Timing of Atropine and Neostigmine in the Reversal of Muscle Relaxants

The antimuscarinic effects of atropine were studied in 46 patients to whom neostigmine had been given after operation to reverse the action of a muscle relaxant. Neostigmine was given to alternate patients three minutes after, or together with, atropine, and the effects of the two procedures were compared by measuring the secretions which collected in the buccal and oropharyngeal cavities and observing the heart rate.It was found that the glands of the oral cavity were stimulated to a greater extent when neostigmine was given with atropine than after atropine. Any dose of atropine sufficient to inhibit peristaltic movements of the bowel is more than enough to block completely secretion by the salivary glands, and the appearance of some secretion in all cases after the administration of neostigmine suggests that the bowel was at liberty to react to the neostigmine in every case, but perhaps particularly so when atropine and neostigmine were given mixed. The integrity of an anastomosis of the bowel could be endangered by vigorous peristalsis in the early postoperative period.Electrocardiograms in about half the patients from each group confirmed earlier work that the muscarinic effects of neostigmine on the heart can be prevented by giving the atropine either before or together with the neostigmine.     

头端延髓腹外侧区在侧脑室注射新斯的明所致升压中的作用

实验在47只乌拉坦(700m/kg)、氯醛糖(35mg/kg)麻醉,肌肉麻痹,人工呼吸的家兔上进行。结果观察到,侧脑室注射(icv)新斯的明引起血压升高,心率(HR)先减慢后有加快趋势,股动脉血流量(FBF)与股动脉血管通道性(COND)减小,左心室内压(LVP)增大,肾交感神经放电(RND)增加,延髓腹外侧头端(rVLM)微量注射阿托品则引起血压下降,HR减慢,FBF与COND增加,LVP与RND减小,若在icv新斯的明之前,预先向rVLM注入阿托品,可阻断新斯的明的升压效应,上述结果提示,rVLM是icv新斯的明升压效应的重要部位,rVLM区M受体功能完整是这种升压作用的关键因素。     

Effect of short — chain fatty acids on electrical activity of the small intestinal mucosa of rat

Intravenous administration of short-chain fatty acid (SCFA), such as propionate, butyrate, valerate and caproate, caused a transient increase in transmural potential difference (p.d.) across the small intestine of rat $\text{in vivo}$. There was a sigmoid relationship between the change in the p.d. and the logarithm of the dose of SCFA. The median effective dose of propionate, n-butyrate, n-valerate and n-caproate, which was calculated from the each dose-response curve obtained from the terminal ileum, 1.31, 1.43, 0.83 and 0.81 μmole, respectively. Repeated administrations of the same dose of propionate evoked progressively smaller response. The dose-response curve of propionate was shifted to the left by neostigmine and to the right by atropine, suggesting that the action of SCFA may be mediated by acetylcholine, which was released from a nerve ending.     

Potentiation of the carotid artery occlusion reflex by a cholinergic system in the posterior hypothalamic nucleus

Bilateral occlusion of the common carotid arteries of urethane-anesthetized rats evoked a pressor response of 14 ± 1 mm Hg. Injection into the lateral cerebral ventricle of neostigmine (0.2–1.0 μg) or physostigmine (10–15 μg) caused a dose-dependent increase in basal blood pressure and in the magnitude of the carotid artery occlusion (CAO) pressor reflex. Neostigmine (1 μg) and physostigmine (15 μg) caused nearly maximal and approximately equal degrees of cholinesterase inhibition in several brain regions. The recovery of the cardiovascular parameters and of brain cholinesterase activity was significantly faster following physostigmine compared to neostigmine. Prior intracerebroventricular injection of atropine (0.3 μg) or hemicholinium-3 (20 μg) prevented the increases in basal pressure and the CAO pressor response. Potentiation of the CAO reflex also followed injection of physostigmine or neostigmine into the posterior hypothalamic nucleus and of injection of physostigmine intravenously. Injection of atropine bilaterally into the posterior hypothalamic nucleus prior to intravenous injection of physostigmine prevented the potentiation of the CAO reflex but not the increase in basal blood pressure. These results indicate that acetylcholine in the posterior hypothalamic nucleus serves as a neurotransmitter in a pathway which can potentiate the pressor response to carotid artery occlusion and thus modulate baroreceptor reflexes.     

Pharmacological analysis of the pendular movements appearing during calcium blocking of peristalsis in the isolated guinea pig ileum]

Calcium chloride acting from the serosal surface blocked the peristaltic reflex and at the same time, after about 30 minutes, evoked pendulum type of activity in the longitudinal muscle of the guinea-pig isolated ileum, subjected to constant intraluminal pressure. Hexamethonium, tetraethylammonium, morphine, methadone and atropine blocked, while, neostigmine potentiated the pendulum movements evoked by calcium chloride. In the Magnus preparation of the guinea-pig isolated ileum calcium chloride also caused pendulum type of activity. From these experiments it is concluded that calcium chloride evoked pendular movements by stimulating the postganglionic cholinergic nerves in the longitudinal muscle of the guinea-pig isolated ileum.     

Extrinsic control of the release of galanin and VIP from intrinsic nerves of isolated, perfused, porcine ileum.

By immunohistochemistry galanin-like immunoreactivity and vasoactive intestinal polypeptide (VIP)-like immunoreactivity were found in nerve cell bodies mostly in the submucous plexus and in nerve fibres in the mucosa, submucosa and muscularis including the myenteric plexus of the porcine ileum and were found to co-exist in most of these structures. Using isolated, perfused porcine ileum we studied the release of galanin and VIP in response to electrical stimulation of the mixed periarterial nerves or to intraarterial infusions of different neuroactive agents. Nerve stimulation (4-10 Hz) inhibited the basal release of galanin and VIP from the ileum (to 69 +/- 6 and 62 +/- 6% of basal release). After infusion of the alpha-adrenergic blocker, phentolamine, (10(-6) M) electrical stimulation increased the release of both galanin and VIP (to 140 +/- 12 and 133 +/- 13% of basal output). This increase was abolished by atropine (10(-6) M) and by hexamethonium (3.10(-5) M). Infusion of norepinephrine (10(-6) M) inhibited, whereas acetylcholine (10(-6) M) stimulated the release of both peptides. The effect of the latter was abolished by atropine. The inhibitory effect of nerve stimulation was not influenced by atropine. Our results suggest that the galanin- and VIP-producing intrinsic neurons receive inhibitory signals by noradrenergic nerve fibers and stimulatory signals mediated by cholinergic nerves, possibly via a cholinergic interneuron.     

A comparison of the central and peripheral antimuscarinic effects of atropine and methylatropine injected systemically and into the cerebral ventricles

We compared the relative abilities of atropine sulfate and methylatropine, injected i.v. and into the cerebral ventricles (icv), to block pharmacological responses mediated through central and peripheral muscarinic receptors. The hypotensive response to i.v. injection of acetylcholine (peripheral muscarinic receptors) was inhibited 50% by i.v. injection of 14.3 nmol (5.5 micrograms)/kg methylatropine and 147.8n molar equivalents (50 micrograms)/kg atropine sulfate. A similar degree of inhibition followed icv injection of 49.4 nmol/kg methylatropine and 384.2 nmol equivalents/kg atropine sulfate, indicating significant leakage out of the ventricular space. The pressor response to icv injection of neostigmine (central muscarinic receptors) also was inhibited more effectively by icv methylatropine than by atropine sulfate. Methylatropine was not effective in blocking central muscarinic receptors when injected i.v.     

Enteric opioid neurons modulate the basal tone of the isolated puppy ileum

We studied the role of enteric opioid neurons in the spontaneous motility of the longitudinal muscle in the isolated puppy ileum. Regular fluctuations in tone that rose above and returned to the basal level occurred at an interval of 4.7 +/- 0.3 min. Naloxone (10(-8) and 10(-7) M) reduced the spontaneous tonic contraction by 42.6 +/- 11.6% (p less than 0.02) and 77.0 +/- 3.6% (p less than 0.001), respectively. Tetrodotoxin (3.1 X 10(-7) M) and atropine (10(-7) M) terminated the fluctuations. Met- and Leu-enkephalins (10(-9)-10(-8) M) caused tonic contraction which was abolished by tetrodotoxin and atropine. The contractile response produced by transmural electrical stimulation was reduced by naloxone (10(-7) M). This response was also abolished by atropine and tetrodotoxin. These results suggest that enteric opioid neurons are spontaneously active and might operate, at least in part, to raise the basal tone of the longitudinal muscle in the puppy ileum through a cholinergic excitatory mechanism.     

Halothane Anesthesia Affects NMDA-Stimulated Cholinergic and GABAergic Modulation of Striatal Dopamine Efflux and Metabolism in the Rat In Vivo

Microdialysis of the striatum of halothane-anesthetized rats was used to study the participation of local cholinergic and GABAergic neurotransmission in NMDA receptor-modulated striatal dopamine release and metabolism. Reverse dialysis.of NMDA (1 mM) evoked a 10-fold increase in dopamine efflux and reduced DOPAC and HVA to > 20% of basal values. The effect of NMDA on dopamine efflux was abolished by atropine (10 microM) but unaffected by (+)-bicuculline (50 microM). NMDA-induced decrease in DOPAC (but not HVA) efflux was potentiated by atropine, whereas (+)-bicuculline attenuated the decrease in DOPAC and HVA. Compared to our previous studies in unanesthetised rats, our data suggest that halothane anesthesia alters the balance between NMDA-stimulated cholinergic and GABAergic influences on striatal dopamine release and metabolism. Differential sensitivity to halothane of NMDA receptors expressed by the neurones mediating these modulatory influences, or loss of specific NMDA receptor populations through voltage-dependent Mg2+ block under anesthesia, could underlie these observations.     

Abattoir-sourced isolated ileum from Gallus gallus domesticus as an experimental tool

A study was undertaken to determine the longevity of active muscarinic receptors on abattoir-sourced isolated ileum preparations from Gallus gallus domesticus, with a view to using the tissue as an experimental tool for functional response assays in laboratory experiments. A concentration-response curve for acetylcholine (1-256 μM) was plotted, in the presence and absence of 1, 3 and 6 nM atropine. In a second experiment, unknown concentrations of acetylcholine samples were determined by using an interpolation method. In this experiment, four sample concentrations were used and the calculated values were found to be almost equal to the actual values. Finally, an experiment was carried out to elucidate the effects of post-sacrifice time on the contractile response of the tissue. The results showed that the tissue maintained considerable contractile response at the 6-hour post-sacrifice time-point. Competitive antagonistic activity was observed between acetylcholine and atropine on the chicken ileum, and the pA2 value was calculated to be 9.21 by using an Arunlakshana-Schild plot. The results suggest that isolated ileum preparations of Gallus gallus domesticus, obtained from a meat abattoir, can be used as a basic experimental tool for bioassays in routine laboratory experiments. However, its potential as a research tool still needs to be confirmed.     

Localisation and neural control of the release of calcitonin gene-related peptide (CGRP) from the isolated perfused porcine ileum

By immunohistochemistry, CGRP-like immunoreactive (CGRP-LI) nerve fibres were found in the lamina propria along small vessels and in the lamina muscularis mucosae in the porcine ileum. Immunoreactive nerve cell bodies were found in the submucous and myenteric plexus. Upon HPLC-analysis of ileal extracts, CGRP-LI corresponded entirely to porcine CGRP plus smaller amounts of oxidised CGRP. Using isolated vascularly perfused segments of the ileum, we studied the release of CGRP-LI in response to electrical stimulation of the mixed extrinsic periarterial nerves and to infusion of different neuroblockers. In addition, the effect of infusion of capsaicin was studied. The basal output of CGRP-LI was 2.9+/-0.7 pmol/5 min (mean+/-S.D.). Electrical nerve stimulation (8 Hz) significantly increased the release of CGRP-LI to 167+/-16% (mean+/-S.E.M.) of the basal output (n=13). This response was unaffected by the addition of atropine (10(-6) M). Nerve stimulation during infusion of phentolamine (10(-5) M) with and without additional infusion of atropine resulted in a significant further increase in the release of CGRP-LI to 261+/-134% (n=5) and 240+/-80% (n=9), respectively. This response was abolished by infusion of hexamethonium (3x10(-5) M). Infusion of capsaicin (10(-5) M) caused a significant increase in the release of CGRP-LI to 485+/-82% of basal output (n=5). Our results suggest a dual origin of CGRP innervation of the porcine ileum (intrinsic and extrinsic). The intrinsic CGRP neurons receive excitatory input by parasympathetic, possibly vagal, preganglionic fibres, via release of acetylcholine acting on nicotinic receptors. The stimulatory effect of capsaicin suggests that CGRP is also released from extrinsic sensory neurons.     

Galanin: an inhibitory neural peptide of the canine small intestine

Galanin injected intraarterially during phasic activity of the canine small intestine in vivo produced inhibition. Fifty percent inhibition occurred at 1.5 +/- 0.5 X 10(-10) mols lasting for 0.7 min. The inhibitory response was not decreased by treatment with atropine, hexamethonium, yohimbine or naloxone, suggesting that muscarinic, nicotinic, alpha 2 adrenergic or opiate receptors were not being stimulated. Since tetrodotoxin blockade of nerves did not reduce the response and galanin at 10(-10) mols was able to eliminate the smooth muscle response to intraarterial acetylcholine, we suggest that galanin acts to inhibit smooth muscle directly. Galanin 10(-9) M added to the muscle bath also inhibited phasic activity of the canine ileum circular muscle in vitro in the presence of tetrodotoxin. These results suggest that the neural peptide galanin may be a non-adrenergic, non-cholinergic, non-opioid neurotransmitter in the canine small intestine.     

The inhibitory effect of halothane on the emetic response in the ferret

Emesis and nausea are often associated with anaesthesia and continue to be a common clinical problem. Past clinical studies have demonstrated that halothane produces a higher incidence of vomiting compared with other anaesthetics, but some investigators have described an antiemetic effect. The purpose of this study was to investigate the effects of various doses of halothane on the emetic response in the decerebrate ferret. Following a control emetic response, a maximum of six increasing cumulative concentrations of halothane were delivered. At the end of each delivery period, the supradiaphragmatic vagal communicating branch, which has been shown to reproducibly elicit vomiting, was electrically stimulated and the emetic response was monitored. An increase in halothane concentration produced a marked depression of tongue, abdominal muscle, and diaphragm EMG activity as well as a decrease in central venous pressure. Licking, a prodromal response comparable to nausea in the human, appeared to be most sensitive. An increase in latency of the emetic response occurred as the concentration of halothane was increased. All phases of the response were observed at concentrations below 0.6 vol% halothane. At 0.6 vol% halothane, 75% of the animals vomited. At higher concentrations, the emetic response was completely abolished. One hour post-halothane, all latencies had returned to near control values. The methods utilized in this study provided a model that was not complicated by a large number of variables usually present in clinical studies. These data demonstrate that halothane exerts an inhibitory, concentration-dependent, and reversible effect on the emetic response in the ferret and provide further support that halothane alone does not possess emetic properties at clinical properties at clinical concentrations.     

Cardiopulmonary,hematological, serum biochemical and behavioral effects of sevoflurane compared with isoflurane or halothane in spontaneously ventilating goats

This study compares cardiopulmonary, hematological, serum biochemical and behavioral effects of sevoflurane, isoflurane or halothane anesthesia in spontaneously breathing, conventionally medicated goats. Six male adult goats were anesthetized repeatedly at 2-week intervals with three anesthetics. Goats were administered atropine (0.1 mg/kg) intramuscularly, and 10 min later, induced to anesthesia by an intravenous infusion of thiopental (mean 14.3 mg/kg). After intubation, goats were anesthetized with halothane, isoflurane or sevoflurane in oxygen and maintained at surgical depth of anesthesia for 3 h. Recovery from anesthesia with sevoflurane was more rapid than that with isoflurane or halothane. Time-related hypercapnia and acidosis were observed during halothane anesthesia, but not observed during sevoflurane or isoflurane anesthesia. Both hypercapnia and acidosis during sevoflurane anesthesia did not differ from isoflurane anesthesia, but were less during halothane anesthesia, especially at prolonged maintenance period. There were no significant differences between anesthetics in respiration and heart rates, arterial pressures, hematological and serum biochemical values. It was concluded that sevoflurane is an effective inhalant for use in goats showing the most rapid recovery from anesthesia, and that cardiopulmonary effects of sevoflurane are similar to isoflurane than halothane.     

Mechanism of tachycardia caused by intracarotid PGE2 in conscious ewes

Conscious adult ewes prepared with nonocclusive indwelling vascular catheters were used to determine the mechanism by which heart rate increases during central administration of prostaglandin E2 (PGE2). Heart rate increased 14 bpm during steady-state intracarotid infusion of PGE2, 10 ng/kg/min (P less than 0.05). Intravenous atropine methyl bromide, 1 mg/kg, increased heart rate 26 bpm (P less than 0.05) 5 min after injection. Heart rate remained elevated 30 min after injection. The heart rate response to PGE2 plus atropine was greater than the heart rate response to either atropine or PGE2 alone (P less than 0.05). Propranolol, 1 mg/kg bolus plus intravenous infusion, 0.025 mg/kg/min, did not change resting heart rate. Propranolol attenuated but did not abolish the increase in heart rate caused by intracarotid PGE2. Although heart rate increased in response to PGE2 after administration of either propranolol or atropine alone, the combination of propranolol and atropine prevented any further increase in heart rate during subsequent PGE2 infusion. The increase in heart rate when all three drugs were given together was not different from the increase observed during atropine alone. Thus, both beta-adrenergic activation and muscarinic deactivation contribute to the PGE2-induced tachycardia.     

A study of carbachol-atropine interaction on intestinal smooth muscle vesicles, using a fluorescent probe.

Plasma membrane vesicles were prepared from guinea pig ileum longitudinal muscle. The vesicles were characterized by electron microscopy and analysis of lipid and protein content. They were shown to be free of gross contamination from actomyosin, sarcoplasmic reticulum, and mitochondria. 8-Anilino-1-naphthalene sulphonic acid (ANS) binding characteristics were similar to those found in other membranes. Both carbachol and atropine increased the fluorescence of ANS bound to this membrane, the maximum increase for atropine being greater than that for carbachol. Since neither drug effected the apparent affinity constant for the ANS-membrane interaction. It may be assumed that the increased fluorescence was due to an increase in the number of ANS binding sites. The carbachol-dependent increase in ANS fluorescence was blocked noncompetitively by atropine but not by tubocurarine or diphenhydramine. These latter two antagonists also increased ANS fluorescence but at much higher concentrations than either carbachol or atropine. Neither atropine nor carbachol increased ANS fluorescence on either erythrocyte ghosts or liposomes (prepared from a lipid extract of the muscle membrane).     

Muscarinic influences on growth hormone secretion in the fetal and neonatal sheep: pharmacological studies and in vitro binding studies

To investigate the ontogenesis of potential cholinergic influences on growth hormone secretion we administered the cholinesterase inhibitor neostigimine, (120 micrograms/kg) to fetal sheep (n = 16) between 77 and 143 days of gestation and to infant lambs (n = 5). Neostigmine administration was associated with a marked rise in fetal growth hormone concentrations. The integrated release of growth hormone in the hour following fetal neostigmine administration was 2880 +/- 425 ng.min/ml compared to -618 +/- 206 ng . min/ml (P less than 0.001) following saline administration (n = 19). There was no relationship between gestational age and the response to neostigmine. In the infant lamb, neostigmine was associated with a lesser (P less than 0.001) but significant (P less than 0.02) growth hormone response. The integrated release was 704 +/- 410 ng . min/ml (n = 5) compared to -44 +/- 40 ng . min/ml following saline (n = 11). The fetal response to neostigmine was abolished by the administration of atropine (200 micrograms/kg bolus followed by 400 micrograms/kg per h infusion) 5 min prior to neostigmine (n = 4). This demonstrates that the effect of neostigmine was mediated by muscarinic receptors. Atropine itself had no effect on fetal growth hormone release (n = 6). In vitro binding studies with the muscarinic ligand, 1-quinuclidinyl [phenyl-4 (n) -3H] benzilate) were performed on homogenates of fetal (n = 3) and adult (n = 3) pituitaries. Scatchard analysis demonstrated both a high affinity and low affinity binding site. The concentration per mg. of original tissue of each of these binding sites was higher (P less than 0.05) in fetal than adult homogenates.(ABSTRACT TRUNCATED AT 250 WORDS)     

CCK-mediated response in the activation of 5-HT receptor types in the guinea-pig ileum

The possible interaction between cholecystokinin (CCK) and 5-hydroxytryptamine (5-HT) was evaluated in vitro in the longitudinal muscle-myenteric plexus of the guinea-pig ileum. Devazepide and L-365,260 were used to block CCKA and CCK(B) receptors and ondansetron and tropisetron to block 5-HT3 and 5-HT4 receptors, respectively. The CCK receptor antagonists blocked, in a dose-dependent manner, the response to 5-HT and to the selective agonists at 5-HT3 and 5-HT4 receptors, 2-methyl-5-hydroxytryptamine (2-Me-5-HT) and 5-methoxytryptamine (5-MeOT), respectively. The blockade was almost complete on the first phase of the concentration response curve to 5-HT and for all the concentrations of 5-MeOT tested. In the 2-Me-5-HT-induced contractile response there was a component with the same sensitivity to devazepide and to the selective NK1 receptor antagonist, GR 82334, and another resistant component that was abolished by atropine. However, the blockade of the NK1 receptor did not produce a significant increase in the inhibition obtained when atropine or devazepide were separately tested on the 5-MeOT-induced response. These results suggest that CCK is involved in the 5-HT-induced contractile response, particularly in the response induced by 5-HT4 receptor stimulation.     

Pituitary-adrenocortical axis, serum serotonin and biochemical response after halothane or isoflurane anaesthesia in rabbits

To document the changes in serum serotonin, adrenocorticotrophic hormone (ACTH), corticosterone levels and select biochemical parameters in response to inhalant anaesthesia, 20 New Zealand White (NZW) rabbits were assigned to two treatment groups: halothane and isoflurane. Induction of anaesthesia was achieved using a face mask (3.5% halothane and 4.5% isoflurane in oxygen) followed by endotracheal intubation and maintenance of anaesthesia for 30 min (1.5% halothane and 2.5% isoflurane in oxygen). Blood samples were obtained before anaesthetic induction, and at 1, 10, 30, 60, 120 min and 24, 48 and 72 h after endotracheal intubation. Serum serotonin and corticosterone levels were measured by competitive enzyme immunoassay, ACTH by radioimmunoassay. Serum glucose, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), blood urea nitrogen (BUN) and creatinine levels were measured using an automated analyser. Significant increases in serum ACTH and corticosterone levels occurred after halothane administration while serum serotonin levels did not change. An increase in serum corticosterone and serotonin levels occurred in the isoflurane group but no changes in ACTH concentrations were detected. Administration of halothane significantly increased serum glucose, ALT, AST, BUN and creatinine levels. After isoflurane administration, there was a significant increase in serum glucose, AST, BUN and creatinine levels. Based on these results, halothane stimulates the hypothalamic-pituitary-adrenal axis to a greater extent than isoflurane, but isoflurane increases serum serotonin levels. Both anaesthetic agents alter select biochemical parameters. These results should be taken into account when blood samples are evaluated in treated isoflurane or halothane anaesthetized rabbits.     

Respiratory compliance during sedation, anesthesia, and paralysis in infants and young children

Although total respiratory compliance (Crs) has been shown to fall in adults on induction of halothane anesthesia, no successful paired studies have been reported in children. The multiple occlusion technique was used to measure Crs in 17 infants and young children during sedated sleep (CrsS) and shortly after, following induction of halothane anesthesia (CrsA). Crs fell in all but one infant after induction of anesthesia, with a mean fall of 34.7% (range 0-58%). This was accompanied by a reduction in tidal volume and increase in frequency in every case. In 7 of the 17 children, who were to be paralyzed for surgical purposes, Crs was also measured in this anesthetized-paralyzed state. When tidal volume administered during manual ventilation was similar to that observed during measurement of CrsA, Crs during this low-volume ventilation was similar to CrsA. When tidal volume was increased and Crs remeasured, there was a significant increase in every case, with the high-volume Crs within 10% of CrsS in all but one child, in whom there was a 31.4% increase with respect to CrsS. Changes in tidal volume accounted for approximately 50% of the variability in each state. These results demonstrate a highly significant fall in Crs in infants and young children after induction of halothane anesthesia. In addition it appears that this reduction in Crs can be reversed by paralyzing the child and manually ventilating with tidal volumes approximating those seen during sedation.