Biomedical subjects
A Livingston
Publications and source records attributed to A Livingston.
Hormone-releasing stimuli do not alter Met-enkephalin levels in the rat neurohypophysis.
The levels of met-enkephalin in the rat neurohypophysis were measured by radioimmunoassay in four groups of animals. The groups were a control untreated group, a sham operated group, a group subjected to 1% body weight haemorrhage which is an acute hormone releasing stimulus, and a group subjected to four days 2% saline imbibition which is a chronic hormone releasing stimulus. In none of the groups was the met-enkephalin level significantly different from the control value of 1.90 +/- 0.18 ng/gland (n = 10), suggesting that there was no depletion of met-enkephalin concomitant with the depletion of neurohypophysial hormones in the rat.
Adverse reactions to drugs.
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Reversal of 6-hydroxydopamine-induced hypotension in Long Evans and diabetes insipidus (Brattleboro) rats.
Brattleboro (diabetes insipidus) rats showed a delayed recovery from 6-hydroxydopamine (6-OHDA) hypotension as compared to Long Evans controls. A slight increase in circulating arginine vasopressin was noted in the 6-OHDA-treated Long Evans rats but no change in circulating oxytocin was apparent in either species. The haematocrit and plasma potassium suggested haemodilution in Long Evans rats following 6-OHDA treatment but no such changes were apparent in similarly treated Brattleboro rats. Since the major difference in Long Evans and Brattleboro rats is the latter's inability to synthesize arginine vasopressin (AVP), it is suggested that AVP may have a role in the restoration of homeostasis following 6-OHDA-induced hypotension. This conclusion is supported by (a) a delayed recovery from hypotension and (b) no change in blood concentration parameters, in the Brattleboro rat.
Interactions of drugs active at opiate receptors and drugs active at alpha 2-receptors on various test systems.
1 The actions of the opiate receptor drugs, morphine, methionine-enkephalin (Met-enkephalin) and naloxone were compared with the actions of the alpha 2-receptor drugs, clonidine, xylazine and yohimbine on analgesic tests, in vitro bioassay (guinea-pig ileum and mouse vas deferens), and radioligand displacement studies on rat brain membrane preparations. 2. Both opiate and alpha 2-agonist drugs showed analgesic activity but whilst the alpha 2-agonist analgesic activity was antagonized by only alpha 2-antagonists, the analgesic activity of morphine was antagonized by both naloxone and yohimbine. In the in vitro tests, both groups of agonists inhibited electrically evoked activity; however in these experiments only antagonism of opiates by naloxone and alpha 2-agonists by yohimbine could be shown and it is concluded that in these systems the activity of the alpha 2-agonists is mediated via the presynaptic alpha 2-receptors only. 3 In the radioligand studies the drugs acting at alpha 2-receptors were active in the micromolar range at displacing labelled opioid ligands but opiates did not displace labelled alpha 2-ligands. 4 It is concluded that drugs which act on alpha 2-receptors interfere with the in vivo analgesic effects of opiates and weakly displace opioid radioligand binding, but opioids do not affect alpha 2 agonist analgesia and do not appear to displace alpha 2-agonist radioligand binding.
Opiate-like analgesic activity in general anaesthetics.
1 The interaction of naloxone with various anaesthetics was studied both in vivo and in vitro.2 Naloxone (10 mg/kg) did not significantly alter the anaesthetic duration of halothane, diethylether, ketamine, pentobarbitone or Althesin.3 Naloxone (10 mg/kg) reduced the analgesic activity of nitrous oxide, ketamine and morphine in the rat tail-flick test. With the exception of pentobarbitone and Althesin, the other anaesthetic agents also induced analgesia but were not antagonized by naloxone.4 Specific [(3)H]-dihydromorphine binding was displaced by the opiates naloxone (IC(50) = 7.6 nm), methionine-enkephalin (Met-enkephalin, IC(50) = 40 nm) and morphine (IC(50) = 54 nm). Similarly, displacement was observed with xylazine (IC(50) = 9 mum), ketamine (IC(50) = 130 mum) and Althesin (IC(50) = 150 mum); other anaesthetics agents tested were inactive in mm concentrations.5 Ketamine (IC(50) = 200 mum) and xylazine (IC(50) = 9.5 mum) were also capable of displacing specific [(3)H]-D-Ala(2)-enkephalin (D-Leu) binding, as were morphine (IC(50) = 95 nm) and Met-enkephalin (IC(50) = 40 nm).6 On the stimulated guinea-pig ileum, Met-enkephalin and morphine inhibited the contractions, the IC(50) values were 30 nm and 50 nm respectively. The anaesthetics ketamine (IC(50) = 10 mum) and Althesin (IC(50) = 8 mum) were active. Xylazine (IC(50) = 12 nm) exhibited considerable potency in inhibiting the contractions on this preparation. Naloxone 0.5 mum produced a 1000 fold shift in the opiate dose-response curve but the anaesthetic responses showed only slight sensitivity to antagonism by naloxone.7 The activity of Althesin was found to be due to the vehicle in which this anaesthetic is solubilised.8 Whilst several anaesthetic agents showed analgesic activity, specific dihydromorphine binding displacement or guinea pig ileum inhibiting activity, these effects showed variable sensitivity to naloxone.
Halothane modifies colchicine binding to tubulin.
Tubulin extracted from rat brains was incubated at 37 degrees C with 3H-colchicine in the presence and absence of 28 mM halothane. The amount of 3H-colchicine bound to tubulin was reduced by nearly 50% at a colchicine concentration of 5 x 10(-5) M when halothane was present. At low (1 x 10(-7) M) and at high (1 x 10(-3) M) concentrations of colchicine, halothane did not affect the binding as much. The inhibition of colchicine-binding to tubulin by halothane appeared to be non-competitive.
Effect of biliary excretion on ketamine anaesthesia in the rat.
Ligation of the common bile duct in rats resulted in a significant prolongation of ketamine sleeping time and a significant increase of plasma concentration of ketamine and its N-demethylated metabolite, when compared with sham-operated control animals. The treated animals also showed significant increases of plasma bilirubin and glutamate pyruvate transaminase. Cannulation of the common bile duct in rats allowed collection of samples of bile which showed high concentrations of ketamine and its N-demethylated metabolite very shortly after i.p. injection of ketamine, the amount of ketamine alone accounting for 10% of the injected dose after 2 h; including the metabolite up to 25% of the injected dose could be accounted for. In view of this we would suggest that ligation of the bile duct in rats produced a prolongation of ketamine anaesthesia by increasing plasma concentrations through interference with a major excretory route for the drug and its main metabolite.
Effects of halothane on microtubules in the sciatic nerve of the rat.
The effect of halothane and colchicine on microtubule repolymerisation after exposure to cold has been examined in the sciatic nerve of the rat. Myelinated axons showed a significant decrease in microtubule numbers and density after exposure to both 20 mM halothane and 10(-5) M colchicine; exposure to both agents simultaneously produced a further significant reduction when compared to halothane alone. It is suggested that halothane can interfere with microtubule repolymerisation in mammalian axons possibly in a similar way to that described in invertebrates.
The effect of physostigmine and neostigmine on ketamine anaesthesia and analgesia [proceedings].
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Effect of halothane on microtubule numbers in unmyelinated axons from rat sciatic nerve [proceedings].
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The internal structure of axons from rat sciatic nerve.
Sciatic nerves from rats were examined electron microscopically following fixation in 4% tannic acid in 2.5% glutaraldehyde, which allowed demonstration of a filamentous network between the usual intra-axonal organelles. The network appears to consist of longitudinal 10 nm in diameter filaments and cross-linking filaments of about 6 nm diameter. Exposure to cold caused disruption of microtubules, but not the filaments, and incubation at 37 degrees C following cold exposure resulted in reformation of the microtubules which again showed linking with the filaments. Exposure of the nerves to cold in the presence of D2O did not cause disruption of the microtubules but there did appear to be some loss of the fine filaments. These findings suggest that the finer cross-linking filaments are of a different nature than the longitudinal 10 nm filaments, and that there is a dynamic relationship between these filaments and microtubules since the cross-linkages reappear following microtubule disruption and reformation.
Effects of hormone-releasing stimuli on the area of the perivascular space in the neural lobe of the rat.
Neural lobes from rats subjected to neurohypophysial hormone-releasing stimuli were examined electron microscopically following fixation in 4% tannic acid in 2.5% glutaraldehyde. This fixation allowed the delineation of the perivascular space in the neural lobe tissue. Measurement of the area of the perivascular space showed that it was significantly increased in the rats subjected to vagal stimulation and intraarterial calcium ions compared to the control rats. The rats which had been subjected to haemorrhage as a hormone-releasing stimulus did not show any significant change in the area of the perivascular space. The significance of these findings in relation to hormone release is discussed.
Effects of age and sex on ketamine anaesthesia in the rat.
Intraperitoneal injections of ketamine 75 mg kg-1 in rats of both sexes (age 1--16 weeks) revealed a significant relationship between increased age and decreased duration of sleeping time for both sexes during the first 3 weeks of age. This decrease in sleeping time seemed to be associated with the increased production of the cyclohexanone oxidation metabolite of ketamine. After 3 weeks of age there was a greater sleeping time in the female rat than the male and this seemed to be associated with a greater ability of the male to produce the cyclohexanone oxidation metabolite.
The development of tolerance to ketamine in rats and the significance of hepatic metabolism.
1. A decrease in sleeping time in rats pretreated with ten daily doses of ketamine compared to controls is shown. 2. This decrease in sleeping time is associated with a more rapid decrease in circulating and brain levels of ketamine and its N-demethylated metabolite and higher levels of the subsequent oxidation metabolite in the pretreated animals. 3. Metabolism of ketamine to its N-demethylated metabolite by liver homogenates in vitro was more rapid when the livers were obtained from ketamine pretreated rats. 4. Microsomal preparations from rat liver were capable of metabolizing ketamine to its N-demethylated metabolite and this metabolite to the subsequent oxidation metabolite in vitro. The Vmax and Km for the first reaction calculated from loss of substrate were 433 mol mg-1 protein h-1 and 0.133 mM respectively and 199 nmol mg-1 protein h-1 and 0.121 mM for the second reaction. 5. The results indicate that tolerance to ketamine in rats is associated with increased hepatic metabolism which can also be demonstrated in vitro in liver homogenates.
Some physiological effects of ketamine in sheep.
The effects of intravenous injections of ketamine in sheep on the cardiovascular and respiratory systems are compared with the effects of intracerebroventricular injections of the same drug and also with the effects of intravenous barbiturate and steriod anaesthetics. Intravenously administered ketamine caused an initial fall in arterial blood pressure the extent of which was dose dependent. This depression was short lived and was occasionally followed by a mild pressor phase. Intracerebroventricular injection of the drug provoked only a mild transient rise in mean arterial blood pressure. The intravenous injection of ketamine gave a brief period of respiratory depression which was mirrored in the PaO2 and PaCO2 levels followed by a period of respiratory stimulation with elevated PaO2 levels. The comparison of the three injection anaesthetics showed that the blood gas tensions with ketamine showed there was a brief period of respiratory depression similar to that seen with the steroid anaesthetic but that the barbiturate caused a much longer depression similar to that seen with the steroid anaesthetic but that the barbiturate caused a much longer depression. The blood gas tensions following the steroid anaesthetic soon returned to normal while the tensions following ketamine indicated an elevated PaO2 after the initial depression. The blood gas tensions following intracerebroventricular injection of ketamine were difficult to evaluate due to the variable period of apnoea which followed the injection.
Effects of bile duct ligation on ketamine anaesthesia in the rat [proceedings].
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The effects of cholinergic and anticholinergic drugs on ketamine anaesthesia in rats [proceedings].
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