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R J Traystman

Publications and source records attributed to R J Traystman.

At least 145 records · Page 8Linked to original sources
PubMed1995

Time-dependent inhibition of oxotremorine-induced cerebral hyperemia by N omega-nitro-L-arginine in cats.

BACKGROUND AND PURPOSE: Oxotremorine (OXO) is a cholinergic agonist that increases cerebral blood flow (CBF) when administered intravenously. We tested the hypothesis that OXO causes a dose-related increase in CBF in cats via a muscarinic mechanism that involves stimulation of nitric oxide synthase. METHODS: Halothane-anesthetized male cats were studied under controlled ventilation. In three groups we measured cerebral blood flow (CBF; microspheres) during 30 minutes of intravenous OXO infusion at doses of 0.5 (n = 3), 5 (n = 6), or 50 micrograms.kg-1.min-1 (n = 6). The role of muscarinic receptor activation in the CBF response to OXO (50 micrograms.kg-1.min-1) was assessed by determining the effect of atropine sulfate (2 mg.kg-1, n = 6) pretreatment in a separate group of cats. The role of nitric oxide synthase was assessed by determining the CBF response to OXO (50 micrograms.kg-1.min-1) either 30 (n = 6) or 60 minutes (n = 5) after administration of 50 mg/kg N omega-nitro-L-arginine (LNA). RESULTS: CBF to forebrain (pre-OXO, 144 +/- 12 mL.min-1.100 g-1) was unchanged with OXO 0.5 or 5 micrograms.kg-1.min-1 but increased at 10 (209 +/- 26 mL.min-1 x 100 g-1) and 30 minutes (243 +/- 35 mL.min-1 x 100 g-1) of OXO infusion at 50 micrograms.kg-1.min-1 (P < .05). Atropine sulfate prevented OXO-induced hyperemia at 10 minutes of infusion but not at 30 minutes of infusion (135 +/- 12% of pre-OXO). LNA decreased baseline CBF by approximately 50%. Treatment with LNA 30 minutes before OXO did not affect the extent of OXO-induced hyperemia (CBF, 142 +/- 15% of pre-OXO at 10 minutes and 153 +/- 18% of pre-OXO at 30 minutes of OXO infusion). Treatment with LNA 60 minutes before OXO ablated OXO-induced hyperemia. CONCLUSIONS: In halothane-anesthetized cats, OXO (50 micrograms.kg-1.min-1) increases forebrain CBF by a muscarinic mechanism that involves stimulation of nitric oxide synthase. The ability of nitric oxide synthase inhibitors to block agonist-induced nitric oxide-mediated vasodilation (response to OXO) is time dependent and may not be predicted by ability of the inhibitor to significantly decrease basal CBF.

Animals↗
PubMed1995

Effect of nitric oxide synthase inhibition on the cerebral vascular response to hypercapnia in primates.

BACKGROUND AND PURPOSE: The role of nitric oxide in cerebrovascular response to changes in PCO2 is unclear. In the present study, we assessed responses at two levels of hypercapnia in a primate model before and after blockade of nitric oxide synthesis. METHODS: We compared the effects of two levels of hypercapnia, defined as PCO2 of approximately 70 mm Hg (high-CO2 group, n = 5) and PCO2 of approximately 50 mm Hg (moderate-CO2 group, n = 6), on increases in regional cerebral blood flow (microspheres) before and after inhibition of nitric oxide synthase with N omega-nitro-L-arginine methyl ester (L-NAME; 60 mg.kg-1) in isoflurane-anesthetized cynomolgus monkeys (1.0% end-tidal concentration). RESULTS: Before L-NAME administration, hypercapnia increased flow in all regions (eg, forebrain, high-CO2 group 69 +/- 10 to 166 +/- 15 mL.min-1.100 g-1; moderate-CO2 group, 49 +/- 7 to 93 +/- 15 mL.min-1.100 g-1) and decreased cerebral vascular resistance (high-CO2, 1.1 +/- 0.1 to 0.4 +/- 0.1 mm Hg.mL-1.min.100 g; moderate-CO2, 1.4 +/- 0.1 to 0.7 +/- 0.1 mm Hg.mL-1.min.100 g). During normocapnia, L-NAME decreased cerebral blood flow (high-CO2, 37 +/- 9%; moderate-CO2, 40 +/- 6%) and increased cerebral vascular resistance (high-CO2, 93 +/- 33%; moderate-CO2, 88 +/- 20%). After L-NAME, hypercapnia still increased blood flow in all regions (eg, forebrain: high-CO2, 56 +/- 7 to 128 +/- 3 mL.min-1.100 g-1, moderate-CO2, 36 +/- 5 to 57 +/- 8 mL.min-1.100 g-1) and decreased vascular resistance (high-CO2, 1.5 +/- 0.1 to 0.6 +/- 0.1 mm Hg.mL-1.min.100 g; moderate-CO2, 2.0 +/- 0.3 to 1.2 +/- 0.1 mm Hg.mL-1.min.100 g). In both groups L-NAME attenuated hypercapnia hyperemia by approximately 30% in cortex but not in other regions. CONCLUSIONS: Nitric oxide contributes to basal vascular tone but is not a major contributor to the mechanism of hypercapnia-induced cerebral vasodilation, except in cortex, in primates.

Amino Acid Oxidoreductases↗
PubMed1995

Deferoxamine reduces early metabolic failure associated with severe cerebral ischemic acidosis in dogs.

BACKGROUND AND PURPOSE: Postischemic metabolic injury may be mediated by acidosis and tissue bicarbonate depletion, with consequent-iron mobilization and oxygen radical formation during reperfusion. We have previously shown that reducing intracellular pH to below 5.7 and bicarbonate ion to below 1 to 2 mmol/L during hyperglycemic ischemia produces a profound secondary deterioration of brain ATP and cerebral blood flow during reperfusion. This study tested the hypothesis that pretreatment with free deferoxamine ameliorates metabolic decay and delayed hypoperfusion after global hyperglycemic ischemia. In addition, deferoxamine conjugated to a high-molecular-weight starch was administered to determine the importance of an intravascular site of action. Iron-loaded deferoxamine was used to determine whether the iron chelation properties of deferoxamine are important to postischemic viability as distinguished from the agent's significant radical scavenging potential. METHODS: Cerebral ATP, phosphocreatine, and pH were measured by 31P magnetic resonance spectroscopy in anesthetized dogs. Tissue bicarbonate concentration was calculated from the Henderson-Hasselbalch equation. Incomplete cerebral ischemia was produced by intracranial pressure elevation for 30 minutes with plasma glucose at 540 +/- 15 mg/dL. Free deferoxamine, saline vehicle, hydroxyethyl starch-conjugated deferoxamine, hydroxyethyl starch vehicle, and deferoxamine loaded with equimolar ferric chloride were administered intravenously in five groups of dogs. The dose of deferoxamine was 50 mg/kg before ischemia, 50 mg/kg at the onset of reperfusion, and 50 mg/kg over the 180-minute reperfusion period. RESULTS: Ischemic hemispheric blood flow (mean, 6 to 8 mL/min per 100 g), intracellular pH (5.7 to 6.0), and bicarbonate levels (1 to 2 mmol/L) were similar in all groups. During reperfusion, cerebral pH and bicarbonate recovered only in the free-deferoxamine group. Both ATP and phosphocreatine initially increased in all groups, but recovery was sustained only in the free-deferoxamine group. Secondary losses of energy phosphates and cerebral oxygen consumption were observed in all other groups, accompanied by progressive reduction of perfusion. CONCLUSIONS: These data support the hypothesis that iron catalyzed oxygen radical production plays an important role in acidosis-mediated mechanisms of ischemic brain injury. The results with free and iron-loaded deferoxamine suggest that iron scavenging is an important, but not necessarily the principal, component of this mechanism. The poor recovery seen with conjugated deferoxamine indicates that the beneficial action of deferoxamine is not localized within the intravascular compartment.

Acidosis↗
PubMed1995

Nitro-L-arginine analogues. Dose- and time-related nitric oxide synthase inhibition in brain.

BACKGROUND AND PURPOSE: The purpose of the present study was to measure cortical nitric oxide synthase (NOS) activity and determine the appropriate doses of N omega-nitro-L-arginine methyl ester (L-NAME) or N omega-nitro-L-arginine (L-NNA) for near-complete enzyme inhibition in dogs, cats, and pigs. We anticipated that NOS inhibition was dose- and time-dependent and questioned if the dose-response relationship was related to the specific drug or animal species. METHODS: Saline or L-NAME or L-NNA in escalating doses was administered to pentobarbital-anesthetized pigs, dogs, and cats. Brain temperature and arterial blood gas, hemoglobin, and blood pressure levels were maintained within the physiological range. Cortical tissue was biopsied at baseline and 30, 120, and 360 minutes after agent administration for measurement of NOS activity by isotopic assay of the conversion of [14C]arginine to [14C]citrulline. RESULTS: L-NAME produced > 70% enzyme inhibition at a dose of 20 mg/kg across the species tested. Arterial blood pressure was elevated at 30 minutes after L-NAME treatment. However, consistent decreases in brain NOS activity required a longer period of time. Near-complete inhibition was apparent in most animals by 120 minutes and persisted for 6 hours after administration. A smaller dose of L-NNA was required for > 70% enzyme inhibition in the cats and dogs (10 mg/kg). Near-complete NOS inhibition was evident in most animals at 30 minutes after L-NNA administration, which also persisted for 6 hours. In pigs, this same level of inhibition required 20 mg/kg. CONCLUSIONS: These results suggest that administration of L-NAME and L-NNA diminishes brain NOS activity in a dose- and time-dependent manner and that the duration of effect is at least 6 hours.

Amino Acid Oxidoreductases↗
PubMed1995

Acidemia and brain pH during prolonged cardiopulmonary resuscitation in dogs.

BACKGROUND AND PURPOSE: Cardiopulmonary resuscitation (CPR) generating low perfusion pressures and beginning immediately after cardiac arrest maintains cerebral ATP but not cerebral pH or arterial pH. We tested the hypothesis that preventing severe arterial acidemia prevents cerebral acidosis, whereas augmenting arterial acidemia augments cerebral acidosis. METHODS: In dogs anesthetized with pentobarbital and fentanyl, cerebral pH and ATP were measured with 31P MR spectroscopy and blood flow was measured with radiolabeled microspheres. A pneumatically controlled vest was placed around the thorax, and chest compressions were begun immediately after electrically induced cardiac arrest. Cerebral perfusion pressure was maintained with epinephrine at 30 mm Hg for 90 minutes. The arterial acidemia observed during CPR was untreated in a control group, corrected to a pH of 7.3 with the use of sodium bicarbonate, or maintained below pH 6.5 with intravenous lactic acid after 14 minutes of CPR. RESULTS: At 10 minutes of CPR, cerebral ATP (99 +/- 1.5%, control), blood flow (35 +/- 3 mL/min per 100 g), O2 consumption (4.0 +/- 0.2 mL/min per 100 g), and cerebral pH (7.05 +/- .03) were unchanged from prearrest values (mean +/- SEM). After 10 minutes of CPR in the control group, cerebral pH progressively fell (6.43 +/- 0.10 at 90 minutes) in parallel with cerebral venous pH. In the bicarbonate group cerebral pH was maintained higher (6.91 +/- 0.08). Cerebral blood flow, O2 consumption, and ATP were sustained near prearrest values in both groups. In the lactate group, however, the rate of decrease of cerebral pH was augmented (6.47 +/- 0.06 by 30 minutes), and cerebral blood flow and metabolism were significantly reduced. CONCLUSIONS: Cerebral pH decreased in parallel with blood pH when resuscitation was started immediately upon arrest even when cerebral O2 consumption and blood flow were near normal. Although cerebral metabolism was near normal during the first hour of CPR, systemic bicarbonate administration ameliorated the cerebral acidosis. This finding indicates that the blood-brain pH gradient is important at the subnormal cerebral perfusion pressures seen in CPR.

Acidosis↗
PubMed1995

Cerebral blood flow during inhibition of brain nitric oxide synthase activity in normal, hypertensive, and stroke-prone rats.

BACKGROUND AND PURPOSE: Because tonic production of nitric oxide (NO) is important in regulating cerebrovascular tone and NO may be important in the mechanism of brain injury from focal ischemia, we speculated that stroke predisposition in spontaneously hypertensive stroke-prone rats (SHR-SP) may be related to impaired tonic production of NO. This study was designed to test the hypothesis that the cerebral blood flow (CBF) response to inhibition of NO synthase in SHR-SP would be different than that observed in normal Wistar-Kyoto (WKY) rats and non-stroke-prone spontaneously hypertensive rats (SHR). METHODS: Pentobarbital-anesthetized, mechanically ventilated rats were tested for CBF response to saline, 5 or 20 mg/kg IV of NG-monomethyl-L-arginine (L-NMMA), or 20 mg/kg IV of N omega-nitro-L-arginine (L-NA). In addition, specificity for an NO-dependent mechanism was assessed by determining the ability to reverse any alteration in CBF with L-arginine. Hemorrhage was used to minimize any increase in mean arterial blood pressure (MABP) from NO synthase inhibition. In a separate cohort of rats, differential sensitivity of NO synthase for inhibition by nitro-arginine analogues was determined. RESULTS: Baseline MABP was greater in SHR-SP (185 +/- 3, n = 38) and SHR (169 +/- 3, n = 38) compared with WKY rats (101 +/- 2 mm Hg, n = 38, P < .05). Baseline CBF was similar between strains; however, cerebrovascular resistance was higher in SHR-SP (2.16 +/- 0.09, n = 27) and SHR (1.94 +/- 0.07, n = 27) compared with WKY rats (1.23 +/- 0.06 mm Hg/mL per minute per 100 g, n = 27, P < .05). CBF was unchanged with 5 mg/kg L-NMMA or with L-arginine in the absence of L-NMMA in each strain. CBF decreased similarly in SHR and SHR-SP (n = 9 each) in response to 20 mg/kg L-NMMA (SHR, 85 +/- 6 to 67 +/- 6; SHR-SP, 87 +/- 7 to 69 +/- 5 mL/min per 100 g) and was completely reversed by L-arginine. CBF did not decrease with 20 mg/kg L-NMMA in WKY rats. Administration of L-NA (n = 5 each) produced similar reduction of CBF (WKY rats, 67 +/- 6%; SHR, 49 +/- 9%; SHR-SP, 61 +/- 6% of baseline) and inhibition of NO synthase in each strain (approximately 80% inhibition). CONCLUSIONS: There was no difference in the cerebrovascular response to NO synthase inhibition in SHR-SP and non-stroke-prone SHR. Therefore, it is unlikely that an altered sensitivity of NO synthase to inhibition can explain predisposition to stroke in SHR-SP.

Amino Acid Oxidoreductases↗
PubMed1995

Adenosine modulates N-methyl-D-aspartate-stimulated hippocampal nitric oxide production in vivo.

BACKGROUND AND PURPOSE: Adenosine acts presynaptically to inhibit release of excitatory amino acids (EAAs) and is thus considered to be neuroprotective. Because EAA-stimulated synthesis of nitric oxide (NO) may play an important role in long-term potentiation and excitotoxic-mediated injury, we tested the hypotheses that adenosine agonists attenuate basal and EAA-induced NO production in the hippocampus in vivo and that adenosine A1 receptors mediate this response. METHODS: Microdialysis probes were placed bilaterally into the CA3 region of the hippocampus of adult Sprague-Dawley rats under pentobarbital anesthesia. Probes were perfused for 5 hours with artificial cerebrospinal fluid containing 3 mumol/L [14C]L-arginine. Recovery of [14C]L-citrulline in the effluent was used as a marker of NO production. In 10 groups of rats, time-dependent increases in [14C]L-citrulline recovery were compared between right- and left-sided probes perfused with various combinations of N-methyl-D-aspartate (NMDA), adenosine agonists, adenosine antagonists, and the NO synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME). RESULTS: Recovery of [14C]L-citrulline during perfusion with artificial cerebrospinal fluid progressively increased to 141 +/- 27 fmol/min (+/- SEM) over 5 hours. Contralateral perfusion with 1 mmol/L NMDA augmented [14C]L-citrulline recovery to 317 +/- 62 fmol/min. Perfusion of 1 mmol/L L-NAME with NMDA inhibited [14C]L-citrulline recovery compared with NMDA alone. Perfusion with 0.1 mmol/L 2-chloroadenosine attenuated basal as well as NMDA-enhanced [14C]L-citrulline recovery. This action of 2-chloroadenosine was reversed by infusion of 0.1 mmol/L 8-cyclopentyl-1,3-dipropylxanthine, a specific A1 receptor antagonist. Infusion of 0.1 mmol/L (2S)-N6-[2-endo-norboryl]adenosine, a specific A1 receptor agonist, also attenuated the 0.1 mmol/L and 1 mmol/L NMDA-enhanced [14C]L-citrulline recovery. CONCLUSIONS: Using an indirect method of assessing NO production in vivo, these data are consistent with in vitro results showing that NMDA receptor stimulation enhances NO production. Furthermore, we conclude that stimulation of A1 receptors can attenuate the basal as well as NMDA-induced production of NO. Because NMDA receptor stimulation amplifies glutamate release, our data are consistent with presynaptic A1 receptor-mediated inhibition of EAA release and consequent downregulation of NO production.

2-Chloroadenosine↗
PubMed1995

PPBP [4-phenyl-1-(4-phenylbutyl) piperidine], a potent sigma-receptor ligand, decreases brain injury after transient focal ischemia in cats.

BACKGROUND AND PURPOSE: We tested the hypothesis that administration of 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP), a potent sigma-receptor ligand, during transient focal ischemia would affect early postischemic brain injury. METHODS: Halothane-anesthetized cats underwent left middle cerebral artery occlusion for 90 minutes followed by 4 hours of reperfusion. Control cats received saline (n = 10). Experimental cats (2 groups, n = 10 per group) were treated with PPBP at a rate of 0.1 mumol/kg per hour (PPBP-0.1) or administered 1 mumol/kg per hour (PPBP-1) intravenously from 75 minutes after initiation of ischemia and continuing during the 4 hours of reperfusion. RESULTS: As measured by the microsphere method, blood flow to the ipsilateral caudate nucleus was decreased similarly in all groups during ischemia. Blood flow to the ipsilateral inferior temporal cortex was decreased during ischemia in all groups but was higher in cats subsequently treated with PPBP at the highest dose, even before drug administration. There was no difference in blood flow to the ipsilateral caudate nucleus or inferior temporal cortex (area of greatest cortical injury) during reperfusion. Triphenyltetrazolium-determined injury volume of the ipsilateral cerebral hemisphere (control, 29 +/- 5%; PPBP-0.1, 17 +/- 3%; PPBP-1, 6 +/- 1% of ipsilateral hemisphere; mean +/- SEM) and caudate nucleus (control, 49 +/- 5%; PPBP-0.1, 39 +/- 6%; PPBP-1, 25 +/- 5% of ipsilateral caudate nucleus) was less in cats treated with 1 mumol/kg per hour of PPBP compared with cats treated with saline. Cats treated with 0.1 mumol/kg per hour had a 45% smaller hemispheric injury volume than the control group without differences in intraischemic blood flow. Recovery of somatosensory evoked potential amplitude was greater in cats treated with PPBP-1 compared with control (control, 18 +/- 11%; PPBP-0.1, 30 +/- 14%; PPBP-1, 54 +/- 14% of baseline). CONCLUSIONS: These data indicate that sigma-receptors may play an important role in the mechanism of acute injury in both the cortex and the caudate nucleus after 90 minutes of transient focal ischemia in the cat. Because PPBP afforded protection when administered at the end of ischemia and during reperfusion, sigma-receptors may contribute to the progression of injury in ischemic border regions.

Animals↗
PubMed1995

Somatosensory evoked potential and brain water content in post-asphyxic immature piglets.

Depression of somatosensory evoked potentials (SEP) after a single episode of complete asphyxia with near cardiac arrest was evaluated to determine whether persistent SEP depression is related to postresuscitation edema in cortical gray matter or subcortical white matter. Piglets (< 7 d of age) were anesthetized with sodium pentobarbital and fentanyl. Asphyxia was produced by occlusion of the endotracheal tube for 7 min. Arterial O2 saturation fell to 5%. Resuscitation was achieved in < 2 min with ventilation, epinephrine, and chest compressions. Regional brain water content was determined from the difference between wet and dry weight. Two control groups were also analyzed; one immediately after (n = 5) and one 6 h after induction (n = 7) of anesthesia. SEP amplitude became isoelectric during asphyxia and recovered to 50 +/- 13% (n = 7) of baseline 6 h after resuscitation. In the 6-h control group, SEP amplitude remained above baseline. The percent water content (mean +/- SEM) among the three groups (asphyxia versus time control versus brief anesthesia control) was not different in the cortical gray matter (83.0 +/- 0.7% versus 82.4 +/- 0.4% versus 83.2 +/- 0.3%) or subcortical white matter (75.6 +/- 0.8% versus 74.8 +/- 0.9% versus 75.6 +/- 0.5%). In seven other piglets, cerebral blood flow and O2 consumption recovered to baseline by 1 h after asphyxia. Therefore, we found that the sustained depression of SEP amplitude, after 7 min of asphyxia in immature piglets, is not related to brain edema or persistent decreases in global cerebral O2 consumption.

Animals↗
PubMed1995

Experimental neuronal injury in the newborn lamb: a comparison of N-methyl-D-aspartic acid receptor blockade and nitric oxide synthesis inhibition on lesion size and cerebral hyperemia.

The purpose of this study was to compare the effects of dizocilipine maleate (MK-801) and NG-nitro-L-arginine methyl ester (L-NAME) on focal excitotoxic brain injury and associated hemodynamic response in the newborn lamb. A 27 gauge needle was placed into the right striatum in 28 anesthetized newborn lambs. Seven animals were placed in each group. A negative control group received 0.2 mL of buffered saline, a positive control group received 5 mumol of N-methyl-D-aspartic acid (NMDA) alone, and two groups received NMDA and pretreatment with L-NAME. Ultrasound images and cerebral blood flow determinations (microspheres) were obtained before, and at 20, 40, and 60 min after, intrastrial injection. Three animals in each group underwent histopathologic evaluation. Sonographic lesions were visible immediately after intracerebral injection. Saline injection resulted in small lesions (mean volume; 13.6 +/- 5 mm3) without hyperemia. NMDA alone resulted in larger lesions (92.9 +/- 24 mm3) and hyperemia to both hemispheres, whereas pretreatment with MK-801 reduced lesion size (11.7 +/- 6 mm3) and completely ablated cerebral hyperemia. Pretreatment with L-NAME showed no effect on lesion size (69.9 +/- 20 mm3) and hyperemia only in the ipsilateral hemisphere. Sonographic lesions correlated well with gross and histopathologic appearance. We concluded that NMDA-induced focal brain injury and associated hyperemia in the newborn lamb appear to be specific NMDA receptor-mediated events. NO production probably does not play a major part in NMDA-induced neonatal neuronal injury, and may be only partly responsible for regional hyperemia during NMDA injection.

Animals↗
PubMed1995

Cerebral responses to maternal cocaine injection in immature fetal sheep.

Previous studies in near-term sheep have shown that maternal cocaine injection causes acute fetal cerebral vasodilation along with transient hypoxemia and hypertension. Preterm sheep fetuses have lower cerebral O2 consumption (CMRO2) and their cerebrovascular responses to hypoxemia are attenuated compared with near-term fetuses. We therefore tested the hypothesis that fetal cerebrovascular responses to maternal cocaine injection may also differ earlier in gestation. We studied nine immature fetal sheep at 0.65 gestation using the same experimental protocol we used in previous studies in near-term sheep. Fetal studies were done in utero, 2 d after vascular catheter placement. We measured cerebral blood flow (CBF) using microspheres, arterial and sagittal sinus O2 content, and cocaine concentrations. We calculated cerebrovascular resistance (CVR) as mean arterial blood pressure divided by CBF. Measurements were made before and 2, 5, and 15 min after a 2 mg/kg maternal cocaine injection. At 2 min, fetal Cao2 decreased (18 +/- 6%, mean +/- SEM), and there was cerebral vasoconstriction (CVR increased by 22 +/- 5%). At 5 min, CBF increased (19 +/- 9%), but because blood pressure increased also, CVR returned to baseline, and therefore there was no vasodilation compared with baseline. Furthermore, at 5 min there was a 22 +/- 6% decrease in Cao2 and a 21 +/- 6% increase in mean arterial blood pressure. There were no changes in CMRo2 throughout the study, but at 2 min, cerebral O2 delivery decreased. Differences in cerebrovascular responses to maternal cocaine injection earlier in gestation may be due to differences in vascular development and/or to developmental differences in responses to cocaine, cocaine metabolites, and/or to hypoxemia.

Animals↗
PubMed1995

Role of nitric oxide scavenging in peripheral vasoconstrictor response to beta beta cross-linked hemoglobin.

Transfusion with many crosslinked hemoglobin solutions causes an increase in arterial pressure that may be mediated by scavenging of nitric oxide (NO). If so, we postulated that inhibiting synthesis of NO after hemoglobin transfusion would fail to cause vasoconstriction ordinarily seen with such inhibition. In pentobarbital anesthetized cats, we tested whether administration of the NO synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), produced peripheral vasoconstriction after isovolemic exchange transfusion with hemoglobin to the same extent as occurs with L-NAME infusion in time controls and in controls matched for reduced hematocrit (17%) with albumin transfusion. Bovine hemoglobin was treated aerobically with bis-(3,5-dibromosalicyl)fumarate to produce beta beta-81 lysine crosslinks. Hemoglobin exchange transfusion increased mean arterial blood pressure and there was no further increase after L-NAME. In contrast, L-NAME increased pressure in the time controls and albumin controls. Hemoglobin transfusion decreased intestinal and renal blood flow, and there was no further decrease after L-NAME. In contrast, L-NAME decreased intestinal and renal blood flow in time controls and albumin controls. With L-NAME pretreatment in a separate group of cats, there was little further increase in arterial pressure or visceral vasoconstriction after hemoglobin transfusion. We conclude that the increase in arterial blood pressure after isovolemic crosslinked hemoglobin transfusion is best explained by scavenging of NO in intestinal and renal vascular beds.

Animals↗
PubMed1994

The cerebrovascular response to prolonged hypoxia with carotid artery and jugular vein ligation in the newborn lamb.

This study was designed to evaluate the effect of ligation of the carotid artery and/or jugular vein, after exposure to prolonged (4 hours) hypoxia, and the effect of acute normalization of PaO2 after prolonged hypoxia with vessel ligation, on the cerebral circulation. Twelve 1- to 7-day-old lambs were anesthetized with pentobarbital. Catheters were placed in the femoral artery and vein, left ventricle, lingual artery, and sagittal sinus. Cerebral blood flow (CBF) was determined using the radiolabeled microsphere technique. After baseline studies, the animals were made hypoxic with a nitrogen/air mixture, to lower PaO2 to 36 +/- 5 mm Hg for 4 hours, followed by 1 hour of normoxia. After four hours of hypoxia, studies were performed. The animals were divided into two groups to evaluate carotid artery and jugular vein ligation separately. In group I, the carotid artery was ligated first, with studies performed after 5 minutes; this was followed by ligation of the jugular vein, with studies after 5 minutes. In group II, the jugular vein was ligated first, with studies after 5 minutes; this was followed by ligation of the carotid artery, with studies after 5 minutes. With regard to physiological variables, there were no differences between the groups. CBF increased 106% (P < .001 compared with the baseline value) after 4 hours of hypoxia, maintaining cerebral oxygen consumption (CMRO2) and oxygen transport (OT) constant in both groups. Ligation of either the carotid artery or jugular vein after 4 hours of hypoxia, did not alter CBF responses to hypoxia.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Nitric oxide synthase does not contribute to cerebral autoregulatory phenomenon in anesthetized dogs.

Nitric oxide (NO) is a potent vasodilator produced by nitric oxide synthase (NOS). We tested the following hypotheses: (1) cerebral blood flow (CBF) is NO dependent, (2) NO contributes to CBF autoregulation, and (3) NO participates in the neurohypophysial vasodilator response to hypotension. Three groups of sodium pentobarbital anesthetized dogs were studied using microspheres. In 7 dogs, N omega-nitro-L-arginine methyl ester (L-NAME; 40 mg/kg, i.v.) increased mean arterial pressure (MAP) by 12%. Cerebrovascular resistance (CVR) increased more than MAP, resulting in a 20 +/- 4% reduction (range 12-67%) in baseline CBF. In unblocked conditions, actively autoregulated regions (e.g. cortex, white matter, median eminence) demonstrated a correlation between CVR and MAP whereas passive regions (neural lobe) did not. NOS block did not effect the relationship between MAP and CVR in most brain regions. However, a significant relationship between CVR and MAP developed in neural lobe after NOS block. Abrupt hypotension increased neural lobe blood flow to 239 +/- 37% control at 3 min, despite NOS block. These results show that baseline cerebral vessel tone depends upon NOS activity. Enhanced NO release cannot explain either cerebral autoregulation or the transient hyperperfusion seen in neural lobe immediately following rapid hemorrhage.

Amino Acid Oxidoreductases↗
PubMed1994

Rat spinal cord neurons contain nitric oxide synthase.

We describe the distribution and characteristics of nitric oxide synthase-containing neurons in rat spinal cord using a polyclonal affinity-purified antibody against rat cerebellar nitric oxide synthase. Numerous neurons were stained throughout the entire rostrocaudal extent of the spinal cord. Cell bodies, dendrites and axons stained in a uniform manner. Nitric oxide synthase immunoreactivity was intense in neurons of laminae I-IV and X throughout the entire spinal cord. Neurons in the intermediolateral cell column of the thoracic and lumbar spinal cord were also intensely stained for nitric oxide synthase. The sacral cord demonstrated substantial nitric oxide synthase immunostaining within lamina VII. For the entire cord, scattered neurons in laminae V, VI, VII, and VIII were weakly positive. In addition, punctate nitric oxide synthase staining throughout laminae I, III and surrounding some large motor neurons in the ventral horn suggested the presence of nitric oxide synthase at synapses. Axons and dendritic terminals located in the gray and white matter were also stained. The majority of nitric oxide synthase positive neurons in the intermediolateral cell column were double-labelled by subcutaneously injected FluoroGold confirming that these cells were preganglionic autonomic neurons. Most NADPH-diaphorase-stained neurons were also nitric oxide synthase-positive. The distribution of nitric oxide synthase-containing neurons in spinal cord suggests that nitric oxide plays a role in spinal cord neurotransmission including: preganglionic sympathetic and parasympathetic, somatosensory, visceral sensory and possibly motor pathways. In particular, the autonomic nervous system appears enriched with nitric oxide synthase immunoreactivity. The precise role of each neuron type remains to be demonstrated in physiologic and pathophysiologic paradigms.

Amino Acid Oxidoreductases↗
PubMed1994

Reduced cerebral blood flow but intact reactivity to hypercarbia and hypoxia following subarachnoid hemorrhage in rabbits.

Subarachnoid hemorrhage (SAH) was produced in rabbits by four subarachnoid injections of blood (n = 7) or saline (n = 6); a control group (n = 6) had no injections. Basilar artery vasospasm was assessed by serial angiograms. Resting CBF (microspheres) and CBF reactivity to hypercapnia (65 and 85 mm Hg) and hypoxia (fractions of inspired oxygen of 0.15 and 0.10) were determined. Basilar artery vasospasm was seen with SAH. Resting CBF was reduced by 31% (SAH 43 +/- 12, saline 65 +/- 17, control 60 +/- 21 ml 100 g-1 min-1), and resting cerebrovascular resistance was increased (SAH 1.84 +/- 0.30, saline 1.31 +/- 0.49, control 1.39 +/- 0.25 mm Hg ml-1 100 g-1 min-1) after SAH. CBF rose to a similar degree in all three groups in response to hypercarbia and hypoxia. We conclude that resting CBF is reduced in this model of SAH, but vascular reactivity remains intact.

Animals↗
PubMed1994

Interaction of fentanyl and nitrous oxide on peripheral and cerebral hemodynamics in newborn lambs.

BACKGROUND: The ability of opioids to produce complete general anesthesia is controversial. Nitrous oxide (N2O) is often added to fentanyl-based anesthetics to produce unconsciousness and amnesia. The addition of N2O may adversely affects fentanyl's hemodynamic stability and safety. The purpose of this study was to determine the physiologic consequences of combining N2O with fentanyl in newborn animals. METHODS: The effects of 50% nitrous oxide in oxygen (O2), and 50% N2O in O2 combined with 3,000 micrograms/kg fentanyl, on cerebral and peripheral hemodynamics were studied in seven unanesthetized newborn lambs, in whom catheters were previously inserted. After a control period, lambs were placed in a hood in which inspired gas concentrations were controlled and which minimized external stimuli. After 30 min of breathing room air, the lambs breathed 50% N2O in O2 for an additional 30 min. The lambs were then given 3,000 micrograms/kg fentanyl by intravenous bolus and by infusion (1,000 micrograms.kg-1 x h-1) for 60 min while continuing to breathe 50% N2O in O2. RESULTS: All animals responded to pain (tail clamp) and alerted to sound when breathing room air or when N2O was used alone. Adding fentanyl to the N2O abolished all responses to pain, but not to sound. Additionally, fentanyl produced immediate apnea necessitating tracheal intubation and mechanical ventilation. Mean arterial pressure and heart rate increased 27% and 23%, respectively, after fentanyl administration, intubation, and ventilation. It did not change over the course of the fentanyl infusion. Cerebral blood flow, O2 consumption, and O2 delivery did not change when N2O was administered alone or in combination with fentanyl. Splanchnic blood flow was unaffected by treatment over time. Renal blood flow decreased by 21% after fentanyl administration, but was unaffected by N2O alone. Right and left ventricular blood flow increased (47% and 26%, respectively) after fentanyl administration, intubation, and ventilation, but not when N2O was administered alone. CONCLUSIONS: Fentanyl (3,000 micrograms/kg) when combined with 50% N2O in O2 produced a plane of general anesthesia in newborn lambs in which the behavioral responses to painful stimuli were abolished. The response to sound was never eliminated, nor was cerebral oxygen consumption decreased. The combination of 50% N2O in O2, 3,000 micrograms/kg fentanyl, tracheal intubation, and mechanical ventilation did not depress heart rate, blood pressure, or blood flow to any of the major organs, except the kidneys.

Anesthesia, General↗