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Biomedical subjects

I L Crawford

Publications and source records attributed to I L Crawford.

At least 19 recordsLinked to original sources
PubMed1999

Kindled seizures activate both branches of the autonomic nervous system.

Amygdaloid kindled seizures in the rat induce an abrupt elevation of blood pressure accompanied by a significant decrease in heart rate. The autonomic pharmacology of this response was examined in unanesthetized kindled rats. Muscarinic receptor blockade with atropine (1 mg/kg, intravenous (i.v.)) abolished the seizure-induced bradycardia. The seizure-induced hypertension was unaffected by beta-adrenergic blockade with timolol (1 mg/kg, i.v.), but was reduced by phentolamine (5 mg/kg, subcutaneous (s.c.)), an alpha-adrenergic receptor antagonist. A chemical sympathectomy was induced with 6-hydroxydopamine (100 mg/kg, i.v.), an agent that does not cross the blood-brain barrier. This eliminated the pressor response but did not completely block the seizure-induced bradycardia. The effectiveness of 6-hydroxydopamine was tested with tyramine (0.5 mg/kg, i.v.) an agent that releases endogenous catecholamines. These results indicate amygdaloid kindled seizures activate both branches of the autonomic nervous system. The bradycardia was mediated by the parasympathetic system; the pressor response was caused by an increase in peripheral resistance due to alpha-adrenergic receptor activation. More important, these findings show that kindling is a useful seizure model for future studies on the effect of seizures on cardiovascular function and possible mechanisms of seizure-related sudden unexplained death.

Adrenergic alpha-Antagonists↗
PubMed1988

Zinc deficiency conditions food aversions in rats.

Zinc (Zn) deficiency is shown to condition aversion to the Zn-deficient diet. After development of a Zn deficiency syndrome during which consumption of the deficient diet decreased, rats readily consumed a familiar Zn-normal diet. After Zn repletion, the previously deficient animals continued to avoid the Zn-deficient diet. These results would not be predicted by the competing hypothesis that Zn-deficiency is anorexigenic.

Animals↗
PubMed1988

Effect of GABA on basal and vagally mediated gastric acid secretion and hormone release in dogs.

To stimulate peripheral gamma-aminobutyric acid (GABA) receptors, GABA, which does not cross the blood-brain barrier, was administered to dogs with vagally innervated gastric fistulas at intravenous doses of 0, 0.66, 2, 6, 18, and 54 micrograms.kg-1.min-1. Mean gastric acid output increased from zero basally to 3.0 +/- 1.4 mmol/h during infusion of 54 micrograms.kg-1.min-1 GABA. Plasma somatostatin-like immunoreactivity decreased significantly below basal levels during infusion of 54 micrograms.kg-1.min-1 GABA (P less than 0.05). To stimulate central nervous system GABA receptors as well as peripheral GABA receptors, progabide, a GABA-receptor agonist, which readily crosses the blood-brain barrier, was injected intravenously. Mean acid output was 3.5 +/- 1.3 mmol/h after 20 mg/kg progabide and 0.6 +/- 0.5 mmol/h after its vehicle (P less than 0.05). Basal serum gastrin concentration increased significantly after progabide injection. Acid output during insulin-induced hypoglycemia was inhibited 59% by 30 mg/kg intravenous progabide. Progabide infusion also diminished or abolished circulating gastrin, somatostatin, and pancreatic polypeptide responses during insulin-induced hypoglycemia (P less than 0.05). Further studies were performed in dogs with a gastric fistula and a vagally denervated Heidenhain pouch to confirm that GABA-receptor stimulation affects acid secretion via peripheral pathways. Intravenous injection of baclofen (0.5 mg/kg), a GABAB-receptor agonist, increased acid secretion significantly from the gastric fistula and the Heidenhain pouch. These studies suggest that GABA may play a role in regulating gastric acid secretion and gastrointestinal and pancreatic endocrine function by both central and peripheral mechanisms.

Animals↗
PubMed1985

Elevated copper and lowered zinc in the placentae of pre-eclamptics.

Selected cations (Ca, Co, Cu, Mg, Zn, Si, and K) were determined in the placentae of 18 women. Between pre-eclamptic and normal subjects there were significant (p less than 0.05) differences in copper and zinc concentrations and borderline significant differences in cobalt concentration. In the placentae of the ten women with a normal pregnancy, the average concentrations of copper and zinc were 53 and 192 micrograms atoms/kg placenta, respectively. In the placentae of 8 women with pre-eclampsia, the concentrations were 124 and 134 micrograms atoms/kg placenta for copper and zinc, respectively. Elevation of copper and decrease in zinc may be an exaggeration of normal pregnancy physiology that occurs in pre-eclampsia.

Adolescent↗
PubMed1985

Interruption of cholinergic afferent pathways to the amygdala failed to alter electrical kindling.

We investigated the hypothesis that the cholinergic system is involved in the process of amygdala kindling. Electrical kindling of the amygdala was associated with an increase in the concentration of acetylcholine in the kindled amygdala and the ipsilateral hippocampus but was not associated with any alteration of choline acetyltransferase activity. Destruction of cholinergic neurons in the lateral preoptic area significantly decreased the activity of choline acetylase in the ipsilateral amygdala, but had no effect on the duration of time to kindling. We interpret these findings as indicating that the cholinergic system is affected by the kindling process, but does not seem to be crucial to the phenomenon.

Acetylcholine↗
PubMed1985

Enhanced acetylcholinesterase staining in hippocampal area CA3 after lesion of granule cells by infusion of colchicine.

Unilateral infusion of colchicine into the lateral ventricle produced relatively selective destruction of dentate granule cells in the ipsilateral dorsal hippocampal formation of the rat. Timms silver sulfide stain is markedly reduced in the mossy fiber layer on the colchicine treated side but is normal contralaterally. After colchicine treatment, an increase in acetylcholinesterase staining is apparent in the apical dendritic zone of CA3 pyramidal cells. This enhanced staining is localized in the proximal apical dendritic layer of CA3, a region normally occupied by the mossy fiber terminals of dentate granule cells. These results suggest that cholinergic fibers proliferate in CA3 after granule cell lesion and may participate in reinnervation of the denervated area.

Acetylcholinesterase↗
PubMed1984

GABAergic agents in the medial septal nucleus affect hippocampal theta rhythm and acetylcholine utilization.

Neurons of the medial septal nucleus are important in regulating the physiological activity of the hippocampus. If intraseptal injection of putative neurotransmitter substances affects the turnover rate of hippocampal acetylcholine, then concomitant changes would be expected in the electrophysiologic activity of the hippocampus. A GABA agonist, muscimol, was injected into the medial septum of rats and the effects on hippocampal electrical activity and acetylcholine utilization were studied. The intraseptally injected muscimol (100 ng) resulted in hippocampal electrographic records containing low amplitude asynchronous waves and significantly less rhythmic slow activity (RSA, 6-9 Hz), compared to control injections of saline. This effect was antagonized by prior intraseptal injection of bicuculline (3 micrograms). The hippocampal electrical activity returned to normal within 100 min. The utilization of acetylcholine was significantly reduced by intraseptal muscimol at times after administration when electrographic activity was also altered, and spontaneous behavioral movement was increased. These results suggest a physiological connection between hippocampal RSA generation and GABAergic mechanisms in the septum.

Acetylcholine↗
PubMed1984

Lorazepam: a controlled trial in patients with intractable partial complex seizures.

Lorazepam was studied in a double-blind, placebo-controlled, crossover trial in eight patients with frequent partial complex seizures refractory to therapy with a combination of standard anticonvulsant drugs. Concomitant antiepileptic drugs were maintained at therapeutic serum levels throughout the study, and concentrations of lorazepam were monitored. Following an 8-week baseline observation, patients were randomly assigned to placebo or lorazepam (1 mg BID). The dose was increased biweekly until seizures stopped or unacceptable side effects occurred. Eight weeks later, patients were crossed over, and the same escalating dose paradigm was followed. When seizure frequency during the last 2 weeks of each treatment was compared, seven of eight patients had fewer seizures on lorazepam, and the eighth had decreased seizure duration (a significant difference: p less than 0.01, two-tailed sign test). Blood level data suggest a narrow therapeutic window, with seizure improvement occurring at concentrations of 20-30 ng/ml and side effects at greater than 33 ng/ml. Lorazepam appears to be a useful adjunct in refractory partial complex seizure therapy. It should not be stopped abruptly, as an increase in seizure frequency may result.

Adult↗
PubMed1983

ATP-citrate lyase and other enzymes of acetyl-CoA metabolism in fractions of small and large synaptosomes from rat brain hippocampus and cerebellum.

The activities of choline acetyltransferase and ATP-citrate lyase were significantly correlated (r = 0.995) in fractions of small and large synaptosomes isolated from rat hippocampus and cerebellum. The activities of these two enzymes did not correlate with those of pyruvate dehydrogenase, carnitine acetyltransferase, citrate synthase, acetyl-CoA synthetase, lactate dehydrogenase, or with the rate of high-affinity glutamate uptake in the synaptosomal fractions. The results provide additional evidence linking ATP-citrate lyase to the cholinergic system in the brain.

ATP Citrate (pro-S)-Lyase↗
PubMed1982

Effects of septal lesions on enzymes of acetyl-CoA metabolism in the cholinergic system of the rat hippocampus.

Electrolytic lesions made in the medial septum of the rat brain caused an 80% decrease in the activity of choline acetyltransferase and a 33% reduction in ATP-citrate lyase activity in the synaptosomal fraction from the hippocampus. Decreases in the activities of the two enzymes in the cytosol (S3) fraction were 70 and 13%, respectively. The activities of pyruvate dehydrogenase, citrate synthase, acetyl-CoA synthase, and carnitine acetyltransferase in crude hippocampal homogenates and in subcellular fractions were not affected by septal lesions. The data indicate that ATP-citrate lyase is linked to the septal-hippocampal pathway and that the enzyme is preferentially located in cholinergic nerve endings that terminate within the hippocampus.

ATP Citrate (pro-S)-Lyase↗
PubMed1981

Neurophysiology and neuropharmacology of cardiovascular regulation and stress.

Evidence has accumulated over the past several years indicating that environmental factors can have a substantial influence on cardiovascular dynamics. It has been hypothesized by many investigators that through these influence environmental stressors may be important to the etiology and maintenance of cardiovascular diseases. Since the nervous system is intimately involved in the regulation of cardiovascular function it may be assumed that environmental influences on cardiovascular dynamics are to a large extent mediated by the nervous system. This assumption is supported by the literature reviewed which indicates that there are many nervous system nuclei and neurotransmitter systems involved in the regulation of cardiovascular dynamics which are also involved in an organisms adjustment to environmental stressors. The conclusion is reached that further multidisciplinary research will reveal underlying neurophysiological and neuropharmacological mechanisms responsible for stress induced cardiovascular disease and lead to new methods of treatment.

Animals↗
PubMed1981

Cyclic nucleotides in the amygdala of the kindled rat.

The basolateral amygdala of rats was stimulated once daily until three successive fully kindled seizures were elicited. Twenty-four hours after the last seizure the rats were sacrificed by focused microwave irradiation to the head. Tissues from homolateral and contralateral amygdala and cerebral cortex were assayed for cAMP and cGMP content. No significant changes in cyclic nucleotides were measured in the kindled animals. These studies indicate that long term changes in the steady-state level of total tissue cyclic nucleotides do not occur concomitant with the persistently altered excitability associated with kindling of the amygdala.

Amygdala↗
PubMed1979

Lorazepam in status epilepticus.

Lorazepam, a dichloro-3-hydroxy-1,4-benzodiazepine, has been shown to be a potent anticonvulsant in animal models of epilsepsy and has minimal depressant effects on respiration and circulation in humans. The effects of this compound were studied in status epilepticus. Twenty-five patients were given intravenous lorazepam during status epilepticus of varying cause. Four or 8 mg of the drug controlled status in 22 of the 25 patients. Although single seizures recurred in 5 of the 22 patients, none experienced recurrence of status during a prolonged follow-up period. Transient respiratory arrest occurred in 1 patient, but no other significant complications were observed. Studies of plasma drug levels suggest that most patients attain good seizure control at concentrations between 30 and 100 ng per milliliter. Clinical observations indicate that repetitive injections are not required for continuing control of seizures in patients whose seizures are initially controlled. Lorazepam appears to be an effective and safe drug for treatment of status epilepticus, with a duration of control longer than that achieved with diazepam.

Adolescent↗
PubMed1979

Effects of central administation of probenecid on fevers produced by leukocytic pyrogen and PGE2 in the rabbit.

1. Single intracerebroventricular (I.C.V.) injections of probenecid (PBCD, 0.125--0.5 mg) enhanced and prolonged fever caused by I.V. administration of leukocytic pyrogen (LP) in rabbits resting in neutral (23 degrees C), cold (10 degrees C) and hot (30 degrees C) environments. Similar effects were produced by single I.C.V. injections of PBCD given before PGE2 (0.5 microgram) was injected I.C.V. in the three ambient temperatures. 2. Fever produced by IV. LP was also prolonged by infusion and by multiple injections of PBCD. 3. PBCD given I.P. (100 mg/kg) enhanced and prolonged fever caused by I.V. injection of Salmonella typhosa endotoxin. 4. Hyperthermia produced by I.C.V. PGE2 was not augmented by subsequent PBCD infusion. However, pre-treatment with PBCD followed by PGE2 injection and PBCD infusion caused hyperthermia that was very high and prolonged, and, in some cases, lethal. 5. Acetaminophen (2 mg, I.C.V.) and indomethacin (10 mg/kg, I.V.) lowered body temperature when given during fever induced by LP and prolonged by PBCD infusion. 6. The concentration of PGE in cerebrospinal fluid (c.s.f.) samples taken from the third or lateral ventricles rose or stabilized during PBCD infusions made during LP fever. However, similar changes in PGE concentration also occurred during control infusions when body temperature was low. 7. We conclude that termination of the actions of both central endogenous pyrogen and centrally administered PGE2, and the subsequent reduction of fevers produced by them, require a PBCD-sensitive facilitated transport system. The reduction of PBCD-prolonged PL fevers by antipyretics which block PGE synthesis suggests that prolongation by PBCD of LP fever is not due to blockade of PGE transport in a subsequent step in fever mediation per se, but is due to inhibition of transport of LP itself, or of other mediators associated with it.

Animals↗
PubMed1976

Effects of subfornical organ extracts of salt-water balance in the rat.

The subfornical organ (SFO) is regarded as a neurosecretory structure but no information is available on the nature or biological effects of the secretory products(s). Supernatants of water homogenates of rat SFO were lyophilized and reconsittuted in artificial cerebrospinal fluid (CSF). Intracerebroventricular (IVT), but not subcutaneous, administration of this material to rats produced diuresis, natriuresis and kaliuresis in the following 8 h daylight period. During the overnight cycle, consummatory behavior and excretion of sodium and potassium were reduced. Similar responses were obtained after IVT administration of cerebellar cortex (CB) or large amounts of plasma. SFO, CB and cerebral cortex (CC) were incubated in potassium-enriched CSF to enhance release of secretory products. Urine volume was increased 8 h after IVT injection of SFO media; in the overnight cycle, food consumption, absolute urinary sodium and potassium, and [Na+-a1 were reduced. These effects were not produced by IVT injection of CC or CB media, or equal amounts of plasma proteins. Additional experiments demonstrated that choroid plexi and SFO effects were similar and that the active SFO material was dialyzable and thermal stable. These data suggest that SFO contains a water-soluble substance which is released into a posassium-enriched medium. The material is heat stable, has a relatively low molecular weight, and alters salt-water balance after injection into ventricular cerebrospinal fluid.

Animals↗
PubMed1975

Permeability changes in the blood-brain barrier: causes and consequences.

1. Generalized changes in blood-brain barrier (BBB) permeability are accompanied by extravasation of plasma proteins; thus, they are readily studied with protein markers or protein-dye complexes. Selective changes in permeability involve alterations in BBB transport systems; they are best studied with techniques which detect the qualitative hallmarks of carrier-mediated transport, namely saturation, competition, and stereospecificity. 2. Quantitative assessments of the selective permeability of the BBB can be made from the saturation data expressed in terms of Michaelis-Menten kinetics. The advantages of the latter are twofold: (a) alterations elicited by modified barrier affinity (Km) can be distinguished from alterations in carrier capacity (Vmax); (b) the relative rates of flux of a metabolite across the BBB can be placed in the perspective of cerebral metabolism. Kinetic data on transport processes in the BBB are obtained by either constant infusion or single injection techniques. Results obtained with both methodologies have been comparable. 3. Independent transport systems for glucose, neutral amino acids, basic amino acids, and monocarboxylic acids have been identified in the BBB. The description of these transport systems in kinetic terms provides a background of information on intact mechanisms to which altered transport can be compared. 4. Experimental evidence indicates that the availability of key metabolic substrates, such as glucose or essential amino acids, may be rate-limiting in cerebral metabolism. A working hypothesis was developed that the consequences of a selective change in barrier permeability to one or more of these essential substrates are directly related to altered rates of reaction in substrate-limited pathways, e.g., cerebral protein or neuro-transmitter biosynthesis. 5. Toxicological causes of generalized changes in BBB permeability include hypertonic solutions, organic solvents, surface-active agents, enzymes, and heavy metals. Some agents, e.g., mercury or hypertonic urea, induce selective changes in BBB transport at doses much lower than those required for nonspecific barrier break-down. Subtle changes in transport of metabolic substrates may remain unrecognized unless specifically investigated, yet may have profound consequences on brain metabolism. 6. Pathological processes can also induce selective changes in BBB permeability. Such changes often temporally precede the more generalized alterations in permeability that can occur during pathogenesis. For example, in brain edema due to an ischemic infarct, glucose transport increases during the early cytotoxic phase, whereas generalized changes are not detected until the later vasogenic phase.

Amines↗