reperfusion. Pretreatment with dibutyl-cAMP resulted in increased postischemic hyperemia at 30 mins of reperfusion (e.g., whole brain: control 40 +/- 6; cAMP 56 +/- 9; dibutyl-cAMP 67 +/- 10 mL/min/100 g [mean +/- SEM, p < .05 control vs. dibutyl-cAMP group]) but no difference in total cerebral blood flow or oxygen consumption during later points of reperfusion. All groups demonstrated rapid ablation of the amplitude of somatosensory evoked potentials during ischemia, with no difference between the groups. At 180 mins of reperfusion, somatosensory evoked potentials recovered to 28 +/- 4% of the preischemic baseline value in dogs treated with saline, whereas the somatosensory evoked potentials recovered to 58 +/- 4% of preischemic baseline value in the cAMP-pretreated group (p < .05), and to 70 +/- 6% of preischemic baseline value in dogs treated with dibutyl-cAMP (p < .05). CONCLUSIONS: cAMP and dibutyl-cAMP improve recovery of cerebral electrical function after complete transient global cerebral ischemia. Although hyperemia was more prolonged in cAMP- and dibutyl-cAMP-treated dogs, there was no difference between groups in degree of postischemic delayed hypoperfusion. Therefore, we believe that the mechanism for cerebral protection afforded by cAMP and dibutyl-cAMP is not related to cerebral circulatory effects.

Animals↗

PubMed1996

Regional blood flow alterations after bovine fumaryl beta beta-crosslinked hemoglobin transfusion and nitric oxide synthase inhibition.

OBJECTIVES: a) To determine whether isovolemic exchange transfusion with cell-free, bovine fumaryl beta beta-crosslinked hemoglobin results in a different pattern of regional blood flow distribution than transfusion with a poor oxygen-carrying, colloidal solution. b) Because of potential nitric oxide scavenging by plasma-based hemoglobin, to determine whether blood flow differences are reduced after nitric oxide synthase inhibition. DESIGN: A prospective, randomized design with repeated blood flow measurements within groups. SETTING: Experimental physiology laboratory in a university medical center. SUBJECTS: Pentobarbital-anesthetized female cats. INTERVENTIONS: Three groups of eight cats were studied: a) a control group with no transfusion (hematocrit of 32%); b) an anemia group in which exchange transfusion with an albumin-containing solution reduced hematocrit to 18% over a 40- to 50-min period; and c) a group in which cell-free hemoglobin was exchanged transfused to reduce hematocrit to 18%, without a proportional reduction in oxygen-carrying capacity. Bovine hemoglobin was covalently crosslinked intramolecularly between the 81-lysine residues on the beta-subunits to stabilize the tetramer. Regional blood flow was measured by the radiolabeled microsphere technique before transfusion and at 10, 100, and 180 mins from the start of transfusion. At 190 mins, N omega-nitro-L-arginine methyl ester (L-NAME; 10mg/kg) was infused to inhibit nitric oxide synthase and blood flow was measured 30 mins later. MEASUREMENTS AND MAIN RESULTS: Mean arterial pressure was unchanged in the control and albumin-transfused groups. However, mean arterial pressure increased rapidly in the hemoglobin-transfused group. With hemoglobin transfusion, there were marked reductions in blood flow to the intestines, kidneys and adrenal glands. Administration of L-NAME after hemoglobin transfusion failed to increase arterial pressure or cause further reductions in intestinal, renal, or adrenal blood flow. Administration of L-NAME to the control and albumin-transfused groups increased arterial pressure and reduced intestinal, renal, and adrenal blood flows to values attained with hemoglobin transfusion. In contrast, in skeletal muscle and left ventricle, blood flow rates increased in the albumin-transfused group and were greater than those values found in the control group and hemoglobin-transfused group. The greater flow in the albumin-transfused group persisted after L-NAME administration. There was no difference in renal sodium, potassium, or osmolar excretion, or in urine flow between groups. CONCLUSIONS: Transfusion with cell-free, bovine crosslinked hemoglobin in cats can selective reductions in blood flow in the intestines, kidneys, and adrenal glands without evidence of renal dysfunction by a mechanism consistent with nitric oxide scavenging. In skeletal and cardiac muscle, the increase in blood flow persisted after nitric oxide inhibition in the albumin group relative to the hemoglobin-transfused group at equivalent hematocrit values. This finding is consistent with compensatory vasoconstriction with hemoglobin transfusion due to improved oxygenation by this oxygen carrier.

Animals↗

PubMed1996

Impairment of cerebral autoregulation during venovenous extracorporeal membrane oxygenation in the newborn lamb.

OBJECTIVE: To study the effects of venovenous extracorporeal membrane oxygenation (ECMO) on cerebral autoregulation in the newborn lamb. DESIGN: Animal studies, using newborn lambs, with comparison of two randomized treatment groups. SUBJECTS: Newborn lambs of mixed breed, 1 to 7 days of age, were randomized into two study groups: control animals, with jugular vein ligation but no ECMO (n = 6), and ECMO animals placed on venovenous ECMO (n = 6). SETTING: Laboratory animal facilities of the Department of Anesthesiology and Critical Care Medicine at The Johns Hopkins Medical Institutions, Baltimore, MD. INTERVENTIONS: Animals were anesthetized with pentobarbital, intubated, and ventilated, and monitoring catheters were inserted. Control animals had their right jugular vein ligated, and a cerebral autoregulation curve was performed after 1 hr of stabilization. ECMO animals were placed on venovenous ECMO and after 1 hr of stabilization, they had a cerebral autoregulation curve performed. Cerebral autoregulation was examined by increasing intracranial pressure, thereby decreasing cerebral perfusion pressure. Intracranial pressure was increased by infusion of artificial cerebrospinal fluid into the lateral ventricle of the brain. MEASUREMENTS AND MAIN RESULTS: Four ranges of cerebral perfusion pressure were evaluated: a) baseline (1 hr after initiation of bypass in venovenous ECMO or completion of surgery in controls); b) cerebral perfusion pressure of 55 to 40 mm Hg; c) cerebral perfusion pressure of 39 to 25 mm Hg; and d) cerebral perfusion pressure of < 25 mm Hg. Cerebral blood flow (radiolabeled microspheres), cerebral oxygen consumption, fractional oxygen extraction, and oxygen transport values were calculated at each study period. In ECMO animals, cerebral blood flow (cerebral hemispheres) decreased from a baseline measurement of 46 +/- 9 (SD) mL/100 g/ min to 29 +/- 12 mL/100 g/min at a cerebral perfusion pressure of < 25 mm Hg. In the control group, cerebral blood flow was unchanged from baseline at any range of cerebral perfusion pressure. Cerebral oxygen consumption was unchanged from baseline as cerebral perfusion pressure decreased in either group. When cerebral oxygen consumption was compared between the two groups, it was lower in the ECMO group at baseline and at a cerebral perfusion pressure of < 25 mm Hg. At a cerebral perfusion pressure of < 25 mm Hg, cerebral blood flow, cerebral oxygen delivery, and metabolic rate were lower in the ECMO group than in the control group, and fractional oxygen extraction and cerebral vascular resistance were higher, indicating that autoregulation was impaired. There was no difference between blood flow in the right and left cerebral hemispheres when autoregulation was impaired in the ECMO animals. CONCLUSIONS: These findings indicate that cerebral autoregulation was altered in animals on venovenous ECMO, with cerebral blood flow decreasing at a cerebral perfusion pressure of < 25 mm Hg, compared with control animals which showed no changes at the same cerebral perfusion pressure. This disruption of cerebral autoregulation decreased cerebral oxygen metabolism despite an increased oxygen extraction in ECMO animals.

Animals↗

PubMed1996

Effect of hemocarboperfusion on organ blood flow and survival in porcine endotoxic shock.

OBJECTIVE: To evaluate the effects of hemocarboperfusion on hemodynamics, organ blood flow, and survival in endotoxin shock. DESIGN: Prospective, placebo-controlled, animal trial. SETTING: Research laboratory in a major university teaching hospital. SUBJECTS: Pentobarbital-anesthetized pigs. INTERVENTIONS: Twenty-eight pentobarbital-anesthetized pigs (18.5 to 22.3 kg) received 100 micrograms/kg of Escherichia coli endotoxin (lipopolysaccharide 0127) over 30 mins. Group 1 animals (n = 14) were controls and had blood diverted through an extracorporeal circuit without activated charcoal for 60 mins after lipopolysaccharide infusion. Group 2 animals (n = 14) underwent nonpulsatile hemocarboperfusion (activated charcoal SCN-1K). MEASUREMENTS AND MAIN RESULTS: Mean arterial pressure, cardiac output, systemic vascular resistance, mean pulmonary arterial pressure, pulmonary vascular resistance, oxygen delivery, and regional blood flow (radiolabeled microsphere technique) were determined at baseline and every 30 mins for 150 mins. Results are presented as mean +/- SD. Parameters in the two groups were compared by two-way analysis of variance. A p < .05 was considered significant. The survival rate was ten (71%) of 14 animals in group 1 compared with 14 (100%) of 14 animals in group 2 (p < .05, Fisher's exact test). The mean cardiac output at the end of hemocarboperfusion was 1.6 +/- 0.6 L/min in group 1 compared with 3.0 +/- 0.9 L/min in group 2, and remained lower in group 1 animals throughout the experiment. Pulmonary arterial pressure and pulmonary vascular resistance were lower in the hemocarboperfusion-treated animals during and after hemocarboperfusion. Systemic vascular resistance increased by 70% after lipopolysaccharide infusion and returned to baseline values in the hemocarboperfusion group but remained increased in controls. Oxygen delivery was lower in group 1 at 90 and 150 mins (287 +/- 34 vs. 478 +/- 48 mL/min and 251 +/- 24 vs. 356 +/- 21 mL/min, respectively). Blood flow rates to the brain (38.5 +/- 7.5 vs. 27.1 +/- 5.4 mL/min/100 g), large intestine (26.6 +/- 1.1 vs. 17.7 +/- 2.5 mL/ min/100 g), and adrenal cortex (200 +/- 45 vs. 139 +/- 41 mL/min/100 g) were higher in the hemocarboperfusion group at the completion of carboperfusion but not at later time points. CONCLUSION: These data suggest that hemocarboperfusion may be of value in the treatment of septic shock.

Animals↗

PubMed1996

Anesthetics and cerebroprotection: experimental aspects.

A number of anesthetic agents have significant cerebroprotective potential and alter ischemic tolerance in vivo, at least within specific experimental conditions such as focal or incomplete, global cerebral ischemia. As compared to the unanesthetized state, each of these agents has some influence on CBF and metabolism, and many have significant effects on vascular responses to dilator stimuli. Relevant studies that provide clues to the mechanisms of anesthetic action in brain injury have been reviewed, and it is likely that these mechanisms are multifactorial and may overlap from one class of agents to another. Lastly, there is a clear need for further studies that specifically evaluate the neuroprotective mechanism of each agent, determine the effect on outcomes when the anesthetic is administered only as a posttreatment at clinically relevant concentrations, and compare anesthetics with the unanesthetized state when possible.

Anesthesia, General↗