Allosteric actions of central nervous system depressants including anesthetics on subtypes of the inhibitory gamma-aminobutyric acidA receptor-chloride channel complex.
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Anesthetics↗
Biomedical subjects
D M Turner
Publications and source records attributed to D M Turner.
The benzodiazepine/alcohol antagonist Ro 15-4513: binding to a GABAA receptor subtype that is insensitive to diazepam.
The imidazobenzodiazepinone Ro 15-4513 has been shown previously to bind to central benzodiazepine receptors as well as to a second, uncharacterized class of sites that do not bind diazepam, differentiating them from the normal benzodiazepine-binding site on the gamma-aminobutyric acid (GABA)-A (GABAA) receptor. This study describes the characterization of these unique diazepam-insensitive (DZ-IS) sites. Ro 15-4513 binding to DZ-IS sites was abundant in cerebellum from cow, rat and human and detectable in cortex, hippocampus and striatum by autoradiography on rat brain sections. These sites represented approximately 20% of the total binding in bovine cerebellar membranes, but only 2 to 3% of the total in cortex. Ro 15-4513 binds with the same affinity (Kd approximately 4.5 nM) to both diazepam-sensitive and DZ-IS sites in the cerebellum. A number of compounds which bind to the classical benzodiazepine receptors also bind to the DZ-IS sites. These compounds include: the pyrazoloquinoline CGS 8216, the beta-carbolines methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate, ZK 95962, ZK 94326 and ZK 93126, as well as the classical benzodiazepine receptor antagonist, Ro 15-1788. Besides binding diazepam poorly, the DZ-IS sites demonstrate a very low affinity for other benzodiazepines. Ligands which bind to the various drug receptor sites on the GABA receptor complex do not directly modulate the binding of Ro 15-4513 to DZ-IS sites nor does ethanol. However, antagonism of Ro 15-4513 binding to the DZ-IS sites by methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate and by CGS 8216 is modulated by the presence of GABA.(ABSTRACT TRUNCATED AT 250 WORDS)
Allosteric Regulation↗
Potency of rapidly acting barbiturates in dogs, using inhibition of the laryngeal reflex as the end point.
Thiopental, thiamylal, and methohexital were administered to 30 dogs to determine equipotent doses necessary to inhibit laryngeal reflexes. The doses studied were 7.1, 10.0, 14.1, 20.0, and 28.3 mg of thiopental/kg of body weight; 5.7, 8.0, 11.3, 16.0, and 22.6 mg of thiamylal/kg; and 3.5, 5.0, 7.1, 10.0, and 14.1 mg of methohexital/kg. At 1, 2.5, 5, and 10 minutes after injection, the presence or absence of the laryngoscopic reflex, pedal reflex, and jaw tone were recorded. The times for return of each reflex, as well as the ability to walk 10 steps without assistance, were also recorded. Using the method of least squares, a probit analysis was performed on the quantal responses at 1 minute. The effective dose in 50% of the population for the laryngoscopic reflex was chosen as the end point for intubation, and the computed doses necessary to achieve this end point were 19.4 mg of thiopental/kg, 18.4 mg of thiamylal/kg, and 9.7 mg of methohexital/kg. When potencies of the drugs were compared with that of thiopental (1), thiamylal was found to be equipotent (1.06) and methohexital twice as potent (2.0). At the accepted clinical dose, recovery times for thiopental (71.1 +/- 7.2 minutes) and thiamylal (75.3 +/- 7.7 minutes) were similar, and twice that for methohexital (33.9 +/- 4.6 minutes).
Animals↗
Cardiovascular and respiratory effects of three rapidly acting barbiturates in dogs.
The cardiovascular and respiratory effects of 3 rapidly acting barbiturates, thiopental sodium, thiamylal sodium, and methohexital sodium, were studied in dogs from completion of injection until 12.5 minutes after injection. The doses administered were 19.4 mg of thiopental/kg of body weight, 18.4 mg of thiamylal/kg, and 9.7 mg of methohexital/kg, which were chosen as equipotent doses necessary to inhibit the laryngoscopic reflex in 50% of the population. To determine the cardiovascular and respiratory effects for each drug, the values at each measurement time following injection were compared with baseline values (T0). At the 15- and 30-second measurement times following thiopental administration, stroke volume (SV) decreased; heart rate (HR), left atrial pressure, and mean pulmonary arterial pressure increased; and cardiac index (CI), myocardial contractility, and systemic and pulmonary vascular resistances were not different from baseline values. Mean arterial pressure (MAP) was not different from the baseline value at 15 seconds, but was increased from 30 seconds to 2 minutes. All values except HR had returned to baseline values by 7.5 minutes. At all measurement times, arterial oxygen tension and arterial pH were decreased, and arterial carbon dioxide tension increased from baseline values. Although the cardiovascular and respiratory changes following administration of thiamylal and methohexital were similar to those described for thiopental, some differences were found. Following thiamylal administration, systemic vascular resistance increased at 1 minute, pulmonary vascular resistance increased at 1 and 2 minutes, and myocardial contractility increased at 1 and 2 minutes. Following methohexital administration, MAP decreased at 15 seconds, and SV decreased at all measurement times.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Keratin gene expression during the resolution of psoriatic plaques: effect of dithranol, PUVA, etretinate and hydroxyurea regimens.
Quantitative changes in the levels of keratin polypeptides extracted from keratotome shavings from psoriatic epidermis were measured by using one-dimensional SDS-PAGE, followed by scanning densitometry. Values obtained were compared with results for non-lesional epidermis and from epidermis from normal individuals. Patients on four different treatment regimens were investigated by repeated sampling over 3-4 months starting before therapy commenced. The levels of four keratins changed significantly: keratins I (70 kd) and 2 (66 kd) tended to rise to normal levels, while keratins 16 (50 kd) and 18 (44 kd) fell to normal levels. There were differential effects as well as differences in the rates of normalization depending upon the treatment regimen. The most rapid normalization of the levels of all four keratins was observed with topical dithranol (anthralin) treatment (five patients) with plaque resolution and keratin level normalization after 7-9 weeks. Oral hydroxyurea (three patients) had similar effects, but over a longer time scale (20 weeks). In contrast, oral etretinate (four patients) caused a normalization of all except keratin 2 (66 kd) over a period of 20-28 weeks, and keratin I (70 kd) levels tended to 'overshoot' the normal level. PUVA (five patients) caused rapid normalization (in 9-12 weeks) of keratins 2 (66 kd) and 18 (44 kd), but had much weaker effects on keratins I (70 kd) and 10 (57 kd). These results suggest that resolution of lesions as judged by clinical criteria can occur without normalization of the keratin electrophoretic profile. Possibly the most reliable marker of clinical resolution was the reduction in keratin 16 (50 kd), since treatment effects on the differentiation of keratins I (70 kd) and 2 (66 kd) were different.
Anthralin↗
Steroid anesthetics and naturally occurring analogs modulate the gamma-aminobutyric acid receptor complex at a site distinct from barbiturates.
The steroid anesthetic alphaxalone and a series of naturally occurring analogs were compared in potency and efficacy with each other and the hypnotic barbiturate pentobarbital for interaction with gamma-aminobutyric acid (GABA) receptors:binding sites in rat brain membranes and functional activity in 36Cl- flux measurements with rat hippocampal slices. The steroids enhanced [3H]muscimol binding to GABA receptor sites, enhanced [3H] flunitrazepam binding to benzodiazepine receptors and inhibited [35S]t-butyl bicyclophosphorothionate binding to picrotoxin/convulsant binding sites on the GABA receptor-chloride channel complex. The same steroids that were active in modulating the binding of ligands to the various receptor sites on the GABA receptor complex at micromolar concentrations enhanced muscimol-stimulated 36Cl- flux in rat hippocampal slices. The steroids, like the barbiturates, increased the maximal response to muscimol but produced little or no potentiation of basal 36Cl- flux in the absence of GABA agonist. Although the effects of steroids and barbiturates were similar, separate sites of action were demonstrated conclusively by the observation that the two classes of compounds, when included together, gave additive or synergistic effects on binding, as well as on 36Cl- flux in the absence of GABA agonist. Structure-activity studies showed that the synthetic steroid anesthetic alphaxalone was the most potent compound tested, followed by the naturally occurring steroids tetrahydro-deoxycorticosterone, allo-tetrahydrocorticosterone, cis-androsterone and 5 alpha-androstan-17 beta-ol-3-one. The ability of several naturally occurring steroids to enhance GABA-mediated inhibition in the brain suggests the possibility of an endogenous steroid modulator of neuronal function.
Anesthetics↗
The faculty fellowship program: uniting service and education.
The outcomes of the pilot year for this project met the goals of increased faculty clinical skills, increased nursing personnel at the unit level and the completion of specified projects based on identified clinical needs. Continued development of the Faculty Fellowship Program will yield further opportunity to study benefits, such as increased student performance in the acute care setting, increased recruitment of graduate nurses and improved integration of nursing education and service in addressing health care issues.
Fellowships and Scholarships↗
Infestation in the dog by the paralysis tick, Ixodes holocyclus. 4. Cardiovascular effects.
To determine the extent and significance of changes in heart rate and rhythm noticed previously in dogs paralysed with Ixodes holocyclus, two studies were undertaken. In one the electrocardiogram was recorded at stages throughout the disease and the traces analysed for changes, while in the second a detailed study of the effect of Ixodes holocyclus on the cardiovascular system was undertaken. The electrocardiographic changes were extremely variable between stages and between dogs. Generally, if a dysrhythmia occurred in stages 1, 2 or 3 it tended to be sinus tachycardia, ventricular tachycardia or sinus arrest. In stage 4 sinus arrest, sinus bradycardia, or sinus or ventricular tachycardia were the prominent dysrhythmias, whereas in stage 5 sinus bradycardia predominated. Cardiovascular measurements indicated an increase in peripheral vascular resistance leading to a significant elevation in mean arterial pressure at all stages of the disease. Cardiac output was decreased significantly only at stage 2, although it was below the control measurements at all stages. Pulmonary arterial pressure was significantly elevated at stages 2, 3 and 4 due most probably to an increase in pulmonary vascular resistance. Myocardial contractility was not significantly changed throughout the disease. The changes observed in the electrocardiogram and the cardiovascular system in stages 1, 2 and 3 are unlikely to be due to hypoxia and could represent dysfunction of the autonomic nervous system. During stages 4 and 5 oxygen levels were below normal and the bradycardia seen terminally is almost certainly due to hypoxaemia.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Infestation in the dog by the paralysis tick, Ixodes holocyclus. 5. Treatment.
In this study the value of drugs administered with hyperimmune serum in the treatment of advanced disease produced by Ixodes holocyclus was compared under controlled conditions. All control dogs died rapidly whereas one dog survived and 3 dogs died after receiving hyperimmune serum alone. When promethazine hydrochloride was administered with hyperimmune serum 2 dogs recovered rapidly while the remaining 2 died. Administration of dexamethasone and hyperimmune serum allowed 3 dogs to survive while administration of phenoxybenzamine hydrochloride in conjunction with hyperimmune serum allowed rapid recovery of all 4 dogs. Phenoxybenzamine hydrochloride, an alpha-adrenergic blocking drug, was chosen because of its potential to attenuate the arterial hypertension previously reported (Ilkiw et al 1988). The survival of all dogs together with the rapid return to normality indicated that this drug was beneficial in the treatment of dogs with advanced signs of tick paralysis.
Animals↗
Enhanced ability of skeletal muscle containing cyclocreatine phosphate to sustain ATP levels during ischemia following beta-adrenergic stimulation.
Breast muscle of young chicks fed chow diets containing the creatine analog 1-carboxymethyl-2-iminoimidazolidine (cyclocreatine) accumulated up to 40 mumol/g wet weight of the synthetic phosphagen 1-carboxymethyl-2-imino-3-phosphonoimidazolidine (cyclocreatine-P2-). ATP levels were sustained at high values substantially longer in breast muscle of cyclocreatine-fed chicks, compared to control-fed chicks, during total ischemia initiated 2 h after injection of both groups with the beta-adrenergic agonist isoproterenol (5 mg/kg subcutaneous). For example, in chicks fed 0.5% cyclocreatine for 10-19 days ATP levels in isoproterenol-stimulated breast muscles after 1 h of ischemia at 37 degrees C were 6.1 mumol/g, compared to 1.9 mumol/g for the control-fed group, and after 2 h of ischemia were 3.5 mumol/g compared to 0.6 mumol/g for controls. Creatine-P reserves in isoproterenol-stimulated breast muscles of all dietary groups were essentially exhausted within the first hour of ischemia. In contrast, breast muscle of chicks fed either 1 or 0.5% cyclocreatine still contained 28 and 19 mumol/g of cyclocreatine-P, respectively, after 1 h of ischemia; after 2 h of ischemia, the respective cyclocreatine-P values were 20 and 13 mumol/g. Isoproterenol-stimulated chick breast muscle provides the first skeletal muscle model system for studying the molecular mechanisms by which dietary cyclocreatine helps sustain ATP levels during ischemia. Although adaptive factors are also involved, it is suggested that a significant portion of the ATP-sustaining activity of dietary cyclocreatine in ischemic breast muscle can be attributed to the unique thermodynamic properties of the accumulated cyclocreatine-P. These properties enable cyclocreatine-P to continue to thermodynamically buffer the adenylate system and transport high energy phosphate throughout the long muscle fibers at cytosolic pH values and phosphorylation potentials well below the range where the creatine-P system can function effectively. Synergism between glycolysis and this long-acting synthetic phosphagen might well help delay depletion of ATP levels in skeletal muscles during ischemia. Cyclocreatine feeding provides a unique experimental tool for quantitative evaluation of the proposed protective role of ATP against irreversible cellular damage in skeletal and cardiac muscles during ischemic episodes.
Adenosine Triphosphate↗
Infestation in the dog by the paralysis tick Ixodes holocyclus. 1. Clinical and histological findings.
Under laboratory conditions 8 dogs were infested with Ixodes holocyclus and the clinical signs and histological findings were recorded. Seven of the dogs developed clinical signs of the disease, died and were subjected to a post-mortem examination, while the eighth dog remained normal. The clinical signs were consistent between animals and enabled the course of the disease to be subdivided into 5 stages to facilitate analysis of data in future experiments. The most prominent feature of the disease was dysfunction of the efferent motor system although some disturbance of the afferent pathways and involvement of the autonomic nervous system did occur. The period elapsing between attachment of the ticks and onset of signs varied from 5.5 to 7 days, while the mean duration of the disease was 23.3 h. The histopathology demonstrated moderate to severe congestion of the liver, kidney and lungs, and in some lung sections pulmonary oedema was present.
Animals↗
Infestation in the dog by the paralysis tick Ixodes holocyclus. 2. Blood-gas and pH, haematological and biochemical findings.
Arterial blood-gas and pH, haematological and biochemical estimations were carried out on 8 dogs infested with Ixodes holocyclus and 2 uninfested controls. The arterial blood-gas and pH measurements did not change significantly until the dogs were recumbent and unable to lift their heads. When affected dogs became moribund, moderate hypoxaemia with acute ventilatory failure was present. The significant haematological and biochemical abnormalities were difficult to interpret individually, but taken together could reflect sympathetic stimulation of the adrenal cortex or medulla.
Animals↗
Infestation in the dog by the paralysis tick Ixodes holocyclus. 3. Respiratory effects.
To assess respiratory function in dogs with tick paralysis, respiratory measurements were recorded on 14 dogs experimentally infested with Ixodes holocyclus. There was a progressive fall in respiratory rate with no change in tidal volume, which resulted in a significant fall in minute respiratory volume in the latter stages of the disease. The fall in respiratory rate was possibly central in origin and was accompanied by an increased alveolar-arterial oxygen tension difference, probably caused by pulmonary congestion and oedema. The "grunting" respiration seen in tick paralysis was due to closure of the vocal cords during expiration and could represent an attempt to re-expand collapsed parts of the lung.
Animals↗
Health care's future shock: an update.
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Costs and Cost Analysis↗
Relative abilities of phosphagens with different thermodynamic or kinetic properties to help sustain ATP and total adenylate pools in heart during ischemia.
Hearts of chicks fed the creatine analog, 1-carboxymethyl-2-iminoimidazolidine (cyclocreatine), accumulated 15 mumol/g wet wt of the synthetic phosphagen, cyclocreatine-3-P; had total creatine levels reduced from the normal 6 mumol/g to only 1.8 mumol/g; and had their glycogen levels tripled. During total ischemia in vitro these hearts utilized the cyclocreatine-P for synthesis of ATP, had greatly prolonged glycolysis, and exhibited a two- to fivefold delay in depletion of both ATP and the total adenylate pool, relative to controls. Accumulation from the diet of comparable levels of the closely related 1-carboxyethyl-2-imino-3-phosphonoimidazolidine (homocyclocreatine-P) by heart was accompanied by only slight lowering of total creatine to 4.2 mumol/g, and a tripling of glycogen levels. During ischemia these hearts exhibited prolonged glycolysis, but they did not utilize the very stable homocyclocreatine-P (200,000-fold less reactive than creatine-P) and thus formed less Pi; most significantly, there was no delay in depletion of ATP levels relative to controls. Feeding of creatine doubled total creatine levels in heart, but had no marked effect on ATP depletion during ischemia; in all dietary groups creatine-P pools had fallen to less than or equal to 1.2 mumol/g by first tissue sampling. Although adaptive responses were also involved, maximal conservation of ATP and total adenylate pools in heart during ischemia apparently required, in addition to adequate glycogen reserves, substantial levels of a kinetically competent phosphagen that is thermodynamically poised to continue to assist glycolysis in buffering decreases and oscillations in the [ATP]/[free ADP] ratio at the lower phosphorylation potentials and more acid pH characteristic of later stages of ischemia. Decreases and oscillations in the [ATP]/[free ADP] ratio cannot be buffered effectively late in ischemia by the creatine-P system for thermodynamic reasons, or by the homocyclocreatine-P system because of kinetic limitations.
Adenine Nucleotides↗
Pharmacological action of FPL 55712 on canine cerebral arterial segments.
The pharmacological action of a leukotriene antagonist FPL 55712 was studied on canine cerebral arterial segments. FPL 55712 at concentrations of 10(-6)M and 10)-5)M showed dose-dependent inhibition of the constrictor responses of the artery to prostaglandin F2 alpha. The constrictor responses of the artery to either serotonin or haemoglobin were suppressed by 10(-5)M FPL 55712, while 10(-6)M FPL 55712 failed to alter the responses. The KCL-induced constriction was not affected by treatment with either 10(-6)M or 10(-5)M FPL 55712. The present results suggest that FPL 55712 has vasodilator properties other than those related to the inhibition of leukotrienes.
Animals↗
The 'Turner' circle absorber: an anaesthetic breathing system for the horse.
An inhalation anaesthetic apparatus for the horse is described and the physiological concepts pertaining to its design presented. The internal diameter of all breathing components is 6.2 cm with no change in cross sectional area throughout the circle system. The soda lime capacity is 25 litres (approximately 20 kg). In the horse, which is apparently predisposed to alveolar hypoventilation during inhalation anaesthesia, it is apparent that adequate anaesthetic apparatus design should be directed towards minimising resistance and dead space and providing maximal and efficient carbon dioxide elimination.
Anesthesia, Inhalation↗