The effect of glycopyrrolate vs. atropine in combination with neostigmine on cardiovascular system for reversal of residual neuromuscular blockade in the elderly: a randomized controlled trial.

BACKGROUND: Glycopyrrolate-neostigmine (G/N) for reversing neuromuscular blockade (NMB) causes fewer changes in heart rate (HR) than atropine-neostigmine (A/N). This advantage may be especially beneficial for elderly patients. Therefore, this study aimed to compare the cardiovascular effects of G/N and A/N for the reversal of NMB in elderly patients. METHODS: Elderly patients aged 65-80 years who were scheduled for elective non-cardiac surgery under general anesthesia were randomly assigned to the glycopyrrolate group (group G) or the atropine group (group A). Following the last administration of muscle relaxants for more than 30 min, group G received 4 ug/kg glycopyrrolate and 20 ug/kg neostigmine, while group A received 10 ug/kg atropine and 20 ug/kg neostigmine. HR, mean arterial pressure (MAP), and ST segment in lead II (ST-II) were measured 1 min before administration and 1-15 min after administration. RESULTS: HR was significantly lower in group G compared to group A at 2-8 min after administration (P < 0.05). MAP was significantly lower in group G compared to group A at 1-4 min after administration (P < 0.05). ST-II was significantly depressed in group A compared to group G at 2, 3, 4, 5, 6, 7, 8, 9, 11, 13, 14, and 15 min after administration (P < 0.05). CONCLUSIONS: In comparison to A/N, G/N for reversing residual NMB in the elderly has a more stable HR, MAP, and ST-II within 15 min after administration.

Evaluation and estimation of diuretic activity of the linalyl acetate in the rats.

This study aimed to explore the diuretic activity of linalyl acetate (LA). LA is an essential oil, it is an integral phyto-constituent of various plants. In this study, acute and chronic diuretic activities were explored by measuring the levels of different electrolytes and pH in the urine of experimental rats. Rats were divided into five groups. The control group was given 10 mg/kg normal saline, the treated group was given 10 mg/kg furosemide, and the remaining 3 groups received different doses of LA including 25, 50, and 75 mg/kg through intraperitoneal route, to determine its diuretic potential. Urine volume for acute diuretic activity was measured for 6 hours however for chronic diuretic activity was measured for 6 days. For a comparative study of LA with a control group and treated group with reference drug, diuretic index was used. Moreover, the underlying mechanism of the diuretic activity was also explored by comparing atropine, L-NAME, and indomethacin. The results of each group with 6 rats in each group were obtained by ± standard error of the mean of every group. Analysis of Variance (ANOVA) was used for statistical analysis. Results revealed that the LA 75 mg/kg dose showed comparable results as of furosemide. Moreover, this study revealed the involvement of muscarinic receptors to produce diuresis in comparison with atropine with very little involvement of prostanoids and no effect on NO pathway induced by indomethacin and L-NAME respectively. It is concluded that LA possess anti-diuretic potential. Muscarinic receptors might be involved in producing diuretic effects.

The role of vasoactive intestinal peptide (VIP) in atropine-related inhibition of the progression of myopia.

OBJECTIVE: This study aimed to investigate the potential involvement of vasoactive intestinal polypeptide (VIP) in myopia development and its contribution to the mechanism of action of the anti-myopia drug, atropine. METHODS: Thirty-three-week-old guinea pigs were randomly divided into normal control (NC, n = 10), monocularly form-deprived (FDM, n = 10), and FDM treated with 1% atropine (FDM + AT, n = 10) groups. The diopter and axial length were measured at 0, 2, and 4 weeks. Guinea pig eyeballs were removed at week four, fixed, and stained for morphological changes. Immunohistochemistry (IHC) and in situ hybridization (ISH) were performed to evaluate VIP protein and mRNA levels. RESULTS: The FDM group showed an apparent myopic shift compared to the control group. The results of the H&E staining were as follows: the cells of the inner/outer nuclear layers and retinal ganglion cells were disorganized; the choroidal thickness (ChT), blood vessel lumen, and area were decreased; the sclera was thinner, with disordered fibers and increased interfibrillar space. IHC and ISH revealed that VIP's mRNA and protein expressions were significantly up-regulated in the retina of the FDM group. Atropine treatment attenuated FDM-induced myopic shift and fundus changes, considerably reducing VIP's mRNA and protein expressions. CONCLUSIONS: The findings of elevated VIP mRNA and protein levels observed in the FDM group indicate the potential involvement of VIP in the pathogenesis and progression of myopia. The ability of atropine to reduce this phenomenon suggests that this may be one of the molecular mechanisms for atropine to control myopia.

Cardiovascular responses and the role of the neurohumoral cardiac regulation during digestion in the herbivorous lizard Iguana iguana.

Carnivorous reptiles exhibit an intense metabolic increment during digestion, which is accompanied by several cardiovascular adjustments responsible for meeting the physiological demands of the gastrointestinal system. Postprandial tachycardia, a well-documented phenomenon in these animals, is mediated by the withdrawal of vagal tone associated with the chronotropic effects of non-adrenergic and non-cholinergic (NANC) factors. However, herbivorous reptiles exhibit a modest metabolic increment during digestion and there is no information about postprandial cardiovascular adjustments. Considering the significant impact of feeding characteristics on physiological responses, we investigated cardiovascular and metabolic responses, as well as the neurohumoral mechanisms of cardiac control, in the herbivorous lizard Iguana iguana during digestion. We measured oxygen consumption rate (O2), heart rate (fH), mean arterial blood pressure (MAP), myocardial activity, cardiac autonomic tone, fH/MAP variability and baroreflex efficiency in both fasting and digesting animals before and after parasympathetic blockade with atropine followed by double autonomic blockade with atropine and propranolol. Our results revealed that the peak of O2 in iguanas was reached 24 h after feeding, accompanied by an increase in myocardial activity and a subtle tachycardia mediated exclusively by a reduction in cardiac parasympathetic activity. This represents the first reported case of postprandial tachycardia in digesting reptiles without the involvement of NANC factors. Furthermore, this withdrawal of vagal stimulation during digestion may reduce the regulatory range for short-term fH adjustments, subsequently intensifying the blood pressure variability as a consequence of limiting baroreflex efficiency.

Efficacy of the oxime HI-6 dimethanesulphonate in the treatment of guinea-pigs exposed to the nerve agents GB and GD.

The bispyridinium oxime HI-6 DMS is in development as an improved therapy for the treatment of patients exposed to organophosphorus nerve agents. The aim of the work described in this paper was to provide non-clinical data to support regulatory approval of HI-6 DMS, by demonstrating efficacy against an oxime-sensitive agent, GB and an oxime-resistant agent, GD. We investigated the dose-dependent protection afforded by therapy including atropine, avizafone and HI-6 DMS in guinea-pigs challenged with GB or GD. We also compared the efficacy of 30 mg.kg-1 of HI-6 DMS to an equimolar dose of the current in-service oxime P2S and the dichloride salt of HI-6 (HI-6 Cl2). In the treatment of GB or GD poisoning there was no significant difference between the salt forms. The most effective dose of HI-6 DMS in preventing lethality following challenge with GB was 100 mg.kg-1; though protection ratios of at least 25 were obtained at 10 mg.kg-1. Protection against GD was lower, and there was no significant increase in effectiveness of HI-6 DMS doses of 30 or 100 mg.kg-1. For GD, the outcome was improved by the addition of pyridostigmine pre-treatment. These data demonstrate the benefits of HI-6 DMS as a component of nerve agent therapy. © Crown copyright (2023), Dstl.

Site-specific autonomic vasomotor responses and their interactions in rat gingiva.

Blood flow in the gingiva, comprising the interdental papilla as well as attached and marginal gingiva, is important for maintaining of gingival function and is modulated by risk factors such as stress that may lead to periodontal disease. Marked blood flow changes mediated by the autonomic (parasympathetic and sympathetic) nervous system may be essential for gingival hemodynamics. However, differences in autonomic vasomotor responses and their functional significance in different parts of the gingiva are unclear. We examined the differences in autonomic vasomotor responses and their interactions in the gingiva of anesthetized rats. Parasympathetic vasodilation evoked by the trigeminal (lingual nerve)-mediated reflex elicited frequency-dependent blood flow increases in gingivae, with the increases being greatest in the interdental papilla. Parasympathetic blood flow increases were significantly reduced by intravenous administration of the atropine and VIP antagonist. The blood flow increase evoked by acetylcholine administration was higher in the interdental papilla than in the attached gingiva, whereas that evoked by VIP agonist administration was greater in the attached gingiva than in the interdental papilla. Activation of the cervical sympathetic nerves decreased gingival blood flow and inhibited parasympathetically induced blood flow increases. Our results suggest that trigeminal-parasympathetic reflex vasodilation 1) is more involved in the regulation of blood flow in the interdental papilla than in the other parts of the gingiva, 2) is mediated by cholinergic (interdental papilla) and VIPergic systems (attached gingiva), and 3) is inhibited by excess sympathetic activity. These results suggest a role in the etiology of periodontal diseases during mental stress.

The effect of topical 1 % atropine on ocular dimensions and diurnal rhythms of the human eye.

The effect of topical 1 % atropine on the diurnal rhythms of the human eye was investigated. Participants wore an activity monitor on Days 1-7. A set of measures (epochs) encompassing intraocular pressure (IOP), ocular biometry, and retinal imaging were obtained on Day 7 (baseline), followed by eight epochs on Day 8, and one on Day 9 from both eyes of healthy participants (n = 22, 19-25 years). The sleep time of participants (collected via actigraphy) was used as a reference in scheduling epochs. Topical 1 % atropine was instilled in the dominant eye on Day 8, 2 h after habitual wake time, using the fellow eye as control (paired-eye design). Sinusoids with a 24-h period were fitted to the data, and a non-linear mixed-effects model was used to estimate rhythmic statistics. There were no interocular differences in any of the measured parameters at baseline. Comparing pre- versus post-atropine in treated eyes revealed lower IOP, deeper anterior chamber (ACD), decreased crystalline lens thickness and shorter axial length (AL). The same trends were observed when comparing atropine-treated versus fellow control eyes, except for IOP and AL (no differences). Both atropine-treated and fellow control eyes showed significant diurnal variations in all ocular parameters, with atropine-treated eyes revealing larger AL and retinal thickness amplitudes, smaller vitreous chamber depth (VCD) amplitudes, and a significant phase advancement for ACD and VCD. There were no interocular differences in choroidal thickness rhythms. In conclusion, while ocular diurnal rhythms persisted after instillation of 1 % atropine, many rhythmic parameters were altered.

Central cholinergic transmission affects the compulsive-like behavior of mice in marble-burying test.

The presence of the cholinergic system in the brain areas implicated in the precipitation of obsessive-compulsive behavior (OCB) has been reported but the exact role of the central cholinergic system therein is still unexplored. Therefore, the current study assessed the effect of cholinergic analogs on central administration on the marble-burying behavior (MBB) of mice, a behavior correlated with OCB. The result reveals that the enhancement of central cholinergic transmission in mice achieved by intracerebroventricular (i.c.v.) injection of acetylcholine (0.01 µg) (Subeffective: 0.1 and 0.5 µg), cholinesterase inhibitor, neostigmine (0.1, 0.3, 0.5 µg/mouse) and neuronal nicotinic acetylcholine receptor agonist, nicotine (0.1, 2 µg/mouse) significantly attenuated the number of marbles buried by mice in MBB test without affecting basal locomotor activity. Similarly, central injection of mAChR antagonist, atropine (0.1, 0.5, 5 µg/mouse), nAChR antagonist, mecamylamine (0.1, 0.5, 3 µg/mouse) per se also reduced the MBB in mice, indicative of anti-OCB like effect of all the tested cholinergic mAChR or nAChR agonist and antagonist. Surprisingly, i.c.v. injection of acetylcholine (0.01 µg), and neostigmine (0.1 µg) failed to elicit an anti-OCB-like effect in mice pre-treated (i.c.v.) with atropine (0.1 µg), or mecamylamine (0.1 µg). Thus, the findings of the present investigationdelineate the role of central cholinergic transmission in the compulsive-like behavior of mice probably via mAChR or nAChR stimulation.

Adiponectin affects ileal contractility of mouse preparations.

Adiponectin (ADPN) has been reported to induce inhibitory effects on gastric motor activity, which, being a source of peripheral satiety signals, would contribute to the central anorexigenic effects of the hormone in rodents. However, peripheral satiety signals can also originate from the small intestine. Since there are no data on the effects of ADPN in this gut region, the present study aimed to investigate whether ADPN affects murine ileal contractility. Immunofluorescence experiments and Western blot were also performed to reveal the expression of ADPN receptors. Mechanical responses of ileal preparations were recorded in vitro via force-displacement transducers. Preparations showed a tetrodotoxin- and atropine-insensitive spontaneous contractile activity. Electrical field stimulation (EFS) induced tetrodotoxin- and atropine-sensitive contractile responses. ADPN induced a decay of the basal tension and decreased the amplitude of either the spontaneous contractility or the EFS-induced excitatory responses. All ADPN effects were abolished by the nitric oxide (NO) synthesis inhibitor NG-nitro l-arginine. The expression of the ADPN receptor, AdipoR1, but not AdipoR2, was also revealed in enteric glial cells. The present results offer the first evidence that ADPN acts on ileal preparations. The hormone exerts inhibitory effects, likely involving AdipoR1 on enteric glial cells and NO. From a physiological point of view, it could be hypothesized that the depressant action of ADPN on ileal contractility represents an additional peripheral satiety signal which, as also described for the ileal brake, could contribute to the central anorexigenic effects of the hormone.NEW & NOTEWORTHY This study provides the first evidence that adiponectin (ADPN) is able to act on ileal preparations. Functional results demonstrate that the hormone, other than causing a slight decay of the basal tension, depresses the amplitude of both spontaneous contractility and neurally induced excitatory responses of the mouse ileum through the involvement of nitric oxide. The expression of the ADPN receptor AdipoR1 and its localization on glial cells was revealed by Western blot and immunofluorescence analysis.

The lesion site of organophosphorus-induced central apnea and the effects of antidotes.

Organophosphorus poisoning kills individuals by causing central apnea; however, the underlying cause of death remains unclear. Following findings that the pre-Bötzinger complex impairment alone does not account for central apnea, we analyzed the effect of paraoxon on the brainstem-spinal cord preparation, spanning the lower medulla oblongata to phrenic nucleus. Respiratory bursts were recorded by connecting electrodes to the ventral 4th cervical nerve root of excised brainstem-spinal cord preparations obtained from 6-day-old Sprague-Dawley rats. We observed changes in respiratory bursts when paraoxon, neostigmine, atropine, and 2-pyridine aldoxime methiodide were administered via bath application. The percentage of burst extinction in the paraoxon-poisoning group was 50% compared with 0% and 18.2% in the atropine and 2-pyridine aldoxime methiodide treatment groups, respectively. Both treatments notably mitigated the paraoxon-induced reduction in respiratory bursts. In the neostigmine group, similar to paraoxon, bursts stopped in 66.7% of cases but were fully reversed by atropine. This indicates that the primary cause of central apnea is muscarinic receptor-mediated in response to acetylcholine excess. Paraoxon-induced central apnea is hypothesized to result from neural abnormalities within the inferior medulla oblongata to the phrenic nucleus, excluding pre-Bötzinger complex. These antidotes antagonize central apnea, suggesting that they may be beneficial therapeutic agents.

Vasovagal Responses to Human Monomorphic Ventricular Tachycardia: Hemodynamic Implications From Sinus Rate Analysis.

BACKGROUND: Factors determining hemodynamic stability during human ventricular tachycardia (VT) are incompletely understood. OBJECTIVES: The purposes of this study were to characterize sinus rate (SR) responses during monomorphic VT in association with hemodynamic stability and to prospectively assess the effects of vagolytic therapy on VT tolerance. METHODS: This is a retrospective analysis of patients undergoing scar-related VT ablation. Vasovagal responses were evaluated by analyzing sinus cycle length before VT induction and during VT. SR responses were classified into 3 groups: increasing (≥5 beats/min, sympathetic), decreasing (≥5 beats/min, vagal), and unchanged, with the latter 2 categorized as inappropriate SR. In a prospective cohort (n = 30) that exhibited a failure to increase SR, atropine was administered to improve hemodynamic tolerance to VT. RESULTS: In 150 patients, 261 VT episodes were analyzed (29% untolerated, 71% tolerated) with median VT duration 1.6 minutes. A total of 52% of VT episodes were associated with a sympathetic response, 31% had unchanged SR, and 17% of VTs exhibited a vagal response. A significantly higher prevalence of inappropriate SR responses was observed during untolerated VT (sustained VT requiring cardioversion within 150 seconds) compared with tolerated VT (84% vs 34%; P < 0.001). Untolerated VT was significantly different between groups: 9% (sympathetic), 82% (vagal), and 32% (unchanged) (P < 0.001). Atropine administration improved hemodynamic tolerance to VT in 70%. CONCLUSIONS: Nearly one-half of VT episodes are associated with failure to augment SR, indicative of an under-recognized pathophysiological vasovagal response to VT. Inappropriate SR responses were more predictive of hemodynamic instability than VT rate and ejection fraction. Vagolytic therapy may be a novel method to augment blood pressure during VT.

The role of the serotonergic system in atropine's anti-myopic effects.

The muscarinic cholinergic antagonist atropine is the most widely used pharmacological treatment for the visual disorder myopia (short-sightedness), the leading cause of low-vision worldwide. This study sought to better define the mechanism by which atropine inhibits myopic growth. Although classified as a muscarinic-cholinergic antagonist, atropine has been found to bind and modulate the activity of several non-cholinergic systems (e.g., serotonin). Thus, this study investigated whether the serotonergic system could underly atropine's anti-myopic effects. Using a chick model of myopia, we report that atropine's growth-inhibitory effects can be attenuated by pharmacological stimulation of the serotonin system. This may suggest that atropine can slow the development of myopia through inhibiting serotonergic receptor activity. We also observed that pharmacological antagonism of serotonergic receptors inhibits the development of experimental myopia in a dose-dependent manner, further demonstrating that modulation of serotonergic receptor activity can alter ocular growth rates. Finally, we found that neither experimental myopia, nor atropine treatment, induced a significant change in retinal serotonergic output (i.e., synthesis, transport, release and catabolism). This may suggest that, although myopic growth can be inhibited through modulation of serotonergic receptor activity (by atropine or serotonergic antagonists), this does not require a change in serotonin levels. These findings regarding a serotonergic mechanism for atropine may have significant ramifications for the treatment of human myopia. This includes assessing the use of atropine in patients who are also undergoing treatment to upregulate serotonergic signaling (e.g., serotonergic anti-depressants).

Carboxylic acid-functionalized multiwalled carbon nanotubes (COOH-MWCNTs) improved production of atropine in callus of Datura inoxia by influencing metabolism, gene regulation, and DNA cytosine methylation; an in vitro biological assessment.

Atropine is a well-known tropane alkaloid commonly employed in medicine class called anticholinergics. This study intends to address biochemical and molecular responses of Datura inoxia calluses to fortifying culture medium with carboxylic acid-functionalized multi-walled carbon nanotubes (COOH-MWCNTs). The application of MWCNTs influenced callogenesis performance and biomass in a dose-dependent manner. The MWCNT at 5 mgL-1 resulted in the highest biomass of calluses by 57%. While, MWCNTs at high concentrations were accompanied by cytotoxicity. On the other hand, MWCNTs at concentrations above 100 mgL-1 exhibited cytotoxicity, decreased callogenesis performance, and reduced Atropine biosynthesis. The MWCNTs increased the activity of phenylalanine ammonia-lyase (PAL) and catalase enzymes. The concentrations of proline and soluble phenols displayed upward trends in response to using MWCNTs. According to the HPLC assessment, enriching culture medium with MWCNTs at 5 mgL-1 elicited Atropine production in calluses by 64%. The quantitative PCR assessment referred to the upregulation in the transcription of the PAL gene. The expression of ornithine decarboxylase (ODC) and putrescine N-methyltransferase 1 (PMT) genes were also upregulated in calluses cultured in a medium supplemented with MWCNTs. Methylation Sensitive Amplification Polymorphism (MSAP) technique indicated that employing MWCNTs altered the DNA methylation profile, reflecting epigenetic modification. Overall, engineering plant cells with MWCNTs as a nano-elicitor can be suggested for large-scale synthesis of industrially-valuable secondary metabolites.

Real-world outcomes of low-dose atropine therapy on myopia progression in an Australian cohort during the COVID-19 pandemic.

BACKGROUND: To report the outcomes of low-dose atropine (0.01% and 0.05%) for preventing myopia progression in a real-world Australian cohort during the COVID-19 pandemic. METHODS: Records of children presenting with myopia, from January 2016 to 2022, were retrospectively reviewed at a comprehensive ophthalmic practice. Children who discontinued treatment, ages >18, and cases with hereditary conditions were excluded. The rate of progression of myopia after treatment with atropine was compared with historical data to evaluate the effectiveness of the regime. RESULTS: One hundred and one children (mean baseline spherical equivalent [SphE] [-3.70 +/- 2.09 D] and axial length [AL] [24.59 +/- 1.00 mm]) were analysed. The mean age of the children was 10.4 +/- 2.89 years and 61% were females. The average follow-up time was 17.9 +/- 12.5 months. The mean rate of progression of AL and SphE on 0.01% atropine eyedrops was 0.219 +/- 0.35 mm and - 0.250 +/- 0.86 D/year, respectively. 68.1% of the children treated with 0.01% atropine were mild progressors (<0.5 D change/year). Non-responders when commenced on a higher dose of atropine (0.05%) experienced a 93% (p = 0.012) and 30% reduction in SphE and AL growth rate, respectively. Family history, higher myopia or younger age at baseline and shorter duration of treatment were associated with steeper progression (p < 0.01). Both doses were well tolerated. CONCLUSIONS: Low-dose atropine was shown to be beneficial in a real-world clinical setting, despite interruptions to follow-ups secondary to COVID-19 pandemic. A 0.05% dose of atropine may be effective in cases where 0.01% was ineffective.

Cardiac Vagal Nerve Activity Increases During Exercise to Enhance Coronary Blood Flow.

BACKGROUND: The phrase complete vagal withdrawal is often used when discussing autonomic control of the heart during exercise. However, more recent studies have challenged this assumption. We hypothesized that cardiac vagal activity increases during exercise and maintains cardiac function via transmitters other than acetylcholine. METHODS: Chronic direct recordings of cardiac vagal nerve activity, cardiac output, coronary artery blood flow, and heart rate were recorded in conscious adult sheep during whole-body treadmill exercise. Cardiac innervation of the left cardiac vagal branch was confirmed with lipophilic tracer dyes (DiO). Sheep were exercised with pharmacological blockers of acetylcholine (atropine, 250 mg), VIP (vasoactive intestinal peptide; [4Cl-D-Phe6,Leu17]VIP 25 µg), or saline control, randomized on different days. In a subset of sheep, the left cardiac vagal branch was denervated. RESULTS: Neural innervation from the cardiac vagal branch is seen at major cardiac ganglionic plexi, and within the fat pads associated with the coronary arteries. Directly recorded cardiac vagal nerve activity increased during exercise. Left cardiac vagal branch denervation attenuated the maximum changes in coronary artery blood flow (maximum exercise, control: 63.5±5.9 mL/min, n=8; cardiac vagal denervated: 32.7±5.6 mL/min, n=6, P=2.5×10-7), cardiac output, and heart rate during exercise. Atropine did not affect any cardiac parameters during exercise, but VIP antagonism significantly reduced coronary artery blood flow during exercise to a similar level to vagal denervation. CONCLUSIONS: Our study demonstrates that cardiac vagal nerve activity actually increases and is crucial for maintaining cardiac function during exercise. Furthermore, our findings show the dynamic modulation of coronary artery blood flow during exercise is mediated by VIP.

Pharmacological prophylaxis with pyridostigmine bromide against nerve agents adversely impact on airway function in an ex vivo rat precision-cut lung slice model.

The carbamate pyridostigmine bromide (PB) is the only fielded pharmacological prophylaxis for military use against nerve agents. Previous studies have shown differences in the PB-pretreatment efficacy for various nerve agents and in the influence of post-exposure treatment with common antidotes. In the present study, the aim was to evaluate the possibility of using an ex vivo rat precision-cut lung slice model to determine the impact of PB pretreatment on VX-induced bronchoconstriction. In addition, the efficacy of post-exposure treatment with atropine sulfate following PB-prophylaxis was investigated.Bronchoconstriction was induced by electric-field stimulation and was significantly aggravated by 10 µM PB. Airway recovery was decreased by both 1 and 10 µM PB. Evaluation of acetylcholineesterese inhibition by PB showed that the lower concentration met the clinical criteria of residual enzyme activity while the higher concentration completely inhibited the activity. Exposure to VX with or without pretreatment demonstrated similar contractions. However, VX-incubation following pretreatment caused decreased airway relaxation compared to pretreatment alone. Atropine treatment following PB- and VX-exposure significantly decreased the maximum airway contraction and increased the relaxation.In conclusion, no beneficial effect of PB-prophylaxis on VX-induced contractions was observed. The atropine efficacy to relax airways was significant demonstrating the importance of efficient post-exposure therapeutics to protect against the life-threatening respiratory contractions.

CNS sites controlling the gastric pyloric sphincter: Neuroanatomical and functional study in the rat.

The pyloric sphincter receives parasympathetic vagal innervation from the dorsal motor nucleus of the vagus (DMV). However, little is known about its higher-order neurons and the nuclei that engage the DMV neurons controlling the pylorus. The purpose of the present study was twofold. First, to identify neuroanatomical connections between higher-order neurons and the DMV. This was carried out by using the transneuronal pseudorabies virus PRV-152 injected into rat pylorus torus and examining the brains of these animals for PRV labeling. Second, to identify the specific sites within the DMV that functionally control the motility and tone of the pyloric sphincter. For these studies, experiments were performed to assess the effect of DMV stimulation on pylorus activity in urethane-anesthetized male rats. A strain gauge force transducer was sutured onto the pyloric tonus to monitor tone and motility. L-glutamate (500 pmol/30 nL) was microinjected unilaterally into the rostral and caudal areas of the DMV. Data from the first study indicated that neurons labeled with PRV occurred in the DMV, hindbrain raphe nuclei, midbrain Edinger-Westphal nucleus, ventral tegmental area, lateral habenula, and arcuate nucleus. Data from the second study indicated that microinjected L-glutamate into the rostral DMV results in contraction of the pylorus blocked by intravenously administered atropine and ipsilateral vagotomy. L-glutamate injected into the caudal DMV relaxed the pylorus. This response was abolished by ipsilateral vagotomy but not by intravenously administered atropine or L-NG-nitroarginine methyl ester (L-NAME). These findings identify the anatomical and functional brain neurocircuitry involved in controlling the pyloric sphincter. Our results also show that site-specific stimulation of the DMV can differentially influence the activity of the pyloric sphincter by separate vagal nerve pathways.

[Preventive effect of atropine premedication on vagal reflex in patients undergoing suspension laryngoscopy during anesthesia induction].

Objective: To evaluate the preventive effect of atropine premedication during anesthesia induction on vagal reflex in patients undergoing suspension laryngoscopy. Methods: A total of 342 patients (202 males and 140 females) scheduled for suspension laryngoscopy under general anesthesia in Beijing Tongren Hospital from October 2021 to March 2022 were prospectively enrolled, with a mean age of (48.1±11.9) years. The patients were randomly divided into two groups using the random number table method: the treatment group (n=171) and the control group (n=171). Patients in the treatment group were administrated with 0.5 mg atropine intravenously guttae (ivgtt) while patients in the control group were given equivalent volume of normal saline. For all patients, if heart rate (HR)<50 beats/min happened during the insertion of the suspension laryngoscope, the operation should be stopped and the laryngoscope should be removed. Patients without HR recovery after the removal of the laryngoscope should be given 0.5 mg atropine, and the operation should be continued after the HR recovered. The primary outcome was the incidence of HR fluctuation over 20% (ΔHR>20%) before and immediately after suspension laryngoscope fixation, and the secondary outcomes included HR, mean arterial pressure (MAP) of the two groups recorded before and after anesthesia induction, before and immediately after suspension laryngoscope fixation, and the incidences of sinus bradycardia, laryngoscope removal and atropine treatment during operation. Results: The incidences of ΔHR>20% and bradycardia immediately after the suspension laryngoscope fixation were 14.6% (25/171) and 12.9% (22/171) in the treatment group, which were significantly lower than those in the control group [28.1% (48/171) and 29.8% (51/171)] (both P<0.05). The HR immediately after the suspension laryngoscope fixation in the treatment group [(66.4±13.5) beats/min] and in the control group [(60.8±15.7) beats/min] was significantly lower than those before the suspension laryngoscope fixation [(74.7±11.1) beats/min and (67.6±12.8) beats/min, respectively] (both P<0.05). There were no significant differences in MAP between the two groups at each time point (all P>0.05). The incidence of laryngoscope removal once plus 0.5 mg atropine administration, laryngoscope removal twice plus 0.5 mg atropine administration and laryngoscope removal twice plus 1.0 mg atropine administration was 9.9% (17/171), 1.8% (3/171) and 0 (0) in the treatment group, respectively, which was significantly lower than those in the control group [24.0% (41/171), 5.8% (10/171) and 2.3% (4/171), respectively] (all P<0.05). Conclusion: Atropine premedication during anesthesia induction can effectively reduce the occurrence of vagal reflex in patients undergoing suspension laryngoscopy.

Atropine facilitates water-evoked swallows via central muscarinic receptors in anesthetized rats.

Anticholinergic medication causes impaired swallowing with hyposalivation. However, the underlying mechanisms by which these drugs modulate the swallowing reflex remain unclear. This study investigated the effects of the muscarinic acetylcholine receptor (mAChR) nonspecific antagonist atropine on the initiation of swallowing. Experiments were performed on 124 urethane-anesthetized rats. A swallow was evoked by either topical laryngeal application of a small amount of distilled water (DW), saline, citric acid, or capsaicin; upper airway distention with a continuous airflow; electrical stimulation of the superior laryngeal nerve (SLN); or focal microinjection of N-methyl-d-aspartate (NMDA) into the lateral region of the nucleus of the solitary tract (L-nTS). Swallows were identified by electromyographic bursts of the digastric and thyrohyoid muscles. Either atropine, the peripheral mAChR antagonist methylatropine, or antagonists of mAChR subtypes M1-M5 were intravenously delivered. Atropine at a dose of 1 mg/kg increased the number of DW-evoked swallows compared with baseline and did not affect the number of swallows evoked by saline, citric acid, capsaicin, or upper airway distention. Methylatropine and M1-M5 antagonists did not significantly change the number of DW-evoked swallows. Bilateral SLN transection completely abolished DW-evoked swallows, and atropine decreased the swallowing threshold of SLN electrical stimulation. Finally, microinjection of NMDA receptor antagonist AP-5 into the L-nTS inhibited DW-evoked swallows, and atropine facilitated the initiation of swallowing evoked by NMDA microinjection into this region. These results suggest that atropine facilitates DW-evoked swallows via central mAChR actions.NEW & NOTEWORTHY Atropine facilitated the distilled water (DW)-evoked swallows in anesthetized rats. Atropine decreased the swallowing threshold evoked by electrical stimulation of the superior laryngeal nerve, which is a primary sensory nerve for the initiation of DW-evoked swallows. Atropine facilitated the swallows evoked by N-methyl-d-aspartate microinjection into the lateral region of the nucleus of the solitary tract, which is involved in the DW-evoked swallows. We speculate that atropine facilitates the DW-evoked swallows via central muscarinic receptor actions.

Combination of acetylcholinesterase inhibitors and NMDA receptor antagonists increases survival rate in soman-poisoned mice.

Organophosphorus nerve agents pose a global threat to both military personnel and civilian population, because of their high acute toxicity and insufficient medical countermeasures. Commonly used drugs could ameliorate the intoxication and overall medical outcomes. In this study, we tested the drugs able to alleviate the symptoms of Alzheimer's disease (donepezil, huperzine A, memantine) or Parkinson's disease (procyclidine). They were administered to mice before soman intoxication in terms of their: i) protection potential against soman toxicity and ii) influence on post-exposure therapy consisting of atropine and asoxime (also known as oxime HI-6). Their pretreatment effect was not significant, when administered alone, but in combination (acetylcholinesterase inhibitor such as denepezil or huperzine A with NMDA antagonist such as memantine or procyclidine) they lowered the soman toxicity more than twice. These combinations also positively influenced the efficacy of post-exposure treatment in a similar fashion; the combinations increased the therapeutic effectiveness of antidotal treatment. In conclusion, the most effective combination - huperzine A and procyclidine - lowered the toxicity three times and improved the post-exposure therapy efficacy more than six times. These results are unprecedented in the published literature.