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Biomedical subjects

J R Tobin

Publications and source records attributed to J R Tobin.

At least 19 recordsLinked to original sources
PubMed1997

Developmental and regional differences in nitric oxide synthase activity and blood flow in the sheep brain.

Nitric oxide synthase (NOS) participates in the regulation of cerebral blood flow and neurotransmitter release and as a second messenger of glutamatergic and cholinergic systems. Developmental differences in NOS activity have been described in the rat, but not in a species with longer gestation and a larger, lobulated brain at birth. We assayed NOS activity by conversion of [14C]L-arginine to [14C]L-citrulline in 50-mg tissue samples from eight brain regions in sheep at 70, 92, 110, and 135 days gestation (term = 145 days); newborns (< 7 days); and adults to test the hypothesis that NOS activity in the brain is developmentally regulated from midgestation through adulthood and matures along the neuroaxis in parallel with the known development of cerebral blood flow and neuronal activity. Three patterns of maturation of NOS activity were evident: increasing to or exceeding adult levels before 70 days gestation in the thalamus, cerebellum, and medulla; increasing to adult levels between 70 and 92 days in the hippocampus; and increasing to adult levels after 92 days in the cortex and caudate. Additionally, there were regional differences in cortical NOS activity: at 70 and 92 days of gestation, frontal cortex NOS activity was greater than parietal or occipital activity, and at 135 days gestation and in the newborn and adult, cortical and caudate activity exceeded that in most of the more caudal regions. The up to fourfold increase in regional cortical NOS activity between 92 and 135 days gestation was associated with twofold increases in cerebral blood flow and oxygen consumption during this period. Inhibition of NOS activity with administration of 60 mg/kg of NG-nitro-L-arginine methylester (L-NAME) resulted in 27% and 25% reductions in cerebral blood flow at 93 and 133 days gestation. While the associated increases in NOS activity with increases in CBF and CMRO2 do not appear causative, at various points in gestation the development of NOS activity may participate in the development of mature patterns of cerebral blood flow regulation in parallel with development of synaptic and electrical activity.

Animals↗
PubMed1996

Neuropathic pain in rats is associated with altered nitric oxide synthase activity in neural tissue.

Peripheral nerve injury may lead to a chronic neuropathic pain state that results from an increase in excitability of central neurons. This central sensitization is mediated via an N-methyl-D-aspartic acid (NMDA) receptor and may involve the production of nitric oxide (NO). As NO is suggested to play a role in nociceptive transmission following nerve injury, we examined for altered NO synthase activity at multiple levels of peripheral and spinal neural tissue in a rat model of neuropathic pain. Peripheral neuropathy was induced in rats (N = 12) by ligation of the left L5 and L6 nerve roots. Six other rats had sham surgery. An ipsilateral decrease in paw withdrawal threshold to mechanical stimuli confirmed the presence of a neuropathic pain state. Samples of the lumbar and thoracic spinal cords, L4, L5, and L6 dorsal root ganglia (DRGs), and the sciatic nerves were obtained from the lesioned and contralateral sides at 2 and 4 weeks after neuropathic surgery (N = 6 per group). In the lumbar spinal cord, a bilateral decrease in nitric oxide synthase (NOS) activity was observed 2 and 4 weeks after neuropathic surgery. NOS activity was increased in the ipsilateral L5 and 6 DRGs 2 weeks following neuropathic surgery. An increase in NOS activity in the DRG may be an early mechanism for inducing more central changes. The bilaterally decreased NOS activity in the lumbar spinal cord may be secondary to a negative feedback mechanism resulting from increased NO production in the spinal dorsal root ganglia. Multiple alterations in expression of NOS activity that occur in both peripheral and central processing may play a role in the pain behavior resulting from peripheral nerve injury. (Preliminary results of these studies have been presented in abstract form at the annual meetings of the Society for Neuroscience, 1994, and the American Society of Anesthesiologists, 1994).

Analysis of Variance↗
PubMed1996

Location and characteristics of nitric oxide synthase in sheep spinal cord and its interaction with alpha(2)-adrenergic and cholinergic antinociception.

BACKGROUND: Nitric oxide synthase is located in the spinal cord dorsal horn and intermediolateral cell column, where it may modulate sensory and sympathetic neuronal activity. However, the biochemical characteristics of this enzyme have not been examined in these different areas in the spinal cord. Although alpha(2)-adrenergic agonists, muscarinic agonists, and nitric oxide may interact in the spinal cord to produce antinociception, these interactions have not been characterized. METHODS: Sheep spinal cord tissue was homogenized ad centrifuged at high sped to separate soluble and membrane-bound fractions. Nitric oxide synthase activity was determined by conversion of [(14)C]-L-arginine to [(14)C]-L-citrulline and its kinetic characteristics, dependency on cofactors, and sensitivity to inhibitors determined. Sheep spinal cord was stained for nicotinamide adenine dinucleotide phosphate diaphorase as a marker for nitric oxide synthase. Antinociception to a mechanical stimulus from intrathecal clonidine alone and with neostigmine was determined and the effects of L-arginine and n-methyl-L-arginine were determined. RESULTS: More than 85% of nitric oxide synthase activity was present in the soluble form and its kinetic, cofactor, and antagonist properties were similar to those of the neuronal isoform of nitric oxide synthase. Biochemical and histochemical studies localized nitric oxide synthase to the superficial dorsal horn and the intermediolateral cell column. Clonidine antinociception was enhanced by L-arginine and neostigmine, but not by D-arginine. Neostigmine's enhancement of clonidine antinociception was blocked by n-methyl-L-arginine. CONCLUSIONS: These results confirm those of previous studies demonstrating localization of nitric oxide synthase to superficial dorsal horn and intermediolateral cell column of mammalian spinal cord, and suggesting its identity as the neuronal isoform. Spinal alpha(2)-adrenergic agonist antinociception may be partly dependent on cholinergic and nitric oxide mechanisms.

Adrenergic alpha-2 Receptor Agonists↗
PubMed1996

Effects of ischemia on cerebrovascular responses to N-methyl-D-aspartate in piglets.

We examined the effects of total global ischemia on cerebral arteriolar responses to N-methyl-D-aspartate (NMDA) in anesthetized newborn pigs. Arteriolar responses to 10(-4) M NMDA were determined before and after 10 to 20 min of ischemia caused by increasing intracranial pressure. Before ischemia, NMDA dilated arterioles by 30 +/- 5% (baseline = 88 +/- 2 microns; n = 6). However, after 10 min of ischemia, arteriolar dilation was reduced to 10 +/- 3% at 1 h (P < 0.05). At 2 and 4 h, NMDA-induced dilation was not different from preischemia values. Twenty minutes of ischemia had similar effects. Coadministration of 100 U/ml of superoxide dismutase did not restore arteriolar dilation to NMDA at 1 h after ischemia. Sodium nitroprusside dilated by 14 +/- 3 and 40 +/- 5% at 10(-6) and 10(-5) M before ischemia, respectively, and arteriolar responsiveness was not changed by ischemia (n = 6). Cortical nitric oxide synthase (NOS) activity, measured by the in vitro conversion of L-[14C]arginine to L-[14C]citrulline, was unaffected by ischemia (n = 12). We conclude that decreases in cerebral arteriolar responsiveness to NMDA are not due to impairment of NOS activity, enhanced degradation or chelation of nitric oxide (NO), or reduced vascular smooth muscle responsiveness to NO.

Animals↗
PubMed1995

Nitric oxide synthase inhibition does not impair visual or spatial discrimination learning.

Nitric oxide (NO) is a candidate retrograde messenger involved in synaptic plasticity, and is linked to the cholinergic system in the brain. We examined the role of NO in the acquisition of visual and spatial discriminations by daily administration of either saline or 1-nitroarginine methyl ester (L-NAME), an NO synthase inhibitor. Brains were assayed for NO synthase activity and two presynaptic cholinergic markers: hemicholinium-3 (HC-3) binding, which determines the number of sodium-dependent high-affinity choline uptake sites, and activity of choline acetyltransferase (ChAT), which is the synthetic enzyme for acetylcholine. In both behavioral tasks, the acquisition rate was not different between groups. L-NAME reduced NO synthase activity by 85% in all brain areas assayed and HC-3 binding by 38% in hippocampus and 48% in posterior cortex. ChAT activity was not different between groups in any region assayed. These data suggest that NO does not play a role in visual or spatial discrimination learning. However, NO synthase inhibition may play a role in the regulation of cholinergic activity.

Animals↗
PubMed1995

Nitric oxide and prostaglandins interact to mediate arteriolar dilation during cortical spreading depression.

We examined whether blockade of prostaglandin synthesis by indomethacin could attenuate the effect of nitric oxide synthase (NOS) inhibition on cerebral arteriolar dilation during cortical spreading depression (CSD). CSD was induced by microinjection of 5% (670 mM) KCl onto the cerebral cortex of anesthetized adult rabbits. A closed cranial window and intravital microscopy were used to measure pial arteriolar diameter, and NOS activity was determined by the conversion assay of [14C]arginine to [14C]citrulline. CSD dilated pial arterioles by 47 +/- 3% (baseline = 80-88 microns) (n = 21, P < 0.05), and inhibition of NOS by NG-nitro-L-arginine (L-NNA) (15 mg/kg iv) reduced dilation during CSD by over one-half (n = 8, P < 0.05) without altering the onset latency to CSD. After indomethacin administration (15 mg/kg iv), CSD dilated arterioles from 73 +/- 2 to 152 +/- 6 microns (n = 4, P < 0.05). However, after administration of both indomethacin and L-NNA (n = 5), CSD-induced arteriolar dilation was not different from the situation where indomethacin alone was given. Thus indomethacin completely abolished the inhibitory effect of L-NNA on CSD-induced dilation. Administration of L-NNA inhibited NOS activity in brain cortex almost completely (n = 8, P < 0.05), whereas indomethacin itself had no effect (n = 8). In addition, L-NNA inhibited topical acetylcholine (10(-5) M)-induced arteriolar dilation (n = 3, P < 0.05), and this effect was not altered by indomethacin (n = 4). In summary, L-NNA reduced arteriolar dilation during CSD. However, after administration of indomethacin, L-NNA does not reduce CSD-induced arteriolar dilation.

Acetylcholine↗
PubMed1995

In vivo production of nitric oxide correlates with NMDA-induced cerebral hyperemia in newborn sheep.

Stimulation of N-methyl-D-aspartate (NMDA) receptors in brain increases nitric oxide production in vitro. We tested the hypothesis that nitric oxide participates in the increase in local cerebral blood flow (CBF) caused by infusion of NMDA in anesthetized newborn sheep. We used the combined hydrogen clearance and microdialysis technique for simultaneous measurement of local CBF, infusion of drugs, and measurement of interstitial levels of L-[14C]citrulline in the parietal cortex. Release of L-[14C]citrulline into the dialysate during continuous infusion of L-[14C]arginine was used as a marker of nitric oxide production in vivo. Citrulline recovery and CBF were measured hourly during a 4-h infusion of cerebrospinal fluid containing either 1) no additional drugs, 2) 1 mM NMDA, 3) 1 mM NG-nitro-L-arginine methyl ester (L-NAME, a nitric oxide synthase inhibitor), 4) 1 mM NMDA + 1 mM L-NAME, 5) 0.1 mM 2-chloroadenosine (adenosine receptor agonist), or 6) 0.1 mM 2-chloroadenosine + 1 mM L-NAME. At 240 min of perfusion, CBF (ml.min-1.100 g-1; means +/- SE) was as follows: control 52 +/- 3, NMDA 116 +/- 11, L-NAME 32 +/- 5, NMDA+L-NAME 40 +/- 4,2-chloroadenosine 201 +/- 63, and 2-chloroadenosine+L-NAME 129 +/- 18. Citrulline recovery (fmol/min) at 240 min of perfusion was as follows: control 38 +/- 12, NMDA 149 +/- 21, L-NAME 9 +/- 1, NMDA+L-NAME 39 +/- 5, 2-chloroadenosine 13 +/- 5, and 2-chloroadenosine+L-NAME 17 +/- 1.(ABSTRACT TRUNCATED AT 250 WORDS)

2-Chloroadenosine↗
PubMed1995

Glutamate-induced cerebral vasodilation is mediated by nitric oxide through N-methyl-D-aspartate receptors.

BACKGROUND AND PURPOSE: It was found that glutamate, a major neurotransmitter, is vasoactive in the cerebral circulation. However, the mechanism is unclear. This study was designed to investigate the role of nitric oxide (NO) and N-methyl-D-aspartate (NMDA) receptors in cerebral arteriolar dilation to glutamate. METHODS: Newborn, chloralose-anesthetized pigs were equipped with a closed cranial window. The diameter of pial arterioles was measured by means of intravital microscopy, and NO synthase (NOS) activity in brain cortex was determined by the conversion assay of [14C]arginine to [14C]citrulline. RESULTS: Topical application of glutamate at 10(-7), 10(-6), and 10(-5) mol/L (n = 5) increased the mean diameter by 12 +/- 3%, 13 +/- 2%, and 18 +/- 3% (+/- SEM), respectively (baseline, 91 +/- 10 microns; P < .05). Similarly, NMDA application at the above doses (n = 5) dilated arterioles by 10 +/- 2%, 16 +/- 3%, and 18 +/- 6%, respectively (baseline, 97 +/- 4 microns; P < .05). Topical application of 10(-4) mol/L NG-nitro-L-arginine (L-NNA), which inhibited NOS activity by 93%, blocked the arteriolar dilation to glutamate or NMDA. Furthermore, administration of MK-801, a potent inhibitor of NMDA receptors, blocked glutamate-induced vasodilation completely in both topical application (10(-5) mol/L; n = 6) and intravenous administration (5 to 10 mg/kg; n = 5). In addition, neither L-NNA nor MK-801 attenuated the vasodilation to hypercapnia (PCO2 = 40 to 68 mm Hg). CONCLUSIONS: Glutamate-induced cerebral arteriolar dilation is mediated by NO through NMDA receptors, and NO does not play a major role in the cerebral arteriolar dilation to hypercapnia (PCO2 = 40 to 68 mm Hg) in newborn pigs.

Animals↗
PubMed1994

Atypical beta-adrenoceptor in bovine adrenal medulla.

Bovine adrenal medullary membranes were incubated with [125I]cyanopindolol to assess beta-adrenoceptor binding. Binding was saturable and specific; a single low affinity site (Kd = 750 pM) was identified. [125I]Cyanopindolol binding was displaced by micromolar concentrations of classic beta-adrenoceptor antagonists and by sodium-4-[-2-[2-hydroxy-2-(-3-chloro-phenyl) ethylamino] propyl] phenoxyacetate. These data are similar to reported binding of beta 3-adrenoceptors and may explain beta-adrenoceptor agonist modulation of chromaffin cell degranulation in this catecholamine rich environment.

Adrenal Medulla↗
PubMed1994

Cerebral blood flow in primates is increased by isoflurane over time and is decreased by nitric oxide synthase inhibition.

BACKGROUND: Cerebral blood flow (CBF) decreases over time in dogs and goats during volatile anesthesia. In the current study, we determined CBF during administration of isoflurane for 4 h in cynomolgus monkeys. In addition, we determined if nitric oxide (NO) contributes to cerebrovascular tone during isoflurane anesthesia by determining the CBF (microsphere) response to inhibition of NO synthase with N omega-nitro-L-arginine methyl ester (L-NAME). METHODS: CBF was measured in five monkeys anesthetized with isoflurane (1.0% end-tidal). After 4 h of isoflurane (1.0% = 1 MAC), the effects of intravenous L-NAME (60 mg/kg over 10 min) followed by intravenous L-arginine (600 mg/kg over 10 min) on CBF were measured at constant cerebral perfusion pressure and arterial carbon dioxide tension. RESULTS: CBF was unchanged over time (4 h) in cerebellum but increased by 50 +/- 18% in both forebrain and hindbrain (P < 0.05). CBF decreased by 41-48% (P < 0.05) 20 min after L-NAME in forebrain, cerebellum, and hindbrain, at which time brain NO synthase activity was less than 10% of baseline. Twenty minutes after L-arginine, CBF was increased in cerebellum by 32 +/- 8% and in forebrain by 41 +/- 9% (P < 0.05). The cerebral metabolic rate of oxygen consumption was unaffected by time or by L-NAME or L-arginine. CONCLUSIONS: These data demonstrate that CBF increases over time during isoflurane anesthesia in primates. Tonic production of NO contributes to control of CBF in primates during isoflurane anesthesia. Increased CBF by L-arginine after L-NAME supports the hypothesis that L-NAME decreases CBF via a mechanism requiring NO synthesis.

Amino Acid Oxidoreductases↗
PubMed1994

Nitric oxide and prostanoids contribute to isoflurane-induced cerebral hyperemia in pigs.

BACKGROUND: The mechanism of isoflurane-induced cerebral hyperemia is poorly understood. Data from studies in vitro suggest that volatile anesthetics release a vasodilator prostanoid. We hypothesized that prostanoids and nitric oxide (NO) are mediators of this response in vivo. If true, inhibition of cyclooxygenase by indomethacin (5 mg/kg intravenously) or of nitric oxide synthase by N omega-nitro-L-arginine methyl ester (L-NAME; 40 mg/kg intravenously) should attenuate isoflurane-induced hyperemia. Any response to L-NAME occurring via nitric oxide should be competitively reversed by L-arginine. METHODS: The cerebral blood flow (microsphere) response to 1 MAC isoflurane was tested at three time points (0, 90, and 180 min) in pentobarbital-anesthetized pigs. Isoflurane challenges were separated by 60-min periods of continuous intravenous pentobarbital alone. Control animals (n = 7) received no additional pharmacologic intervention. Experimental animals were randomized to receive L-NAME before the second and indomethacin before the third isoflurane challenge (n = 7); L-NAME before the second and L-arginine (400 mg/kg intravenously) before the third isoflurane challenge (n = 9); or indomethacin before the second and L-NAME before the third isoflurane challenge (n = 8). RESULTS: In control animals, isoflurane reproducibly increased cerebral blood flow (whole brain; 113 +/- 18%, 120 +/- 18%, and 103 +/- 19% increase above baseline at each time point, respectively). Both indomethacin and L-NAME attenuated (10 +/- 10% and 52 +/- 11% increase, respectively) the hyperemic response to isoflurane. The effect of L-NAME was reversed by L-arginine. CONCLUSIONS: We conclude that both prostanoids and nitric oxide contribute to isoflurane-induced hyperemia. We are unable to determine from our data what, if any, interaction exists between these two mechanisms.

Amino Acid Oxidoreductases↗
PubMed1994

Selective anesthetic inhibition of brain nitric oxide synthase.

BACKGROUND: It has been postulated that nitric oxide (NO) is a neurotransmitter involved in consciousness, analgesia, and anesthesia. Halothane has been shown to attenuate NO-mediated cyclic guanosine monophosphate accumulation in neurons, and a variety of anesthetic agents attenuate endothelium-mediated vasodilation, suggesting an interaction of anesthetic agents and the NO-cyclic guanosine monophosphate pathway. However, the exact site of anesthetic inhibitory action in this multistep pathway is unclear. The current study examines effects of volatile and intravenous anesthetic agents on the enzyme nitric oxide synthase (NOS) in brain. METHODS: NOS activity was determined by in vitro conversion of [14C]arginine to [14C]citrulline. Wistar rats were decapitated and cerebellum quickly harvested and homogenized. Brain extracts were then examined for NOS activity in the absence and presence of the volatile anesthetics halothane and isoflurane, and the intravenous agents fentanyl, midazolam, ketamine, and pentobarbital. Dose-response curves of NOS activity versus anesthetic concentration were constructed. Effects of anesthetics on NOS activity were evaluated by analysis of variance. RESULTS: Control activities were 57.5 +/- 4.5 pmol.mg protein-1.min-1 in the volatile anesthetic experiments and 51.5 +/- 6.5 pmol.mg protein-1.min-1 in the intravenous anesthetic experiments. NOS activity was not affected by ketamine (< or = 1 x 10(-4) M), pentobarbital (< or = 5 x 10(-5) M), fentanyl (< or = 1 x 10(-5) M), and midazolam (< or = 1 x 10(-5) M). Halothane decreased NOS activity to 36.7 +/- 2.5 (64% of control, P < 0.01 from control), 23.8 +/- 4.3 (41%, P < 0.01 from control and < 0.05 from 0.5% halothane), 25.2 +/- 3.8 (44%, P < 0.01 from control and < 0.05 from 0.5% halothane), and 19.7 +/- 2.8 (34%, P < 0.01 from control and < 0.05 from 0.5% halothane) pmol.mg protein-1.min-1 at 0.5, 1.0, 2.0, and 3.0% vapor. Isoflurane decreased NOS activity to 48.9 +/- 6.1 (85% of control), 46.0 +/- 3.2 (80%, P < 0.05 from control), 40.3 +/- 5.1 (70%, P < 0.05 from control), and 34.2 +/- 4.0 (60%, P < 0.05 from control and 0.5% and 1.0% isoflurane) pmol.mg protein-1.min-1 at 0.5, 1.0, 1.5, 2.0% vapor, respectively. CONCLUSIONS: Volatile anesthetics inhibit brain NOS activity in an in vitro system, but the intravenous agents examined have no effect at clinically relevant concentrations. This inhibition suggests a protein-anesthetic interaction between halothane, isoflurane, and NOS. In contrast, intravenous agents appear to have no direct effect on NOS activity. Whether intravenous agents alter signal transduction or regulatory pathways that activate NOS is unknown.

Amino Acid Oxidoreductases↗
PubMed1994

Brain nitric oxide synthase activity in normal, hypertensive, and stroke-prone rats.

BACKGROUND AND PURPOSE: Nitric oxide-mediated cerebral vasodilation is altered in spontaneously hypertensive stroke-prone rats. Stroke predisposition in this strain could be related to a genetic defect of brain nitric oxide synthase, the enzyme responsible for nitric oxide production. We tested the hypothesis that brain nitric oxide synthase activity is altered in spontaneously hypertensive stroke-prone rats compared with spontaneously hypertensive or Wistar-Kyoto rats. METHODS: A colony of spontaneously hypertensive stroke-prone rats was bred, in which the rate of neurological events under salt load was assessed. In a separate cohort of animals brain nitric oxide synthase activity was measured in spontaneously hypertensive stroke-prone rats (n = 6) and in spontaneously hypertensive (n = 6) and genetically related Wistar-Kyoto rats (n = 6). Calcium dependency of nitric oxide synthase was also assessed in cortical brain samples from the three rat strains to determine if altered calcium-dependent activation of nitric oxide synthase was present. RESULTS: Brain nitric oxide synthase activity was highest in the cerebellum (eg, spontaneously hypertensive stroke-prone rats: cerebral cortex, 10.6 +/- 0.9; cerebellum, 50.1 +/- 12.0; brain stem, 14.7 +/- 10.3 pmol/mg protein per minute); however, there was no difference among the three rat strains in any region (eg, cerebral cortex: spontaneously hypertensive stroke-prone, 10.6 +/- 0.9; spontaneously hypertensive, 10.8 +/- 0.5; Wistar-Kyoto, 10.9 +/- 0.7 pmol/mg protein per minute) or at any calcium concentration tested. CONCLUSIONS: A genetic defect of brain nitric oxide synthase is unlikely to be the cause of stroke predisposition in spontaneously hypertensive stroke-prone rats.

Amino Acid Oxidoreductases↗
PubMed1994

Probable succinylcholine-induced hyperkalemia in a trauma victim after recent benign anesthetics with succinylcholine.

Throughout its pharmacological history in anesthesia practice, succinylcholine has been notorious for its role in causing life-threatening hyperkalemia. Normally the serum potassium level will increase .5 to 1.0 mEq/L because of a sustained opening of the receptors in the neuromuscular junction and release of myoplasmic potassium. However, in certain patients the drug will result in a much higher level of serum potassium. The literature points out numerous conditions that predispose particular patients to this exaggerated intensification of potassium leakage from within the cell. Traumatized, neuromuscular diseased, infected, exsanguinated, acidotic, and closed head injury patients among this list. This case report describes a trauma patient requiring numerous orthopedic repairs in a relatively short period of time. He received succinylcholine on three separate occasions within a 20-day span without any untoward effects. However, during his sixth surgery and the fourth administration of succinylcholine, he developed ventricular fibrillation requiring defibrillation and cardiopulmonary resuscitation before converting to a sinus tachycardia. After ruling out other causes of the arrhythmia, the most probable one was hyperkalemia. A possible explanation of this probable succinylcholine-induced hyperkalemia may have been a combination of the trauma, tissue wasting, infection, immobility, or acute respiratory acidosis. The potassium elevation was treated successfully with hyperventilation, calcium chloride, sodium bicarbonate, glucose, and insulin. The patient recovered without complications and was later discharged to home. Succinylcholine definitely has its use in anesthesia, but it is imperative for the provider to be discriminatory in its administration. An all-encompassing history is paramount to discover any hidden rationale not to use succinylcholine.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Epidural analgesia in the management of severe vaso-occlusive sickle cell crisis.

OBJECTIVES: To determine whether continuous epidural analgesia could effectively decrease pain and thereby improve the management of severe vaso-occlusive crisis in children with sickle cell disease who were unresponsive to conventional analgesic therapy. DESIGN: Retrospective observational study. SETTING: A tertiary care hospital with a large pediatric sickle cell patient referral population. PATIENTS: The study describes nine children in 11 painful vaso-occlusive crises, unresponsive to high-dose systemic opioids, nonsteroidal anti-inflammatory drugs, and adjunctive measures, who underwent continuous epidural analgesia to control pain. OUTCOME MEASURES: Subjective pain scores, arterial oxygen saturation monitoring, and plasma lidocaine levels. METHODS: Placement of an epidural catheter for the administration of a continuous infusion of local anesthetic, alone, or in combination with fentanyl, in the management of vaso-occlusive crisis. RESULTS: An initiation of epidural analgesic therapy, 8 of 9 patients reported severe pain (8 to 10 on a scale of 0 to 10, 0 = no pain, 10 = the worst pain they ever experienced). Analgesic was immediate (pain score 0 to 2) in 8 of 9 patients, and continuously effective in 9 of 11 crises. Five patients required either the addition of fentanyl or changing the local anesthetic from lidocaine to bupivacaine to maintain analgesia for 2 to 5 days. In 7 of 9 patients, oxygen saturation dramatically increased from 87 to 95% to 99 to 100% after epidural analgesia was initiated. In all patients, plasma lidocaine levels ranged from 1.1 to 4.6 mg/L and dose-related toxicity did not occur. One patient developed hypotension secondary to high sympathetic blockade (T-4), one had an inadvertent dural puncture during insertion of the catheter, one had the epidural catheter removed for fever, and one achieved analgesia only transiently. There were no other complications, and epidural analgesia was not associated with sedation, respiratory depression, or limitation of movement. All epidural catheters were cultured on removal, and colonization did not occur. CONCLUSIONS: Epidural analgesia with local anesthetics administered alone or in combination with fentanyl effectively and safely treats the pain of sickle cell vaso-occlusive crisis unresponsive to conventional pain management and does so without causing sedation, respiratory depression, or significant limitation on ambulation. Furthermore, early treatment of painful crisis with this technique may improve oxygenation, a critical factor in the evolution of further sickling.

Analgesia, Epidural↗
PubMed1994

Basal forebrain lesions in monkeys disrupt attention but not learning and memory.

Cognitive impairments in humans and animals have been linked to dysfunction of neurons in the basal forebrain cholinergic system (BFCS). Degeneration of these cells may be, in part, responsible for some of the cognitive deficits observed in Alzheimer's disease (AD). Although memory deficits are associated with lesions of the BFCS in rats, impairments in memory have been more subtle following similar lesions in monkeys. To evaluate the effects of BFCS lesions on cognitive processes in monkeys, we have systematically investigated the behavioral effects of ibotenic acid injections in the medial septum, nucleus of the diagonal band of Broca, and nucleus basalis of Meynert in cynomolgus monkeys, using a large series of cognitive tasks that examined different mnemonic and attentional abilities. These lesions did not impair accuracy in delayed nonmatching-to-sample, delayed response, simple or concurrent visual discriminations, spatial discriminations, or discrimination reversals. However, these lesions disrupted attentional focusing. Similar impairments in attention have been noted in patients with AD. BFCS lesions increased sensitivity to injections of the cholinergic antagonist scopolamine in a delayed nonmatching-to-sample task, indicating that the central cholinergic system was compromised in these monkeys. In concert, the results of this study suggest that the primate basal forebrain may be more involved in attentional than mnemonic processes, and that degeneration of neurons in the BFCS in cases of AD may contribute to the attention deficits observed in these individuals.

Animals↗
PubMed1993

Nitric oxide as a regulator of adrenal blood flow.

To determine whether nitric oxide (NO) is involved in adrenal medullary vasodilation during splanchnic nerve stimulation (NS)-induced catecholamine secretion, blood flow (Q) and secretory responses were measured in pentobarbital-anesthetized dogs before and after administration of the NO synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME). L-NAME (40 mg/kg iv over 5 min, followed by 40 mg.kg-1.h-1) reduced NO synthase activity of medullary and cortical homogenates from 5.2 +/- 0.3 to 0.7 +/- 0.1 pmol.min-1.mg protein-1 and from 1.2 +/- 0.2 pmol.min-1.mg protein-1 to undetectable levels, respectively. L-NAME reduced resting medullary and cortical Q by 42 and 60%, respectively. NS before L-NAME increased medullary Q from 181 +/- 16 to 937 +/- 159 ml.min-1.100 g-1 and epinephrine secretion from 1.9 +/- 0.8 to 781 +/- 331 ng/min. NS after L-NAME had no effect on medullary Q (103 +/- 14 vs. 188 +/- 34 ml.min-1.100 g-1), while epinephrine secretion increased to the same extent as in control animals (1.9 +/- 0.7 vs. 576 +/- 250 ng/min). L-NAME also unmasked NS-induced cortical vasoconstriction; cortical Q decreased from 96 +/- 8 to 50 +/- 5 ml.min-1.100 g-1. Administration of hexamethonium (30 mg/kg iv), a nicotinic receptor antagonist, reduced NS-induced epinephrine secretion by 90%. These data suggest independent neural control of medullary Q and catecholamine secretion, the former by NO and the latter by acetylcholine.

Adrenal Glands↗