The effect of previous administration of adrenaline or isoprenaline on the activity of several hypnotics in mice]

Previous administration of adrenaline (0.5 mg/kg i.p.) and isoprenaline (10 mg/kg i.p.) enhances activity of several hypnotic drugs (pentobarbital, barbital, chloral hydrate) in mice but is without effect upon hypnotic activity of ethanol. This potentialisation is blocked by previous administration of pindolol, but not by phentolamine. Administration of SKF 525 A demonstrates that metabolism of pentobarbital is modified by this enzymatic inhibitor, which is not the case for other hypnotics.     

Enhancement of pentobarbital effect by continuous administration of morphine in the mouse

These studies demonstrated that continuous morphine treatment from implantation of a 75 mg morphine pellet for 3 days potentiated pentobarbital narcosis and enhanced pentobarbital hypothermia. In the morphine implant mice, sleeping time after two different doses of pentobarbital was greater than 2.5 × the sleeping time in placebo pellet implant animals and also greater than sleeping time in animals treated acutely with morphine prior to pentobarbital. Moreover, in the morphine implant mice both the degree and duration of pentobarbital induced hypothermia were enhanced. The above findings were due to slower rate of metabolism of pentobarbital as evidenced by inhibition of hepatic N-demethylation, and higher levels of brain and serum pentobarbital in the morphine implant mice compared to both placebo and acute morphine mice.     

Different Effects of Adrenergic Beta-receptor Blockade on Heart Rate Response to Mental Stress,Catecholamines, and Exercise

The magnitude and duration of effect of a single 40-mg oral tablet of oxprenolol on the tachycardias associated with motor-car driving, isoprenaline infusion, and walking were compared against placebo in six normal people by a double-blind study. The tachycardias due to driving and isoprenaline were both conspicuousy reduced for over eight hours; the magnitude and duration of the reduction in exercise tachycardia was substantially less. Thus relatively small doses of beta-receptor antagonists will suppress the increase in heart rate induced by mental stress or catecholamines with relatively little effect on the response to everyday exercise. Possibly smaller doses of these drugs would relieve emotionally-induced anginal pain and tachycardia.     

Studies on bradycardia mechanism in the moderately hypothermic dog.

Chronotropic action of isoprenaline on the heart was studied in anesthetized dogs, in euthermic and moderate hypothermic conditions, before and after intravenous administration of atropine and oxprenolol or a cervical bilateral vagotomy. In moderate hypothermia we observed: i) larger duration of the positive chronotropic response to isoprenaline with a delayed and slightly lesser intensity in its maximum; ii) relating to euthermic conditions, delayed but superimposed potentiation of the chronotropic isoprenaline response in atropinized or vagotomized dogs; iii) a small negative chronotropic response to isoprenaline 15 min after oxprenolol, that diminished after atropine; iiii) oxprenolol induced a marked bradycardia nearly twice as intense as in euthermic dogs, almost completely blocked subsequently by atropine. It is concluded that progressive bradycardia in the moderately hypothermic dog is due, among other factors, to a cholinergic action but not to a lesser ability of beta-adrenergic cardiac effectors to chronotropic responses.     

Effects of MK-771, A TRH analog,on pentobarbital-induced alterations of cholinergic parameters in discrete regions of rat brain

MK-771 (l-pyro-2-aminoadipyl-histidyl-thiazolidine-4-carboxamide) was administered intraventricularly to conscious and pentobarbital-narcotized rats. In the conscious rats MK-771 did not affect the regional levels of acetylcholine (ACh) or the rate of sodium-dependent high-affinity choline uptake (HACU). MK-771 was found to antagonize pentobarbital-induced elevations of ACh levels in the cortex, hippocampus and striatum. MK-771 also reversed the depressant effects of pentobarbital on the HACU of the cortex and hippocampus. Striatal HACU was unaltered by the administration of pentobarbital or the combination of pentobarbital and MK-771.     

The influence of naloxone on barbiturate anesthesia and toxicity in the rat

In rats 1 mg/kg naloxone significantly delayed the development and decreased the duration of the loss of righting reflex caused by 35 mg/kg intraperitoneally, or subcutaneously administered pentobarbital or by the same dose of intraperitoneally injected methohexital. Naloxone also antagonized the toxicity of 50–125 mg/kg intraperitoneally administered pentobarbital and increased the LD50 of pentobarbital from 59.0 (50.0–69.6) to 101.1 (85.5–119.1) mg/kg. The findings of this study indicate that therapeutic trials with relatively large doses of naloxone are justifiable in patients intoxicated with barbiturates.     

Effects of olfactory stimulation with jasmin and its component chemicals on the duration of pentobarbital-induced sleep in mice.

The effect of olfactory stimulation with jasmin and its component chemicals on pentobarbital sleep time was investigated using mice. In the present study we sought to determine which component of jasmin influences pentobarbital sleep time via olfactory stimulation. Sleep time was defined as the time elapsed between intraperitoneal pentobarbital administration and the first time that the animal was able to spontaneously right itself. Sleep time was significantly decreased by olfactory stimulation with jasmin, and also by one of the fractions obtained by fractional distillation at 150 degrees C and 0.1 mmHg. The fraction which influenced the sleep time was found to consist of benzyl benzoate, isophytol, geranyl linalool, phytol and phytyl acetate, which were identified using gas chromatography with mass and infrared spectrometry. In experiments using authentic samples of these components, phytol significantly shortened the pentobarbital sleep time, while the others had no effect. We conclude that phytol is the component of jasmin which reduces the duration of pentobarbital-induced sleep.     

Comparative stability of physiological parameters during sustained anesthesia in rats

Rats were anesthetized with pentobarbital, pentobarbital and atropine, inactin [5-ethyl-5-(1'-methyl-propyl)-2-thiobarbiturate], ether and inactin, or urethane. Cardiovascular and arterial acid-base parameters were monitored over a 3-hour period of anesthesia. Heart rate, arterial pressures, and pH progressively decreased with duration of pentobarbital anesthesia. Changes observed in rats anesthetized with the thiobarbiturate, inactin, were similar although generally less severe. Most subjects treated with the barbiturates were markedly hypercapnic. Urethane anesthesia was characterized by a higher and more stable heart rate and greater pulse pressure. Arterial carbon dioxide and bicarbonate levels in the urethane group were substantially lower at all sampling times than the values obtained in the barbiturate groups.     

Comparison between the effects of pentobarbital or ketamine/nitrous oxide anesthesia on metabolic and endothelial components of coronary reactive hyperemia

Barbiturates induce reduction of myocardial contractility and metabolism, whereas ketamine exerts a sympathomimetic effect that can mask its direct depressant effect on contractility. However, it is unclear whether barbiturates, which interfere with the cytochrome P-450 pathway, or ketamine, which inhibits nitric oxide synthesis, also alter the responsiveness of the coronary vessels to vasodilator stimuli. We hypothesized that the parameters of coronary reactive hyperemia (CRH), which reflect both the degree of myocardial metabolism and vascular reactivity, could be modified by the type of anesthesia used. In two groups of goats, anesthesia was induced either using ketamine plus nitrous oxide or pentobarbital alone. To record coronary flow an electromagnetic flow-probe was placed around the left circumflex coronary artery. In the ketamine group (n = 14) and in the pentobarbital group (n = 16) CRH was studied using the indices of myocardial metabolism and vascular dilator responsiveness. In the pentobarbital group all of the indices of myocardial metabolism were lower than in the ketamine group (i.e. the excess to debt flow ratio was 2.3+/-0.8 vs. 4.6+/-2.4; p< 0.001). Yet, some indices of vascular responsiveness (time derivative of coronary flow and the peak to basal flow ratio) were not different in the two groups. Moreover, the duration of the reactive hyperemia was shorter in the ketamine than in the pentobarbital group (118+/-47 vs. 153+/-45 s, p<0.05). It is suggested that pentobarbital decreases the indices of CRH related to metabolic activity, whereas ketamine reduces the duration of the hyperemic response, which suggests an impairment of endothelial function.     

戊巴比妥钠和乌拉坦对超声检测兔肾血流动力学变化的影响探讨

目的比较戊巴比妥钠和乌拉坦两麻醉剂在超声监测兔肾血流动力学变化的影响。方法选用日本大耳白兔24只,随机分组,戊巴比妥钠和乌拉坦麻醉两组,每组12只。采用频谱多普勒检测兔肾各级肾动脉血流参数。结果乌拉坦组各级肾动脉收缩期峰值流速（Vmax）,舒张期最低流速（Vmin）均明显高于戊巴比妥钠组（P〈0.05）,动脉搏动指数（PI）和阻力指数（RI）无明显变化（P〉0.05）。结论为保证超声监测兔肾血流动力学实验数据的准确性,戊巴比妥钠麻醉较乌拉坦麻醉更适合。     

Mannose, glucosamine and inositol monophosphate inhibit the effects of insulin on lipogenesis. Further evidence for a role for inositol phosphate-oligosaccharides in insulin action.

The mechanism of insulin signalling is not yet understood in detail. Recently, a role for inositol phosphate (IP)-oligosaccharides as second messengers transmitting the insulin signal at the post-kinase level was proposed. To evaluate this hypothesis further, we studied whether IP-oligosaccharides isolated from 'haemodialysate' have insulin-like activity. We found that these compounds mimic, in a dose-dependent fashion, the following effects of insulin in adipocytes. (1) Lipogenesis. Incorporation of [3H]glucose into lipids (expressed in nmol/min per 10(6) cells): basal, 0.74 +/- 0.05; insulin (1 mu unit/ml), 4.43 +/- 0.21; IP-oligosaccharide (2 micrograms/ml), 4.07 +/- 0.19. (2) Inhibition of isoprenaline (isoproterenol) (1 microM)-stimulated cyclic AMP levels and lipolysis. Cyclic AMP (pmol/10(5) cells): basal 0.84 +/- 0.05; isoprenaline, 4.03 +/- 0.19; isoprenaline + insulin (200 mu units/ml), 2.06 +/- 0.7; isoprenaline + IP-oligosaccharides (2 micrograms/ml), 2.4 +/- 0.29. Inhibition of lipolysis (mumol of glycerol/mg of protein): isoprenaline (1 microM), 166 +/- 11; isoprenaline+insulin (150 mu units/ml), 53 +/- 3.5; isoprenaline+IP-oligosaccharides (2 micrograms/ml), 58 +/- 5. (3) Stimulation of 3-O-methylglucose transport; basal, 9 +/- 3%; insulin (1 mu unit/ml), 67 +/- 4%, IP-oligosaccharides (2 micrograms/ml), 54 +/- 2%. To identify the active molecules of the IP-oligosaccharide fraction, competition experiments were performed. IP-oligosaccharide effects on lipogenesis were blocked by inositol monophosphate, glucosamine and mannose. In contrast, these compounds did not inhibit IP-oligosaccharide effects on membrane-mediated functions (3-O-methylglucose transport, cyclic AMP levels, lipolysis). We also found that the effect of insulin on lipogenesis was blocked by mannose, glucosamine and inositol monophosphate, whereas the insulin effects on 3-O-methylglucose, cyclic AMP and lipolysis were unaffected. The following conclusions were reached. (1) IP-oligosaccharides mimic the major metabolic effects of insulin in adipocytes. This is consistent with the proposed role of IP-oligosaccharides as second messengers of certain insulin effects. (2) Mannose and glucosamine are functionally important sugar residues for the effect of IP-oligosaccharide on lipogenesis. (3) The observation that mannose, inositol monophosphate and glucosamine block the action of insulin of on lipogenesis supports a role of mannose- and glucosamine-containing IP-oligosaccharides as second messengers for this insulin effect.     

Breathing of phrenicotomized rats

Bilateral paralysis of the diaphragm can result in normo or hypoventilation, according to the species studied. Our aim was to ascertain the results of bilateral phrenicotomy in the rat and, if hypoventilation should be present, to try to identify its pathophysiology. We used 33 male rats under urethane anaesthesia (1.3 g/kg i.p.). They were divided into three groups: control animals, rats with bilateral phrenicotomy and a group with two doses of pentobarbital (25 mg/kg i.p. each) on top of the urethane anaesthesia. We observed pronounced hypoventilation both in the rats after phrenicotomy and those with pentobarbital. At comparable levels of hypoventilation (PaCO2 = 5.61 +/- 0.28 kPa immediately after phrenicotomy and 5.91 +/- 0.25 kPa after the first dose of pentobarbital; and 7.21 +/- 0.47 kPa 4 hours after phrenicotomy and 7.38 +/- 0.39 kPa after the second dose of pentobarbital) the only difference was a longer relative duration of inspiration in phrenicotomized rats; (0.39 +/- 0.04 and 0.34 +/- 0.04 after phrenicotomy; 0.32 +/- 0.04 and 0.24 +/- 0.05 in rats after pentobarbital). Immediately after phrenicotomy and 2 and 4 hours later, and also after both doses of pentobarbital breathing was stimulated by hypoxia and hypercapnia due to the additional external dead space (0.5 ml) for 5 min. There was no pronounced differences in the ventilatory response to the dead space between the two groups; the response changed from an isocapnic (in control rats and before phrenicotomy or pentobarbital) to an isoventilatory one (four hours after phrenicotomy and after the second dose of pentobarbital). The rats after the second dose of pentobarbital did not, however, survive the added dead space.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of halothane, pentobarbital and ketamine on serum melatonin levels in the early scotophase in New Zealand white rabbits

In mammals, the nocturnal rise in pineal melatonin is regulated by signals from the endogenous clock, the hypothalamic suprachiasmatic nuclei. There have been few reports on whether anaesthetics which modulate multisynaptic neuronal functions affect melatonin secretion. We studied the effects of three commonly used anaesthetics, halothane, pentobarbital and ketamine, on serum melatonin levels in male New Zealand white rabbits. Seven blood samples were collected, 30-60 min apart, before, during and after anaesthesia. Experiments were performed in the late light and early dark period, so that changes in melatonin secretion would be reflected in the onset and/or level of nocturnal serum melatonin. Serum melatonin levels were determined by radioimmunoassay. Our results indicated that halothane attenuated the release of melatonin and pentobarbital had no apparent effect, whereas ketamine potentiated the release of melatonin. These findings suggest that melatonin levels may be affected in patients anaesthetized with halothane or ketamine, resulting in disturbed biological rhythms, especially the sleep-wake cycle following recovery.     

Potentiation by cocaine of relaxations of the guinea-pig colon caused by noradrenaline and by stimulation of adrenergic nerves.

The distal colon of the guinea-pig is relaxed by noradrenaline, by isoprenaline and by the stimulation of fibres running with the colonic nerves or intramurally. The relaxations in response to stimulation of the colonic nerves have a guanethidine-sensitive (adrenergic) and a guanethidine-insensitive (non-adrenergic) component. Cocaine causes a three-fold sensitization of the muscle to noradrenaline but no sensitization to isoprenaline. Cocaine increases the duration, but does not affect the amplitude, of the relaxation observed when adrenergic nerves are stimulated, and affects neither duration nor amplitude of the non-adrenergic response. The adrenergic nerve terminals lie in Auerbach's plexus, not in the longitudinal muscle. It is concluded that the sensitization to noradrenaline and the increases in durations of responses to adrenergic nerve stimulation are due to inhibition of catecholamine uptake into adrenergic nerves by cocaine. It appears that, even where the neuromuscular separation is large as it is in the colon, the concentration of exogenous noradrenaline at the receptors can be decreased by neuronal uptake, and the uptake mechanism can modify responses to nerve stimulation in vitro.     

Isoprenaline, propranolol and in vivo phosphorus metabolism of the rat salivary gland]

Chronic treatment with isoprenaline causes hypersecretion and a marked enlargement of submaxillary glands. Isoprenaline, given to normal rats or treated animals with hypertrophied salivary glands, increases the incorporation of 32P in tissue inorganic and organic phosphates and phospholipids. Propranolol given alone is inactive on phosphorus metabolism, but inhibits the effect of isoprenaline. The phospholipid effect is probably related to the increase of membranes in hypertrophied acinar cells; a correlation with the hypersecretion induced by isoprenaline needs further study. The results show that in experimental sialadenosis and hypersialorrhea induced by isoprenaline in the whole rat stimulation of glandular beta-adrenoreceptors and phosphorus metabolism are involved.     

Effect of pentobarbital and urethane on the release of hypothalamic somatostatin and pituitary growth hormone

Hypothalamic somatostatin release was investigated in the rat to elucidate the mechanism of anesthetic action on growth hormone (GH) release from the pituitary. Intraperitoneal injection of sodium pentobarbital (5 mg/100 gm B.W.) significantly elevated serum GH levels and increased hypothalamic somatostatin concentration from basal values of 0.98 +/- 0.01 to 1.21 +/- 0.06 ng/mg wet wt. In contrast, urethane (150 mg/100 gm B.W., IP) administration lowered serum GH levels and hypothalamic somatostatin concentration (0.64 +/- 0.04 ng/mg wet wt.). However, the mean concentration of pancreatic somatostatin showed no change in either case. In rats receiving passive immunization with 0.5 ml rabbit antiserum to somatostatin (SRIF-AS), serum GH levels were significantly increased (67.5 +/- 12.3 ng/ml) and did not differ from those in the group treated with normal rabbit serum (NRS) plus pentobarbital (101.3 +/- 18.5 ng/ml). However, serum GH levels in rats injected with SRIF-AS plus pentobarbital were increased to higher values than in rats given SRIF-AS alone. When urethane was administered to rats after passive immunization with SRIF-AS, urethane-induced suppression of serum GH levels was markedly inhibited (5.5 +/- 2.0 vs. 33.5 +/- 7.5 ng/ml). These results suggest a possibility that the changes in serum GH levels observed with pentobarbital or urethane administration may be induced at least in one part by somatostatin released from the hypothalamus.     

Electrical activation of expiratory muscles increases with time in pentobarbital-anesthetized dogs.

Although the pentobarbital-anesthetized dog is often used as a model in studies of respiratory muscle activity during spontaneous breathing, there is no information regarding the stability of the pattern of breathing of this model over time. The electromyograms of several inspiratory and expiratory muscle groups were measured in six dogs over a 4-h period by use of chronically implanted electrodes. Anesthesia was induced with pentobarbital sodium (25 mg/kg iv), with supplemental doses to maintain constant plasma pentobarbital concentrations. Phasic electrical activity increased over time in the triangularis sterni, transversus abdominis, and external oblique muscles (expiratory muscles). The electrical activity of the costal diaphragm, crural diaphragm, and parasternal intercostal muscles (inspiratory muscles) was unchanged. These changes in electrical activity occurred despite stable plasma levels of pentobarbital and arterial PCO2. They were associated with changes in chest wall motion and an increased tidal volume with unchanged breathing frequency. We conclude that expiratory muscle groups are selectively activated with time in pentobarbital-anesthetized dogs lying supine. Therefore the duration of anesthesia is an important variable in studies using this model.     

Effect of pentobarbital dependence on adenylate cyclase activity and calmodulin levels in rat cerebral cortex

The effect of calcium (Ca2+) on the adenylate cyclase activity and calmodulin level of cerebral cortex was determined in pentobarbital dependent rats and age matched controls. Female Sprague-Dawley rats were made dependent and maintained on pentobarbital by eating a mixture of pentobarbital and rat chow (350 mg pentobarbital/30 g chow). Ca2+ activated then inhibited the adenylate cyclase activity associated with a 20,000 X g particulate fraction from pentobarbital dependent and age matched control rats. The values for one-half maximal stimulation and inhibition by Ca2+ did not differ significantly in either cortical preparation. However, the ability of Ca2+ to activate adenylate cyclase from pentobarbital dependent animals was significantly decreased (p less than 0.05) when compared to control animals. Pentobarbital (10(-4) - 10(-3) added to particulate fractions from naive control rats did not alter the ability of Ca2+ to activate adenylate cyclase. The calmodulin levels in the particulate fraction from pentobarbital dependent animals (30.2 +/- 6.7 ng calmodulin/mg protein) did not differ significantly when compared to control (33.0 +/- 4.7 ng/mg). By contrast, the calmodulin levels (37.9 +/- 5.9 ng/mg) in the 20,000 X g supernatant from cortex of pentobarbital dependent animals was significantly greater than the level in the supernatant from control animals (28.6 +/- 2.6 ng/mg). The ability of forskolin, dopamine, GTP or forskolin plus GTP (all at a concentration of 100 microM) to activate adenylate cyclase was significantly decreased in particulate preparations from pentobarbital dependent animals. In summary, our data show that alterations in calmodulin levels and a decreased responsivity of adenylate cyclase occur in animals physically dependent on pentobarbital.     

Role of NMDA Receptors in Pentobarbital Tolerance/Dependence

Effects of continuous pentobarbital administration on binding characteristics of [³H]MK-801 in the rat brain were examined by autoradiography. Animals were rendered tolerant to pentobarbital using i.c.v. infusion of pentobarbital (300g/10l/hr for 7 days) by osmotic minipumps and dependent by abrupt withdrawal from pentobarbital. The levels of [³H]MK-801 binding were elevated in rats 24-hr after withdrawal from pentobarbital while there were no changes except in septum and anterior ventral nuclei in tolerant rats. For assessing the role of NMDA receptor in barbiturate action, an NMDA receptor antagonist (MK-801, 2.7 femto g/10l/hr) was co-infused with pentobarbital. The pentobarbital-infused group had a shorter duration of pentobarbital-induced loss of righting reflex (sleeping time) than that of the control group, and MK-801 alone did not affect the righting reflex. However, co-infusion of MK-801 blocked hyperthermia, and prolonged the onset of convulsions induced by t-butylbicyclophosphorothionate (TBPS) in pentobarbital withdrawal rats. In addition, elevated [³⁵S]TBPS binding was significantly attenuated by co-infusion with MK-801. These results suggest the involvement of NMDA receptor up-regulation in pentobarbital withdrawal and that the development of dependence can be attenuated by the treatment of subtoxic dose of MK-801.     

Cardioprotective effect of magnesium chloride in experimental acute myocardial infarction

Cardioprotective role of intravenous administration of magnesium chloride was evaluated in rabbits by biochemical and histopathological parameters. Myocardial damage was induced by injecting (i.v.) isoprenaline 1, 2.5, 5 and 7.5 mg/kg body weight of animal. There was a dose dependent increase in the activity of cardiac enzyme creatinine kinase CK (C Max). Maximal elevation of CK (C Max) was observed with 2.5 mg isoprenaline. The mean T-max (mean of the time duration in hr at which maximum creatinine kinase activity of individual rabbit was observed in a group) shifted early, significantly with 2.5, 5 and 7.5 mg isoprenaline compared to control group. Histopathologically, myocardial damage was quite significant in 2.5 mg isoprenaline subgroup of animals. A mortality of 29% was observed in animals injected with 5 and 7.5 mg isoprenaline, whereas all animals subjected with 1 and 2.5 mg isoprenaline were alive for 72 hr. Considering the data on serial determination of cardiac enzyme CK and histopathological changes, 2.5 mg isoprenaline was chosen as standard dose to study efficacy of cardioprotection by gold standard verapamil and magnesium chloride. Verapamil (5 microM) injected prior to 2.5 mg isoprenaline administration revealed significant reduction of CK (C Max) activity (P < 0.05) compared to animals infused with isoprenaline alone. T-max value did not show any alteration in both the groups. Histopathological findings showed no areas of necrosis and cellular infiltrates in animals primed with 2.5 mg isoprenaline following verapamil. Highly significant reduction in CK (C-max) activity was observed in animals administered with 40 mg magnesium chloride prior to isoprenaline compared to animals treated with isoprenaline alone (P < 0.001). In addition to this, significant delay in T-max of CK activity was observed in group treated with 40 mg magnesium chloride and isoprenaline compared to group treated with only isoprenaline (P < 0.01). The study clearly highlighted and confirmed the valuable role of magnesium chloride as cardioprotective agent.