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Alcohol, a widely commercialized psychotropic drug, and the benzodiazepine Flunitrazepam, an anxiolytic widely prescribed for patients with anxiety and insomnia problems, are well known drugs and both act on the central nervous system. The misuse and the association of these two drugs are public health concerns in several countries and could cause momentary, long-lasting and even lethal neurophysiological problems due to the potentiation of their adverse effects in synergy. The present study observed the result of the association of these drugs on electrophysiological responses in the brain, heart, and respiratory rate in Wistar rats. 8 experimental groups were determined: control, one alcohol group (20% at a dose of 1 ml/100 g VO), three Flunitrazepam groups (doses 0.1; 0.2 and 0.3 mg/kg) and three alcohol-Flunitrazepam groups (20% at a dose of 1 ml/100 g VO of alcohol, combined with 0.1; 0.2 and 0.3 mg/kg of Flunitrazepam, respectively). The results showed that there was a more pronounced reduction in alpha and theta wave power in the alcohol-Flunitrazepam groups, a decrease in the power of beta oscillations and greater sedation. There was a progressive decrease in respiratory rate linked to the increase of Flunitrazepam dose in the alcohol-Flunitrazepam associated administration. It was observed alteration in heart rate and Q-T interval in high doses of Flunitrazepam. Therefore, we conclude that the association alcohol-Flunitrazepam presented deepening of depressant synergistic effects according to the increase in the dose of the benzodiazepine, and this could cause alterations in low frequency brain oscillations, breathing, and hemodynamics of the patient., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: Compared with the use of ultrasound for noninvasive monitoring of the anesthetic sodium pentobarbital versus tribromoethanol in an animal model of renal ischemia-reperfusion injury in rats., Methods: Adult rats were randomly assigned to a renal ischemia-reperfusion injury model, and preoperative anesthetics were administered as either sodium pentobarbital or tribromoethanol. Color Doppler ultrasound and spectral Doppler ultrasound were used to detect changes in respiratory rate and heart rate during and after the surgery, as well as measure renal hemodynamic parameters including peak systolic velocity, end-diastolic velocity, and resistance index., Results: The frequency of changes in respiration and heart rate was significantly higher in the sodium pentobarbital anesthesia group compared to the tribromoethanol anesthesia group. The peak systolic velocity and end-diastolic velocity values in the sodium pentobarbital anesthesia group were significantly lower than those in the tribromoethanol group. However, the resistance index in the sodium pentobarbital group was higher than that in the tribromoethanol group., Conclusion: Ultrasound can be used to dynamically monitor the effects of anesthesia during the experiment, including changes in respiratory rate and heart rate, as well as semi-quantitatively monitor hemodynamic changes in the kidneys, which indirectly reflects whole-body hemodynamic changes in rats., (© 2024 Wiley Periodicals LLC.)

Cadmium (Cd) is a dangerous heavy metal that is non-degradable in the environment. Many organs can accumulate Cd and adversely affect organ function and health. Cd is considered as a teratogenic and embryotoxic agent. This study aims to evaluate the teratogenicity of Cd at concentrations lesser than the permissible and its effects on the heart during chick embryogenesis. Fertilized eggs of the chick Gallus domesticus were divided into; control, saline injected and four experimental groups injected with single doses of 5, 25, 50 or 75 µM of CdCl 2 . Histological observations of the heart before hatching and the cardiomyocytes after hatching were recorded. Morphometric measurements of heart chambers were achieved at 3, 4 and 6 days of incubation. Electrocardiograph and respiratory rate were recorded at tenth day. Different cardiac problems had been brought on by Cd. In comparison to controls, the heart looked much larger, and in certain cases, growth retardation was seen. Degeneration in heart walls and malformations of dorsal aorta were noticed. Morphometrically, the width and wall thickness of heart chambers showed significant changes. Heart beats and respiratory rate significantly decreased compared to control. The cardiotoxic effect of Cd on heart compartments structure and function was dose dependent. One of Cd toxicity is its ability to induce cellular oxidative stress. The heart in particular is sensitive to oxidative stress. Cardiac oxidative stress might intensify heart failure and promote disease progression. Calcium is one of the components that is needed for normal heart work. Cd might interfere with calcium metabolism by removing it from the body., (© 2024. The Author(s).)

Objective: To compare the effects of propofol, ketamine-propofol and isoflurane, at similar anesthetic depth, on cardiopulmonary variables in unpremedictated chickens., Study Design: Prospective, randomized, crossover experimental trial., Animals: A total of 10 male Leghorn domestic chickens, aged 3 months and body mass 1.4-2.0 kg., Methods: Birds were randomly assigned to each of three anesthetic protocols, 7 days apart: intravenous propofol, intravenous ketamine-propofol or isoflurane. Anesthesia was induced (indicated by loss of righting reflex and tracheal intubation) and maintained with propofol (10 mg kg -1 minute -1 , then 1.1 mg kg -1 minute -1 ), ketamine-propofol (5 mg mL -1 ketamine and 5 mg mL -1 propofol combined; 10 mg kg -1 minute -1 , then 1.1 mg kg -1 minute -1 ) or isoflurane [5% vaporizer setting initially, then end-tidal concentration (Fe'Iso) of 2%] for 65 minutes. Anesthesia was maintained at a similar anesthetic depth based upon positive or negative responses to toe pinch. Heart rate (HR), respiratory rate (f R ), noninvasive arterial blood pressure and arterial blood gases were measured during anesthesia. Propofol or ketamine-propofol infusion rates and Fe'Iso required to prevent movement in response to a noxious stimulus and recovery times were recorded., Results: Anesthesia induction dose was 9.0 ± 0.8 (mean ± SD) and 12.2 ± 0.3 mg kg -1 for propofol and ketamine-propofol, respectively. Propofol and ketamine-propofol infusion rates and Fe'Iso required to prevent movement in response to the noxious stimulus were 0.88 ± 0.14 mg kg -1 minute -1 , 0.92 ± 0.14 mg kg -1 minute -1 and 1.45 ± 0.28%, respectively. Cardiopulmonary variables remained clinically acceptable, but ketamine-propofol was associated with a significantly higher HR (p = 0.0001) and lower f R (p = 0.0001). Time to extubation did not differ among treatments., Conclusions and Clinical Relevance: Cardiovascular and respiratory variables were maintained within normal ranges in all treatments. Coadministration of ketamine with propofol significantly reduced the induction and maintenance dose of propofol., (Copyright © 2024 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved.)

The lateral parabrachial nucleus (PBL) is implicated in the regulation of respiratory activity. Sodium leak channel (NALCN) mutations disrupt the respiratory rhythm and influence anesthetic sensitivity in both rodents and humans. Here, we investigated whether the NALCN in PBL glutamatergic neurons maintains respiratory function under general anesthesia. Our results showed that chemogenetic activation of PBL glutamatergic neurons increased the respiratory frequency (RF) in mice; whereas chemogenetic inhibition suppressed RF. NALCN knockdown in PBL glutamatergic neurons but not GABAergic neurons significantly reduced RF under physiological conditions and caused more respiratory suppression under sevoflurane anesthesia. NALCN knockdown in PBL glutamatergic neurons did not further exacerbate the respiratory suppression induced by propofol or morphine. Under sevoflurane anesthesia, painful stimuli rapidly increased the RF, which was not affected by NALCN knockdown in PBL glutamatergic neurons. This study suggested that the NALCN is a key ion channel in PBL glutamatergic neurons that maintains respiratory frequency under volatile anesthetic sevoflurane but not intravenous anesthetic propofol., (© 2024. Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences.)

Objectives: The aim of this study was to evaluate the efficacy of a single dose of oral pregabalin (PGB) for sedation and its impact on physiological and echocardiographic variables in healthy cats., Methods: This study was a randomised, blinded, crossover trial. Eight cats were randomly assigned to receive PGB or placebo, with a 1-week washout period between each administration. Cats in the treatment group received oral PGB at varying doses (low dose: 2.5 mg/kg, medium dose: 5 mg/kg, high dose: 10 mg/kg). Systolic blood pressure (SBP), pulse rate (PR), respiratory rate (RR) and sedation score were measured at intervals of 30 mins after administration. Echocardiography was performed 120 mins after administration., Results: Oral administration of PGB 2.5 mg/kg and 5 mg/kg significantly increased sedation scores starting at 150 mins, while 10 mg/kg PGB showed a significant increase in sedation scores starting at 120 mins compared with placebo. PGB 5 mg/kg and 10 mg/kg resulted in a significant reduction in SBP compared with placebo, with minimal impact on PR and RR. In addition, PGB 10 mg/kg resulted in significant changes in the peak velocity of late diastolic transmitral flow (A) and the ratio of peak velocity of early diastolic transmitral flow and A; however, these changes were of marginal clinical significance., Conclusions and Relevance: A single dose of oral PGB could cause mild to moderate sedation. Hypotension was more prevalent in the PGB 5 mg/kg and 10 mg/kg groups among the majority of cats, but it was less frequently observed in the PGB 2.5 mg/kg group., Competing Interests: Conflict of interestThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Taurine is a nonessential amino acid that has been increasingly consumed due to its various beneficial biological effects. Excessive taurine intake has been linked to the positive regulation of inflammatory responses and endoplasmic reticulum stress through the modulation of intracellular calcium levels. However, research on the potential adverse effects of taurine consumption on the respiratory system is limited. To address this, we investigated the respiratory responses of 6-week-old male Sprague-Dawley rats to taurine administered orally at 0, 100, 200, and 400 mg/kg. Respiratory rate, tidal volume, and minute volume were monitored in accordance with the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) Harmonized Tripartite Guideline S7A for Safety Pharmacology Studies for Human Pharmaceuticals. We found that taurine administration did not significantly alter respiratory rate or tidal volume; however, a significant increase in minute volume was observed 6 h after administration of 200 mg/kg taurine.

Guinea pigs are often used in translational research, but providing them with safe and effective anesthesia is a challenge. Common methods like inhalant anesthesia and injectable ketamine/xylazine induce surgical anesthesia but can negatively affect cardiovascular, respiratory, and thermoregulatory systems and complicate the interpretation of research outcomes. Several alternative anesthetic regimens have been investigated, but none have consistently achieved a surgical plane of anesthesia. Therefore, identifying an anesthetic regimen that achieves a stable state of the surgical plane of anesthesia while preserving cardiorespiratory function would be a valuable contribution. To address this issue, we compared the efficacy of 3 anesthetic combinations in female Dunkin-Hartley guinea pigs: 1) alfaxalone, dexmedetomidine, and fentanyl (ADF); 2) alfaxalone, midazolam, and fentanyl (AMF); and 3) alfaxalone, midazolam, fentanyl, and isoflurane (AMFIso). We monitored anesthetic depth, heart rate, oxygenation, respiratory rate, respiratory effort, blood pressure, and body temperature every 15 min from injection to recovery. We also recorded the time to loss of righting reflex, duration of anesthesia, and time to achieve a surgical plane. The results showed no statistically significant differences in induction and recovery times among the groups. In the AMFIso group, 100% of the animals achieved a surgical plane of anesthesia, whereas only 10% of the animals in the AMF group reached that level. None of the animals in ADF group reached a surgical plane of anesthesia. Respiratory rate was significantly lower in the AMFIso as compared with the ADF group ( P < 0.001) but was not different between the AMF and ADF groups. Temperature was significantly lower in the AMFIso group as compared with both the ADF and AMF groups ( P < 0.001). In conclusion, both combinations of solely injectable anesthetics assessed in this study can be used for short, nonpainful procedures without significant cardiorespiratory depression. However, for mildly to moderately painful surgical procedures, the addition of an inhalant anesthetic like isoflurane is necessary for female guinea pigs.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive loss of dopaminergic neurons in the substantia nigra compacta (SNpc). In a mouse model of PD induced by the injection of 6-hydroxydopamine (6-OHDA) into the caudate putamen (CPu) dyspnea events are very common. Neuroanatomical and functional studies show that the number of glutamatergic neurons in the pre-Bötzinger Complex (preBötC) are reduced. We hypothesize that the neuronal loss, and consequently loss of glutamatergic connections in the respiratory network previously investigated, are responsible for the breathing impairment in PD. Here, we tested whether ampakines (CX614), a subgroup of AMPA receptor positive allosteric modulators, could stimulate the respiratory activity in PD-induced animals. CX614 (50 µM) injected intraperitoneally or directly into the preBötC region reduced the irregularity pattern and increased the respiratory rate by 37% or 82%, respectively, in PD-induced animals. CX614 also increased the respiratory frequency in healthy animals. These data suggest that ampakine CX614 could become a tool to restore breathing in PD., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Noninvasive ventilation (NIV) and High-flow nasal cannula (HFNC) are the main forms of treatment for acute respiratory failure. This study aimed to evaluate the effect, safety, and applicability of the NIV and HFNC in patients with acute hypoxemic respiratory failure (AHRF) caused by COVID-19., Methods: In this retrospective study, we monitored the effect of NIV and HFNC on the SpO 2 and respiratory rate before, during, and after treatment, length of stay, rates of endotracheal intubation, and mortality in patients with AHRF caused by COVID-19. Additionally, data regarding RT-PCR from physiotherapists who were directly involved in assisting COVID-19 patients and non-COVID-19., Results: 62.2 % of patients were treated with HFNC. ROX index increased during and after NIV and HFNC treatment (P < 0.05). SpO 2 increased during NIV treatment (P < 0.05), but was not maintained after treatment (P = 0.17). In addition, there was no difference in the respiratory rate during or after the NIV (P = 0.95) or HFNC (P = 0.60) treatment. The mortality rate was 35.7 % for NIV vs 21.4 % for HFNC (P = 0.45), while the total endotracheal intubation rate was 57.1 % for NIV vs 69.6 % for HFNC (P = 0.49). Two adverse events occurred during treatment with NIV and eight occurred during treatment with HFNC. There was no difference in the physiotherapists who tested positive for SARS-COV-2 directly involved in assisting COVID-19 patients and non-COVID-19 ones (P = 0.81)., Conclusion: The application of NIV and HFNC in the critical care unit is feasible and associated with favorable outcomes. In addition, there was no increase in the infection of physiotherapists with SARS-CoV-2., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

The opioid buprenorphine alters breathing and the cytokine leptin stimulates breathing. Obesity increases the risk for respiratory disorders and can lead to leptin resistance. This study tested the hypothesis that buprenorphine causes dose-dependent changes in breathing that vary as a function of obesity, leptin status, and sex. Breathing measures were acquired from four congenic mouse lines: female and male wild type C57BL/6J (B6) mice, obese db/db and ob/ob mice with leptin dysfunction, and male B6 mice with diet-induced obesity. Mice were injected intraperitoneally with saline (control) and five doses of buprenorphine (0.1, 0.3, 1.0, 3.0, 10 mg/kg). Buprenorphine caused dose-dependent decreases in respiratory frequency while increasing tidal volume, minute ventilation, and respiratory duty cycle. The effects of buprenorphine varied significantly with leptin status and sex. Buprenorphine decreased minute ventilation variability in all mice. The present findings highlight leptin status as an important modulator of respiration and encourage future studies aiming to elucidate the mechanisms through which leptin status alters breathing., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The EP2 receptor has emerged as a therapeutic target with exacerbating role in disease pathology for a variety of peripheral and central nervous system disorders. We and others have recently demonstrated beneficial effects of EP2 antagonists in preclinical models of neuroinflammation and peripheral inflammation. However, it was earlier reported that mice with global EP2 knockout (KO) display adverse phenotypes on fertility and blood pressure. Other studies indicated that EP2 activation with an agonist has a beneficial effect of healing fractured bone in animal models. These results impeded the development of EP2 antagonists, and EP2 antagonism as therapeutic strategy. To determine whether treatment with EP2 antagonist mimics the adverse phenotypes of the EP2 global KO mouse, we tested two EP2 antagonists TG11-77. HCl and TG6-10-1 in mice and rats while they are on normal or high-salt diet, and by two different administration protocols (acute and chronic). There were no adverse effects of the antagonists on systolic and diastolic blood pressure, heart rate, respiratory function in mice and rats regardless of rodents being on a regular or high salt diet. Furthermore, chronic exposure to TG11-77. HCl produced no adverse effects on blood cell counts, bone-volume and bone-mineral density in mice. Our findings argue against adverse effects on cardiovascular and respiratory systems, blood counts and bone structure in healthy rodents from the use of small molecule reversible antagonists for EP2, in contrast to the genetic ablation model. This study paves the way for advancing therapeutic applications of EP2 antagonists against diseases involving EP2 dysfunction., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Cold-water coral (CWC) reefs are numerous and widespread along the Norwegian continental shelf where oil and gas industry operate. Uncertainties exist regarding their impacts from operational discharges to drilling. Effect thresholds obtained from near-realistic exposure of suspended particle concentrations for use in coral risk modeling are particularly needed. Here, nubbins of Desmophyllum pertusum (Lophelia pertusa) were exposed shortly (5 days, 4h repeated pulses) to suspended particles (bentonite BE; barite BA, and drill cuttings DC) in the range of ~ 4 to ~ 60 mg.l-1 (actual concentration). Physiological responses (respiration rate, growth rate, mucus-related particulate organic carbon OC and particulate organic nitrogen ON) and polyp mortality were then measured 2 and 6 weeks post-exposure to assess long-term effects. Respiration and growth rates were not significantly different in any of the treatments tested compared to control. OC production was not affected in any treatment, but a significant increase of OC:ON in mucus produced by BE-exposed (23 and 48 mg.l-1) corals was revealed 2 weeks after exposure. Polyp mortality increased significantly at the two highest DC doses (19 and 49 mg.l-1) 2 and 6 weeks post-exposure but no significant difference was observed in any of the other treatments compared to the control. These findings are adding new knowledge on coral resilience to short realistic exposure of suspended drill particles and indicate overall a risk for long-term effects at a threshold of ~20 mg.l-1., Competing Interests: This study and the writing of the manuscript was financed by Equinor AS. There are no patents, products in development or marketed products associated with this research to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

The clinical use of opioids is restricted by its deleterious impacts on respiratory system. Gaining a better understanding of an individual's susceptibility to adverse opioid effects is important to recognize patients at risk. Ancestral drug addiction has been shown to be associated with alterations in drug responsiveness in the progenies. In the current study, we sought to evaluate the effects of preconception paternal morphine consumption on respiratory parameters in response to acute morphine in male offspring during adulthood, using plethysmography technique. Male Wistar rats administered 10 days of increasing doses of morphine in the period of adolescence. Thereafter, following a 30-day abstinence time, adult males copulated with naïve females. The adult male offspring were examined for breathing response to morphine. Our results indicated that sires who introduce chronic morphine during adolescence leads to increase irregularity of respiratory pattern and asynchronization between inter-breath interval (IBI) and respiratory volume (RV) time series in male offspring. These findings provide evidence that chronic morphine use by parents even before pregnancy can affect respiratory pattern and response to morphine in the offspring., (Copyright © 2021 Elsevier B.V. All rights reserved.)

While a considerable body of literature has characterized the clinical features induced by organophosphate pesticides, the field lacks scrutiny into cardio-respiratory changes in different phases of poisoning. Herein, we evaluated the impact of chlorpyrifos (CPF) and its active metabolite chlorpyrifos-oxon (CPO) on the cardiorespiratory system during acute and subacute phases of poisoning using an in situ experimental rodent model. CPF (30 mg/kg) was injected intraperitoneally to rats beforehand (24 h) whereas CPO (15 mg/kg) was added into the perfusate reservoir to evaluate the effects on the motor outputs throughout the three phases of the respiratory cycle: inspiration, post-inspiration and late expiration. Phrenic, recurrent laryngeal (RLN) and thoracic sympathetic nerve activity (tSNA) were recorded. Heart rate was derived from the electrocardiogram (ECG) and the baro- and chemo-reflexes tested. CPF and CPO led to a time-dependent change in cardiorespiratory motor outputs. In the acute phase, the CPO induced bradypnea, transiently reduced the inspiratory time (TI), and increased the amplitude of phrenic. Post-inspiratory (PI) discharge recorded from the RLN was progressively reduced while tSNA was increased. CPO significantly depressed the chemoreflex but had no effect on baroreflex. During subacute phase, CPF prolongated T I with no effect on respiratory rate. Both the RLN PI discharge, the chemoreflex and the baroreflex sympathetic gain were reduced. In addition, both CPF and CPO shifted the cardiac sympatho-vagal balance towards sympathetic dominance. Our data show that different phases of poisoning are associated with specific changes in the cardio-respiratory system and might therefore demand distinct approaches by health care providers., (Copyright © 2022 Elsevier Inc. All rights reserved.)

In this study, the therapeutic efficacy of quercetin in combination with remdesivir and favipiravir, were evaluated in severe hospitalized COVID-19 patients. Our main objective was to assess the ability of quercetin for preventing the progression of the disease into critical phase, and reducing the levels of inflammatory markers related to SARS-Cov-2 pathogenesis. Through an open-label clinical trial, 60 severe cases were randomly divided into control and intervention groups. During a 7-day period, patients in the control group received antivirals, i.e., remdesivir or favipiravir, while the intervention group was treated with 1000 mg of quercetin daily in addition to the antiviral drugs. According to the results, taking quercetin was significantly associated with partial earlier discharge and reduced serum levels of ALP, q-CRP, and LDH in the intervention group. Furthermore, although the values were in normal range, the statistical outputs showed significant increase in hemoglobin level and respiratory rate in patients who were taking quercetin. Based on our observations, quercetin is safe and effective in lowering the serum levels of ALP, q-CRP, and LDH as critical markers involved in COVID-19 severity. However, according to the non-significant borderline results in comparing the mortality, the ICU-admission rate, and the duration of ICU-admission, further studies can be helpful to compensate the limitations of our study and clarify the therapeutic potential of quercetin in COVID-19 treatments., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Brainstem respiratory neuronal network significantly contributes to cough motor pattern generation. Neuronal populations in the pre-Bötzinger complex (PreBötC) represent a substantial component for respiratory rhythmogenesis. We studied the role of PreBötC neuronal excitation and inhibition on mechanically induced tracheobronchial cough in 15 spontaneously breathing, pentobarbital anesthetized adult cats (35 mg/kg, iv initially). Neuronal excitation by unilateral microinjection of glutamate analog d,l-homocysteic acid resulted in mild reduction of cough abdominal electromyogram (EMG) amplitudes and very limited temporal changes of cough compared with effects on breathing (very high respiratory rate, high amplitude inspiratory bursts with a short inspiratory phase, and tonic inspiratory motor component). Mean arterial blood pressure temporarily decreased. Blocking glutamate-related neuronal excitation by bilateral microinjections of nonspecific glutamate receptor antagonist kynurenic acid reduced cough inspiratory and expiratory EMG amplitude and shortened most cough temporal characteristics similarly to breathing temporal characteristics. Respiratory rate decreased and blood pressure temporarily increased. Limiting active neuronal inhibition by unilateral and bilateral microinjections of GABA A receptor antagonist gabazine resulted in lower cough number, reduced expiratory cough efforts, and prolongation of cough temporal features and breathing phases (with lower respiratory rate). The PreBötC is important for cough motor pattern generation. Excitatory glutamatergic neurotransmission in the PreBötC is involved in control of cough intensity and patterning. GABA A receptor-related inhibition in the PreBötC strongly affects breathing and coughing phase durations in the same manner, as well as cough expiratory efforts. In conclusion, differences in effects on cough and breathing are consistent with separate control of these behaviors. NEW & NOTEWORTHY This study is the first to explore the role of the inspiratory rhythm and pattern generator, the pre-Bötzinger complex (PreBötC), in cough motor pattern formation. In the PreBötC, excitatory glutamatergic neurotransmission affects cough intensity and patterning but not rhythm, and GABA A receptor-related inhibition affects coughing and breathing phase durations similarly to each other. Our data show that the PreBötC is important for cough motor pattern generation, but cough rhythmogenesis appears to be controlled elsewhere.

Exhaust fumes from petrol/diesel-powered electric generators contribute significantly to air pollution in many developing countries, constituting health hazards to both humans and animals. This study evaluated the serum concentrations of Troponin I (TnI), C-reactive protein (CRP) and serum levels/activities of oxidative stress markers: catalase (CAT), reduced glutathione (GSH), malondialdehyde (MDA), nitric oxide (NO) and superoxide dismutase (SOD) in dogs experimentally exposed to graded levels of petrol generator exhaust fume (PGEF). Sixteen (16) healthy and adult male Basenji dogs were randomly assigned into four groups (A-D). Group A was the unexposed control while groups B, C and D were exposed to PGEF for 1, 2 and 3 h per day, respectively, for 90 days. Repeated analysis were performed at the baseline, and every thirty days, for a total of 90 days. There was a significant interaction (p < 0.05) between the effects of PGEF exposure level (in h/day) and duration of exposure (in months) on all the tested serum parameters. There was a significant main effect (p < 0.05) for PGEF exposure level on the serum parameters. As the level of PGEF exposure was increased, the serum concentrations of TnI, CRP, CAT, MDA and NO increased, GSH decreased, whereas SOD activity increased by day 30 but declined at the end. Moreover, there was a significant simple main effect (p < 0.05) for duration of PGEF exposure. All the parameters increased as the duration of PGEF exposure was increased to 90 days except GSH concentration which decreased, whereas SOD activity increased initially but declined at the end of the study. Thus, there was increased serum concentrations of TnI, CRP and increased oxidative stress in the PGEF-exposed dogs. These findings are instructive and could be grounds for further studies on air pollutants-induced cardiovascular disease given the widespread use of electricity generators in many low-resource countries., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

We recently demonstrated that peripheral and central administration of nesfatin-1 in fasting and satiety states generate hyperventilation activity by increasing tidal volume (TV), respiratory rate (RR), and respiratory minute ventilation (RVM). The present study aimed to investigate the mediation of central cholinergic receptors effective in respiratory control in the hyperventilation activity of nesfatin-1. Besides this, we intended to determine possible changes in blood gases due to hyperventilation activity caused by nesfatin-1 and investigate the mediation of central cholinergic receptors in these changes. Intracerebroventricular (ICV) administration of nesfatin-1 revealed a hyperventilation response with an increase in TV, RR, RMV, and pO 2 and a decrease in pCO 2 in saturated Sprague Dawley rats. ICV pretreatment with the muscarinic receptor antagonist atropine partially blocked the RR, RMV, pO 2 , and pCO 2 responses produced by nesfatin-1 while completely blocking the TV response. However, central pretreatment with nicotinic receptor antagonist mecamylamine blocked the respiratory and blood gas responses induced by nesfatin-1. The study's conclusion demonstrated that nesfatin-1 had active hyperventilation effects resulting in an increase in pO 2 and a decrease in pCO 2 . The critical finding of the study was that activation of central cholinergic receptors was involved in nesfatin-1-evoked hyperventilation and blood gas responses., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Non-invasive physiological monitoring can induce stress in laboratory animals. Sedation reduces the level of restraint required, thereby improving the validity of physiological signals measured. However, sedatives may alter physiological equilibrium introducing unintended bias and/or, masking the experimental outcomes of interest. We aimed to investigate the cardiorespiratory effects of four short-acting sedatives in juvenile guinea pigs., Method: 12 healthy, 38 (26-46) day-old Dunkin Hartley guinea pigs were included in this blinded, randomised, crossover design study. Animals were sedated by intramuscular injection using pre-established minimum effective doses of either alfaxalone (5 mg/kg), diazepam (5 mg/kg), ketamine (30 mg/kg), or midazolam (2 mg/kg) administered in random order with a minimum washout period of 48 hours between agents. Sedative depth, a composite score comprised of five assessment criteria, was observed every 5-min from dosing until arousal. Physiological monitoring of cardiorespiratory status included measures of heart rate, blood pressure, respiratory rate, and peripheral microvascular perfusion., Results: Ketamine and alfaxalone were most effective in inducing stable sedation suitable for physiological monitoring, and diazepam less-so. Midazolam was unsuitable due to excessive hypersensitivity. All sedatives significantly increased heart rate above non-sedated control rates (P<0.0001), without altering blood pressure or microvascular perfusion. Alfaxalone and ketamine reduced respiratory rate relative to their control condition (P<0.0001, P = 0.05, respectively), but within normative ranges., Conclusion: Ketamine and alfaxalone are the most effective sedatives for inducing short duration, stable sedation with minimal cardiorespiratory depression in guinea pigs, while diazepam is less-so. However, alfaxalone is the most appropriate sedative for longitudinal studies requiring multiple physiological timepoints., Competing Interests: The authors have declared that no competing interests exist.

Urethane, an acute laboratory anesthetic, produces distinct neurophysiological and physiological effects creating an effective model of the dynamics of natural sleep. As a model of both sleep-like neurophysiological activity and the downstream peripheral function urethane is used to model a variety of physiological and pathophysiological processes. As urethane is typically administered as a single-bolus dose, it is unclear the stability of peripheral physiological functions both within and between brain-states under urethane anesthesia. In this present study, we recorded respiration rate and heart rate concurrently with local field potentials from the neocortex and hippocampus to determine the stability of peripheral physiological functions within and between brain-states under urethane anesthesia. Our data shows electroencephalographic characteristics and breathing rate are remarkable stable over long-term recordings within minor reductions in heart rate on the same time scale. Our findings indicate that the use of urethane to model peripheral physiological functions associated with changing brain states are stable during long duration experiments., Competing Interests: The authors have declared that no competing interests exist.

Difelikefalin, a selective kappa opioid receptor agonist designed to limit central nervous system (CNS) penetration, is under development for the treatment of pruritus. Its hydrophilic, small-peptidic structure limits CNS entry, minimizing potential CNS-mediated adverse events (AEs). This study assessed the effect of difelikefalin on key relevant measures of respiratory depression in healthy volunteers. This single-center, randomized, double-blind, placebo-controlled, three-way crossover study enrolled healthy, nonsmoking volunteers. Subjects were randomized to 1 of 3 treatment sequences of difelikefalin (1.0 or 5.0 mcg/kg i.v.) or placebo on sequential days with an intervening 24 (±2) h washout period. The primary end points included incidence of increased end-tidal carbon dioxide (ETCO 2 ) greater than or equal to 10 mm Hg versus baseline or a level greater than 50 mm Hg sustained greater than or equal to 30 seconds, and incidence of reduction in saturation of peripheral oxygen (SpO 2 ) to less than 92% sustained greater than or equal to 30 seconds. Secondary end points included incidence of reduced respiratory rate and other safety assessments. Fifteen subjects were randomized and completed the study. No subject on placebo or difelikefalin met the increased ETCO 2 or reduced SpO 2 primary end point criteria for respiratory depression. All respiratory measures in each group remained near baseline values during 4-h postdose observations. No subject met the reduced respiratory rate criterion or experienced clinically significant changes in ETCO 2 , SpO 2 , or respiratory rate. The most commonly reported treatment-emergent AEs (TEAEs; ≥20% of subjects) were paresthesia, hypoesthesia, and somnolence in the difelikefalin arms. All TEAEs were mild and resolved without intervention. Difelikefalin 1.0 and 5.0 mcg/kg i.v. did not produce respiratory depression., (© 2021 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

QXOH-Levobupivacaine (LB) is a fixed-dose combination of 35-mM QXOH and 10-mM LB. It was developed for perioperative analgesia because of its long-acting analgesic effect. The purpose of this study was to evaluate the potential toxicity of QXOH-LB in beagle dogs in accordance with the Guidance on the repeated-dose toxicity published by the China Food and Drug Administration. Groups of five male and five female beagle dogs received normal saline, QXOH-LB (2, 4, and 8 mg/kg, calculated as QXOH), QXOH (2, 4, and 8 mg/kg), or LB (2 mg/kg, equals the concentration of LB in 8-mg/kg QXOH-LB group) at the volume of 1 mL/kg once per day for 14 days through subcutaneous injection. No mortality was observed. Dogs in the control group as well as animals treated with 2-mg/kg QXOH or QXOH-LB exhibited normal behaviors. Clinical signs of toxicity in dogs treated with 4 and 8 mg/kg of QXOH or QXOH-LB included decreased activity, unsteady gait, jerks, tremors, vocalization, emesis, ataxia, lateral/sternal recumbency, deep/rapid respiration, and gasping. Additionally, neurological function was found to be affected by QXOH and QXOH-LB at the doses of 4 and 8 mg/kg. All clinical signs were recovered within 24 h. The no-observed-adverse-effect level of QXOH and QXOH-LB was considered to be 2 mg/kg. Toxicokinetic data showed that exposure to QXOH and LB increased as QXOH-LB doses were increased from 4 to 8 mg/kg. There was no evidence of drug accumulation or any effect of gender., (© 2020 John Wiley & Sons, Ltd.)

α 2 -Adrenoceptor agonists such as clonidine and dexmedetomidine are used as adjuvants to local anesthetics in regional anesthesia. Fadolmidine is an α 2 -adrenoceptor agonist developed especially as a spinal analgesic. The current studies investigate the effects of intrathecally administered fadolmidine with a local anesthetic, bupivacaine, on antinociception and motor block in conscious rats and dogs. The antinociceptive effects of intrathecal fadolmidine and bupivacaine alone or in combination were tested in the rat tail-flick and the dog's skin twitch models. The durations of motor block in rats and in dogs were also assessed. In addition, the effects on sedation, mean arterial blood pressure, heart rate, respiratory rate and body temperature were evaluated in telemetrized dogs. Concentrations of fadolmidine in plasma and spinal cord were determined after intrathecal and intravenous administration in rats. Co-administration of intrathecal fadolmidine with bupivacaine increased the magnitude and duration of the antinociceptive effects and prolonged motor block without hypotension. The interaction of the antinociceptive effect was synergistic in its nature in rats. Concentration of fadolmidine in plasma was very low after intrathecal dosing. Taken together, these studies show that fadolmidine as an adjuvant to intrathecal bupivacaine provides enhanced sensory-motor block and enables a reduction of the doses of both drugs. The results indicate that co-administration of fadolmidine with intrathecal bupivacaine was able to achieve an enhanced antinociceptive effect without hypotension and could thus represent a suitable combination for spinal anesthesia., (© 2021 The Authors. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics.)

The aim of the study was to evaluate the analgesic efficacy of tramadol compared to butorphanol administered locally in ventral surface of the hind paw of rats. Prospective, randomized experimental study; twenty-one adult male Wistar rats were selected. Heart rate (beats minute-1), respiratory rate (breaths minute-1), and paw withdrawal latency (onset of radiant heat until paw withdrawal/seconds) were measured prior (T0) and after (T5, T10, T15, T20) intraplantar injection with saline solution 0,9% (group S), butorphanol 1 mg kg-1 (group B), and tramadol 1 mg kg-1 (group T). Shapiro-Wilk normality test and Friedman test were used to analyze the data expressed by median and range. Statistical significance was set at p < 0.05. Statistical analysis of heart rate showed that there were significant differences between groups at different monitoring times. There were no significant differences in respiratory rate after intraplantar injection in any of the treatment groups. The paw withdrawal latency values at T5, T10, and T15 minutes after intraplantar injection in the group B were significantly higher compared to baseline value and to the values of the other groups. The paw withdrawal latency were no significant changes in the measurements of intragroup in S and T. Intraplantar administration of butorphanol provides a good analgesia and significantly increases paw withdrawal latency compared to tramadol. Intraplantar injection of butorphanol could be useful and safe and safe technique to achieve local analgesia for minor surgical procedures in rats., Competing Interests: The authors have declared that no competing interests exist.

Background: Opioid-induced respiratory compromise remains a significant challenge in etorphine-immobilised wildlife. Serotonergic agonists offer a potential avenue for preventing or treating opioid-induced respiratory compromise. We therefore aimed to determine whether the selective 5-hydroxytryptamine receptor 4 (5-HT4) agonist, BIMU-8, reverses opioid-induced respiratory compromise in etorphine-immobilised goats., Methods: Seven healthy adult goats were immobilised with etorphine, then treated with BIMU-8 or sterile water 5 minutes later in a randomised, prospective cross-over study. Cardiorespiratory variables were measured at 1-minute intervals from 4 minutes before etorphine to 15 minutes after its administration. Arterial blood gas analyses were also performed before and after etorphine administration and the respective treatments., Results: Intravenous injection of BIMU-8 attenuated etorphine-induced respiratory compromise, as indicated by improvements, compared to baseline and between treatments, in respiratory rate (f R ), peripheral arterial blood oxygen saturation (SpO 2 ), partial pressure of arterial oxygen (PaO 2 ) and the alveolar-arterial oxygen partial pressure gradient (P(A-a)O 2 ). BIMU-8 caused an increase in heart rate and a temporary decrease in arterial blood pressure. Mild movements and slight muscle spasm occurred but BIMU-8 did not reverse immobilisation., Conclusion: Our results indicate that BIMU-8 may be a potential drug candidate for the treatment, or prevention, of etorphine-induced respiratory compromise in immobilised ungulates., (© 2021 The Authors. Veterinary Record published by John Wiley & Sons Ltd on behalf of British Veterinary Association.)

Eupnea and gasping in infancy depend on central nervous system (CNS) serotonin (5-hydroxytryptamine; 5-HT). Although previous in vitro preparations have provided some evidence that 5-HT acts through type 2 A receptors (5-HT 2A ) to facilitate eupnea and gasping, here the hypothesis addressed is that 5-HT 2A receptor activation is necessary for eupnea and the proper generation of gasping in vivo. To test this, we administered 2,5-dimethoxy-4-iodoamphetamine (DOI; 0.25 mg/kg i.p.), a 5-HT 2A agonist, 8-hydroxy-2-(di- n -propylamino)tetralin (8-OH-DPAT; 0.25 mg/kg i.p.), a 5-HT 1A agonist, or vehicle (saline) to 7-9-day-old tryptophan hydroxylase 2 knockout (TPH2 -/- ) mice. A second experiment assessed the effect of MDL-11,939 (MDL; 10 mg/kg i.p.), the specific 5-HT 2A antagonist, or vehicle (DMSO) on the gasping of wild-type (TPH2 +/+ ) animals. Drugs were given 15 min prior to five episodes of severe hypoxia that elicited gasping. TPH2 -/- breathed more slowly but had the same V̇e and V̇e/V̇o 2 compared with TPH2 +/+ . As previously reported, the gasping of TPH2 -/- was significantly delayed ( P < 0.001) and occurred at a significantly lower frequency compared with TPH2 +/+ ( P = 0.04). For both genotypes, DOI hastened eupneic frequency but had no effect on V̇e or V̇e/V̇o 2 . The gasping of TPH2 -/- , although unaffected by 8-OH-DPAT, was indistinguishable from the gasping of TPH2 +/+ following DOI. In TPH2 +/+ , application of MDL led to hypoventilation ( P = 0.01), a delay in the appearance of gasping ( P = 0.005), and reduced gasp frequency ( P = 0.05). These data show that, in vivo, 5-HT 2A receptors facilitate both eupnea and gasping. As has been shown in vitro, 5-HT 2A probably promotes gasping by exciting hypoxia-resistant pacemaker neurons. NEW & NOTEWORTHY Previous in vitro studies suggest that 5-HT 2A receptors contribute to eupnea and are necessary for fictive gasping. The current study shows that the impaired gasping displayed by neonatal TPH2 -/- mice, deficient in CNS serotonin, is restored by 5-HT 2A receptor activation. Following 5-HT 2A blockade, wild-type mice hypoventilated and their gasping resembled that of TPH2 -/- mice. This study shows that both eupnea and gasping in vivo rely on the activation of 5-HT 2A receptors.

Organisms have evolved endogenous timing systems that enable them to predict temporal changes and to coordinate complex internal processes. However, temporal dynamics of biological responses are most often ignored in fields such as dietary supplementation of farm animals exposed to artificial environmental challenges. Herein, we hypothesized that the potential for thymol (2-isopropyl-5-methylphenol) to alleviate physiological and behavioral consequences of heat stress is time-dependent on both long-term (i.e. weeks) and short-term (i.e. within day) time scales. First, during 3-weeks adult female Japanese quail (Coturnix japonica) were exposed daily to 9h of increased environmental temperature (34.2 ± 0.1 °C). Controls remained at standard temperatures (23.6 ± 0.1 °C). Simultaneously, half received thymol dietary supplementation and the other half a control basal diet. On day 4, both thymol and heat stress decreased body weight and feed intake respect to controls (basal, standard temperature). After three weeks, feed intake recovered for thymol groups. Therefore, we performed a second experiment focused on the critical first week of treatment, sampling variables three times a day. The beneficial effects of thymol supplementation were mainly observed during the morning, including prevention of high respiratory rates and reduction in the weight of droppings induced by heat stress, and increased walking under both temperatures. In summary, thymol's potential for alleviating heat stress consequences is time-dependent, and can be conceived as an emergent property resulting from the complex interplay between the dynamics of the biological response to thymol and heat stress. Findings highlight the importance of considering time-related factors when developing supplementation protocols to mitigate environmental challenges., (Copyright © 2021. Published by Elsevier Ltd.)

Study objectives were to evaluate the effects of replacing 40 mg/kg of dietary Zn from Zn sulfate (ZS) with Zn amino acid complex (ZA; Zinpro Corporation, Eden Prairie, MN) on inflammation and intestinal integrity in heat-stressed and pair-fed (PF) ruminants. Forty Holstein steers (173.6 ± 4.9 kg) were randomly assigned to 1 of 5 dietary-environmental treatments: (1) thermoneutral (TN) ad libitum with 75 mg/kg of dry matter (DM) ZS (ZSCON); (2) TN pair-fed with 75 mg/kg DM ZS (ZSPF); (3) TN pair-fed with 40 mg/kg DM ZA and 35 mg/kg DM ZS (ZAPF); (4) heat stress (HS) ad libitum with 75 mg/kg DM ZS (ZSHS); and (5) HS ad libitum 40 mg/kg DM ZA and 35 mg/kg DM ZS (ZAHS). Before study initiation, calves were fed their respective diets for 21 d. Following the pre-feeding phase, steers were transferred into environmental chambers and were subjected to 2 successive experimental periods. During period 1 (5 d), all steers were fed their respective diets ad libitum and housed in TN conditions (20.2 ± 1.4°C, 30.4 ± 4.3% relative humidity). During period 2 (6 d), ZSHS and ZAHS steers were exposed to cyclical HS conditions (27.1 ± 1.5°C to 35.0 ± 2.9°C, 19.3 ± 3.5% relative humidity), whereas the ZSCON, ZSPF, and ZAPF steers remained in TN conditions and were fed ad libitum or pair-fed relative to their ZSHS and ZAHS counterparts. Overall, steers exposed to HS had markedly increased rectal temperature (0.83°C), respiration rate (26 breaths per min), and skin temperature (8.00°C) relative to TN treatments. Rectal temperature from ZAHS steers was decreased (0.24°C) on d 4 to 6 of HS relative to ZSHS steers. Regardless of diet, HS decreased DMI (18%) relative to ZSCON steers. Circulating glucose from HS and PF steers decreased (16%) relative to ZSCON steers. Heat stress and nutrient restriction increased circulating nonesterified fatty acids 2- and 3-fold, respectively, compared with ZSCON steers. Serum amyloid A increased ~2-fold in PF relative to ZSCON and HS steers. We detected no treatment effect on blood pH; however, ZAHS steers had increased HCO 3 relative to ZSHS. Relative to ZSHS, ZAHS steers had increased jejunum villi height (25%), a tendency for increased ileum villi height (9%), and decreased duodenal villi width (16%). In summary, ZA supplementation has some beneficial effects on thermal indices, intestinal architecture characteristics, and biomarkers of leaky gut in heat-stressed steers, indicative of an ameliorated heat load, and thus may be a nutritional strategy to minimize negative consequences of HS., (The Authors. Published by Elsevier Inc. and Fass Inc. on behalf of the American Dairy Science Association®. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).)

The pontine Kölliker-Fuse nucleus (KFn) is a core nucleus of respiratory network that mediates the inspiratory-expiratory phase transition and gates eupneic motor discharges in the vagal and hypoglossal nerves. In the present study, we investigated whether the same KFn circuit may also gate motor activities that control the resistance of the nasal airway, which is of particular importance in rodents. To do so, we simultaneously recorded phrenic, facial, vagal and hypoglossal cranial nerve activity in an in situ perfused brainstem preparation before and after bilateral injection of the GABA-receptor agonist isoguvacine (50-70 nl, 10 mM) into the KFn (n = 11). Our results show that bilateral inhibition of the KFn triggers apneusis (prolonged inspiration) and abolished pre-inspiratory discharge of facial, vagal and hypoglossal nerves as well as post-inspiratory discharge in the vagus. We conclude that the KFn plays a critical role for the eupneic regulation of naso-pharyngeal airway patency and the potential functions of the KFn in regulating airway patency and orofacial behavior is discussed., (Copyright © 2020. Published by Elsevier B.V.)

Coronavirus disease 2019 (COVID-19) can lead to a massive cytokine release. The use of the anti-interleukin-6 receptor monoclonal antibody tocilizumab (TCZ) has been proposed in this hyperinflammatory phase, although supporting evidence is limited. We retrospectively analyzed 88 consecutive patients with COVID-19 pneumonia that received at least one dose of intravenous TCZ in our institution between 16 and 27 March 2020. Clinical status from day 0 (first TCZ dose) through day 14 was assessed by a 6-point ordinal scale. The primary outcome was clinical improvement (hospital discharge and/or a decrease of ≥2 points on the 6-point scale) by day 7. Secondary outcomes included clinical improvement by day 14 and dynamics of vital signs and laboratory values. Rates of clinical improvement by days 7 and 14 were 44.3% (39/88) and 73.9% (65/88). Previous or concomitant receipt of subcutaneous interferon-β (adjusted odds ratio [aOR]: 0.23; 95% confidence interval [CI]: 0.06-0.94; P = .041) and serum lactate dehydrogenase more than 450 U/L at day 0 (aOR: 0.25; 95% CI: 0.06-0.99; P = .048) were negatively associated with clinical improvement by day 7. All-cause mortality was 6.8% (6/88). Body temperature and respiratory and cardiac rates significantly decreased by day 1 compared to day 0. Lymphocyte count and pulse oximetry oxygen saturation/FiO 2 ratio increased by days 3 and 5, whereas C-reactive protein levels dropped by day 2. There were no TCZ-attributable adverse events. In this observational single-center study, TCZ appeared to be useful and safe as immunomodulatory therapy for severe COVID-19 pneumonia., (© 2020 Wiley Periodicals LLC.)

Anesthesia is frequently used to facilitate physiological monitoring during interventional animal studies. However, its use may induce cardiovascular (central and peripheral), respiratory, and thermoregulatory depression, confounding results in anesthetized animals. Despite the wide utility of guinea pigs as a translational platform, anesthetic protocols remain unstandardized for extended physiological studies in this species. Therefore, optimizing an anesthetic protocol that balances stable anesthesia with intact cardiorespiratory and metabolic function is crucial. To achieve this, 12 age and sex-matched juvenile Dunkin Hartley guinea pigs underwent extended anesthesia (≤150 min) with either (a) isoflurane (ISO: 1.5%), or (b) isoflurane + N 2 O (ISO+ N 2 O: 0.8% +70%), in this randomized cross-over designed study. Cardiovascular (HR, SBP, peripheral microvascular blood flow), respiratory (respiratory rate, SpO 2 ), and thermal (T re and T sk ) measures were recorded continuously throughout anesthesia. Blood gas measures pre- and post- anesthesia were performed. Incorporation of 70% N 2 O allowed for significant reductions in isoflurane (to 0.8%) while maintaining an effective anesthetic depth for prolonged noninvasive physiological examination in guinea pigs. ISO+N 2 O maintained heart rate, peripheral blood flow, respiratory rate, and thermoregulatory function at levels closest to those of conscious animals, especially in females; however, it did not fully rescue anesthesia-induced hypotension. These results suggest that for studies requiring prolonged physiological examination (≤150 min) in guinea pigs, 0.8% isoflurane with a 70% N 2 O adjuvant provides adequate anesthesia, while minimizing associated cardiorespiratory depression. The preservation of cardiorespiratory status is most marked throughout the first hour of anesthesia., (© 2021 The Authors. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics.)

Background: Tiletamine/zolazepam is a dissociative anesthetic combination commonly used in small animals but information is limited in rats. The alpha-2 agonist, dexmedetomidine, has gained popularity in laboratory animal anesthesia. Tramadol is a weak opioid mu agonist. The aim of this study was to assess whether the tiletamine/zolazepam/dexmedetomidine (ZD) combination effectively provides a surgical anesthesia plane comparable to tiletamine/zolazepam/dexmedetomidine with tramadol (ZDT) in a minor procedure in rats., Methods: Rats were induced with ZD or ZDT. After the loss of paw withdrawal, a small incision was made on the rats' left thighs as a surgical stimulus. Rats were maintained under a surgical anesthesia plane by assessing the loss of the paw withdrawal reflex for 45 minutes, then atipamezole was administered. Monitored anesthesia parameters included: (a) physiological parameters - pulse rate (PR), respiratory rate (RR), tissue oxygen saturation (%SpO 2 ), and body temperature; (b) duration parameters - induction time, onset and duration of surgical anesthesia plane, onset of recovery, and recovery time., Results: PR was significantly lower at 10 minutes in ZD and 5 minutes in ZDT groups. No difference was observed for RR, %SpO 2 , and body temperature. Likewise, there were no differences for duration parameters: induction time was less than 3 minutes; onset and duration of surgical anesthesia plane were approximately 5 and 45 minutes, respectively; onset of recovery (time to move) was 51 minutes; and recovery time was 52 minutes, respectively., Conclusion: These data suggest the ZD combination provides a surgical anesthesia plane comparable to ZDT in a rat incisional pain model., (© 2021 The Authors. Animal Models and Experimental Medicine published by John Wiley & Sons Australia, Ltd on behalf of The Chinese Association for Laboratory Animal Sciences.)

Aims: We investigated the involvement of the renin angiotensin system (RAS) on the cardiorespiratory control in rats from dams fed with a low-protein diet., Main Methods: Male offspring were obtained from dams fed a normoprotein diet (NP, 17% casein) and low-protein diet (LP, 8% casein) during pregnancy and lactation. Direct measurements of arterial pressure (AP), heart rate (HR) and respiratory frequency (RF) were recorded in awake 90-day-old at resting and after losartan potassium through either intracerebroventricular (ICV) microinjections or intravenous (IV) administration. Cardiovascular variability was evaluated by spectral analysis. Peripheral chemoreflex sensitivity was assessed through the potassium cyanide (KCN; 40 μg/0.1 ml/rat, IV). Gene expression was evaluated by qPCR, and MAPK (Mitogen Activated Protein Kinase) expression was evaluated by western blot., Key Findings: The LP offspring had higher mean AP (MAP) and RF than NP offspring. In the spectral analysis, the LP rats also showed higher low frequency of systolic AP (NP: 2.7 ± 0.3 vs. LP: 5.0 ± 1.0 mmHg). After ICV losartan, MAP and RF in LP rats remained higher than those in NP rats, but without changes in HR. The peripheral chemoreflex was similar between the groups. LP group had lower gene expression of Rac1 (Ras-related C3 botulinum toxin substrate 1) (NP: 1.13 ± 0.06 vs. LP: 0.88 ± 0.08). Peripherally, LP rats had larger delta of MAP after IV losartan (NP: -9.8 ± 2 vs. LP: -23 ± 6 mmHg), without changes in HR and RF., Significance: In rats, the RAS participates peripherally, but not centrally, in the maintenance of arterial hypertension in male offspring induced by maternal protein restriction., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Anesthesia is used to sedate aquatic animals during transportation or to immobilize them for surgery. However, most studies have focused on the behavioral effects of induction and recovery, without addressing the effect of anesthetic on neural activity. This study investigated the neural response of anterior lateral line afferent fibers in the oyster toadfish, Opsanus tau, during exposure to incremental increases of AQUI-S 20E (0.001-0.006%), to determine if eugenol (the active ingredient of AQUI-S 20E) influences neural activity of the fish lateral line system. Ventilation rate significantly decreased following AQUI-S 20E exposure with the surgical plane of anesthesia reached at 0.003%, characterized by shallow ventilation, equilibrium loss, and no response to tactile stimuli. Spontaneous and evoked firing rates of anterior lateral line fibers also significantly decreased following exposure, although the effect was transitory as neural activity recovered in the majority of fibers (70%) within 30 min of anesthetic withdrawal. While AQUI-S 20E proved effective in inducing the surgical plane of anesthesia without compromising survival, it is not recommended for acute neural preparations due to its depression of neural activity. However, the depression of lateral line sensitivity at low concentrations could play a role in reducing the stress response during fish transport.

Objectives: The aim of this study was to describe the pharmacokinetics of oral transmucosal (OTM) detomidine gel in healthy cats and assess its effects on sedation and hemodynamic variables., Methods: Eight adult cats weighing 4.12 kg ± 0.72 received 4 mg/m 2 detomidine gel onto the buccal mucosa. Level of sedation, heart rate (HR), blood pressure (BP) and respiratory rate ( f  R) were assessed at predetermined intervals following administration. Blood samples for plasma detomidine concentrations and venous blood gas variables were collected from a medial saphenous catheter. Plasma detomidine concentrations were analyzed using ultra-high-pressure liquid chromatography with mass spectrometry detection, and pharmacokinetic estimates were obtained with compartmental methods. Data were analyzed using ANOVA and paired t -test or appropriate non-parametric tests., Results: Sedation occurred in all cats, and was increased from baseline at 30 mins ( P <0.001). Decreases in HR occurred from 15-60 mins, ranging from 140 to 165 beats per min ( P <0.001). Blood glucose increased from 101 ± 12 mg/dl to 168 ± 27.3 mg/dl at 60 mins ( P  = 0.004). Systolic blood pressure decreased from baseline (139 ± 14.8 mmHg) to 103 ± 23.0 mmHg at 60 mins ( P  = 0.023). All changes abated by 120 mins. Emesis occurred in 7/7 cats within 2 mins of gel administration. Geometric mean (coefficient of variation) for clearance was 220.7 ml/min/kg (35.3 ml/min/kg), volume of distribution was 14.9 l/kg (39.9 l/kg) (both a function of bioavailability) and elimination half-life was 46.9 mins (16.0 mins). Maximum plasma concentrations of 10.5 ng/ml (35.5 ng/ml) detomidine occurred at 36.9 mins (21.5 mins)., Conclusions and Relevance: OTM detomidine gel produced moderate sedation with minimal undesirable side effects in healthy cats, although emesis occurred in all cats. The pharmacokinetic profile supports short-term, minimally invasive sedation in this species. Further studies are warranted to assess its safety and feasibility for use in debilitated cats, or prior to general anesthesia.

Currently no drugs are employed clinically to reverse the unconsciousness induced by general anesthetics. Our previous studies showed that caffeine, when given near the end of an anesthesia session, accelerated emergence from isoflurane anesthesia, likely caused by caffeine's ability to elevate intracellular cAMP levels and to block adenosine receptors. These earlier studies showed that caffeine did not rouse either rats or humans from deep anesthesia (≥ 1 minimum alveolar concentration, MAC). In this current crossover study, we examined whether caffeine reversed the unconsciousness produced by light anesthesia (< 1 MAC) in the continued presence of isoflurane. The primary endpoint of this study was to measure isoflurane levels at the time of recovery of righting reflex, which was a proxy for consciousness. Rats were deeply anesthetized with 2% isoflurane (~1.5 MAC) for 20 minutes. Subsequently, isoflurane was reduced to 1.2% for 10 minutes, then by 0.2% every 10 min; animals were monitored until the recovery of righting reflex occurred, in the continued presence of isoflurane. Respiration rate, heart rate and electroencephalogram (EEG) were monitored. Our results show that caffeine-treated rats recovered their righting reflex at a significantly higher inspired isoflurane concentration, corresponding to light anesthesia, than the same rats treated with saline (control). Respiration rate and heart rate increased initially after caffeine injection but were then unchanged for the rest of the anesthesia session. Deep anesthesia is correlated with burst suppression in EEG recordings. Our data showed that caffeine transiently reduced the burst suppression time produced by deep anesthesia, suggesting that caffeine altered neuronal circuit function but not to a point where it caused arousal. In contrast, under light anesthesia, caffeine shifted the EEG power to high frequency beta and gamma bands. These data suggest that caffeine may represent a clinically viable drug to reverse the unconsciousness produced by light anesthesia., Competing Interests: The authors have declared that no competing interests exist.

A cellular model of cardiomyocytes (H9c2 cell line) and mitochondria isolated from mouse liver were used to understand the drug action of BPDZ490 and BPDZ711, two benzopyran analogues of the reference potassium channel opener cromakalim, on mitochondrial respiratory parameters and swelling, by comparing their effects with those of the parent compound cromakalim. For these three compounds, the oxygen consumption rate (OCR) was determined by high-resolution respirometry (HRR) and their impact on adenosine triphosphate (ATP) production and calcium-induced mitochondrial swelling was investigated. Cromakalim did not modify neither the OCR of H9c2 cells and the ATP production nor the Ca-induced swelling. By contrast, the cromakalim analogue BPDZ490 (1) induced a strong increase of OCR, while the other benzopyran analogue BPDZ711 (2) caused a marked slowdown. For both compounds, 1 displayed a biphasic behavior while 2 still showed an inhibitory effect. Both compounds 1 and 2 were also found to decrease the ATP synthesis, with pronounced effect for 2, while cromakalim remained without effect. Overall, these results indicate that cromakalim, as parent molecule, does not induce per se any direct effect on mitochondrial respiratory function neither on whole cells nor on isolated mitochondria whereas both benzopyran analogues 1 and 2 display totally opposite behavior profiles, suggesting that compound 1, by increasing the maximal respiration capacity, might behave as a mild uncoupling agent and compound 2 is taken as an inhibitor of the mitochondrial electron-transfer chain., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Due to their unpredictability and variable effects, injectable anesthetic regimens in laboratory rodent species warrant refinement. In our study we sought to evaluate alfaxalone, which has gained recent popularity in veterinary medicine, alone and in combination with dexmedetomidine to evaluate their anesthetic ability in Sprague-Dawley rats when administered intraperitoneally. Three doses of alfaxalone only and 4 dose combinations of alfaxalone-dexmedetomidine were tested in males and female rats. The time to induction, anesthetic duration, pulse rate, respiratory rate, temperature, and time to recovery were recorded by a blind observer. The level of anesthesia induced by the various anesthetic protocols was assessed by using pedal withdrawal reflex to a noxious stimulus and scored according to the response. Dependent on the treatment group, atipamezole or saline was administered intraperitoneally once animals reached 60 min of anesthesia. Regardless of the dose, alfaxalone alone achieved only a sedative level of anesthesia, whereas all alfaxalone-dexmedetomidine combinations led to a surgical level of anesthesia in all animals. Anesthesia regimens using alfaxalone alone and in combination with dexmedetomidine demonstrated sex-associated differences, with female rats maintaining longer durations of sedation or anesthesia than their male counterparts. Both male and female rats displayed decreases in physiologic parameters consistent with the effects of dexmedetomidine. Given the results described herein, we recommend 20 mg/kg alfaxalone for sedation and 30 mg/kg alfaxalone combined with 0.05 mg/kg dexmedetomidine for surgical anesthesia in female rats. Appropriate doses of alfaxalone only and alfaxalone-dexmedetomidine for male rats were not determined in this study and need further evaluation.

Intraperitoneal (IP) injection is a common route of anesthetic administration in mice. Ketamine-xylazine (KX) anesthesia is one of the most widely used IP protocols, but has limitations. Etomidate is an alternative to ketamine that has been used in both human and veterinary medicine yet has not been widely studied in mice. The purpose of this study was to evaluate etomidate-xylazine (EX) anesthesia as an alternative to KX. We hypothesized that EX would be as safe and effective as KX, with both sex- and strain-dependent differences. Male and female Crl:CD1(ICR), C57BL/6NCrl, BALB/cJ and NU/J mice were given a single IP dose of ketamine 100 mg/kg and xylazine 10 mg/kg or etomidate 20 mg/kg and xylazine 10 mg/kg. Sedation times were similar between KX and EX, with CD1 mice exhibiting shorter sedation times. Surgical anesthesia was achieved in 44% of EX mice, compared with 4% of KX mice. C57BL/6NCrl mice were significantly more likely to achieve surgical anesthesia when given EX (94%) or KX (18%) than were other strains. In all strains except C57BL/6NCrl mice, females were more likely to reach surgical anesthesia than males. Several mice experienced an adverse hyperexcitement response during induction, with BALB/cJ (79%) and NU/J (87%) mice given EX significantly more likely than other strains to experience hyperexcitement. EX and KX protocols had no overall differences in lowest respiration rate, lowest systolic blood pressure, lowest rectal temperature, or levels of acidosis, although the lowest heart rates were significantly higher with EX, indicating that EX and KX have similar safety profiles. Thus, EX and KX administration were associated with several significant physiologic differences when comparing sexes or individual strains. Our results indicate that EX is an equally effective sedative and a more effective surgical anesthetic than KX; however, EX is only recommended for invasive procedures in C57BL/6 mice due to the high rate of hyper-excitement and inconsistent surgical depth seen in other strains. Further study is needed to optimize EX for use in multiple mouse strains.

This study aimed to investigate the effects of alkaline agents on reducing strong inspiratory effort. Rabbits with hypercapnia or lung injury, induced via repeated lung lavage following injurious ventilation, were treated with Saline, NaHCO 3 , or Trometamol. In the hypercapnia, minute ventilation and tidal volume were unchanged during NaHCO 3 administration; however, one hour after the end of NaHCO 3 these parameters decreased (82.1+/-7.8 %, 90.8+/-6.0 % of the baseline, respectively, p < 0.05). Trometamol reduced minute ventilation, tidal volume, and respiratory rate after infusion (59.8+/-19.0 %, 87.0+/-9.2 %, 68.2+/-18.4 % of the baseline, respectively, p < 0.05). Alkaline agents did not cause a large change in the cerebrospinal fluid acid-base balance. In the lung injury model, NaHCO 3 and Trometamol had little effect on ventilation. However, Trometamol reduced transpulmonary pressure. Trometamol exerted more inhibitory effects on ventilation than NaHCO 3 in the hypercapnia model, and Trometamol reduced the transpulmonary pressure in the lung injury model., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Natural biotic and anthropogenic stressors can interact to alter contaminant toxicity. Energetic restrictions are potential mechanisms causing this pattern. To identify processes underlying observed effects of predation risk and copper (Cu) on delayed copepod age at maturity, we examined how these 2 stressors affect respiration rates. We tested 2 very different copepod species: the large, pelagic calanoid Calanus finmarchicus and the small, semibenthic harpacticoid Tigriopus brevicornis. Adult individuals were exposed for 12 h to the treatments: predation risk, Cu (23 µg L -1 ), combined predation risk and Cu (23 µg L -1 ), or control. Oxygen concentrations were monitored continuously. The 2 species differed in their responses. We found no clear effects of either stressor in C. finmarchicus. In T. brevicornis, predation risk increased respiration rates, whereas Cu alone had little impact. In contrast, combined exposure to predation risk and Cu interacted to reduce respiration rates to less than expected. We further observed an effect of sex because female-biased T. brevicornis replicates were more sensitive to both predation risk (increased respiration rates) and Cu exposure (reduced respiration rates). The present study provides further evidence that predation risk can interact with copepod responses toward Cu exposure. Interactive effects of biotic stressors ought to be considered to improve future marine environmental monitoring. Environ Toxicol Chem 2020;39:1765-1773. © 2020 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC., (© 2020 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.)

In this study, adult intact male and female ( n = 10) naked mole rats ( Heterocephalus glaber ) were anesthetized by using a combination of ketamine (20 mg/kg IM), and alfaxalone (4.0 mg/kg IM). Induction and recovery times were recorded. Vital parameters, including heart rate, respiratory rate, and reflexes, were monitored every 5 min during the anesthetic period. Anesthetic induction was smooth and rapid. Induction time was significantly longer in male rats (median, 325 s; range, 180 to 385 s) than in females (median, 145 s; range, 118 to 180 s). In addition, overall duration of loss of righting reflex was shorter in male mole rats (median, 50 min; range, 36 to 65 min) than females (median, 70 min; range, 60 to 85 min). Males largely had intact withdrawal reflexes, whereas females showed variable loss of both forelimb and hindlimb withdrawal reflexes. Neither recovery time (mean ± 1 SD, 16 ± 13 min) nor vital parameters differed between sexes. None of animals showed any anesthesia-related adverse responses. According to these findings, intramuscular AK is a safe and effective protocol that provides brief, light anesthesia in male naked mole rats and deeper anesthesia in females. We recommend adding analgesics when this AK protocol is used for pain-inducing or invasive procedures, and further studies evaluating higher doses and different combinations are indicated.

Background: Legalization of cannabis encourages the development of specific cultivars to treat disease such as neuropathic pain. Because of the large number of cultivars, it is necessary to prioritize extracts before proceeding to clinical trials., Purpose: To compare extracts of two unique cannabis cultivars (CT-921, CT-928) for treatment of neuropathic pain induced by constriction of sciatic nerve in mice and to illustrate the use of this animal model to set priority for future trials., Methods: Pain severity was measured by threshold force causing paw withdrawal. Dose-response relationships and time course were determined for intravenously injected extracts of cultivars and vehicle. The doses for allodynia relief were correlated with decreased respiratory rate, temperature and behavioral changes., Results: Effective analgesic dose for 50 and 95% (ED 50An and ED 95An ) was 15, and 29 mg/kg for CT-921 and 0.9 and 4.7 for CT-928. At ED 50An , for both extracts, the duration was 120 min. At ED 95An , administration of CT-928 significantly decreased respiratory rate while CT-921 did not. CT-928 decreased temperature more than CT-921. CT-928 produced frantic hyperactivity not seen with CT-921. At equivalent analgesic doses, THC was much less in CT-921 than in CT-928 suggesting interactions with components other than THC influenced the analgesia. At equivalent analgesic doses, efficacy-to-adverse effect profile for CT-928 was worse than for CT-921., Conclusion: Both extracts relieved neuropathic pain; however, CT-921 had a better efficacy-to-adverse effect profile, a rational basis for prioritizing cultivars for future clinical evaluation., Competing Interests: Dr Elham Rouhollahi had Postdoctoral Fellowship supported by the MITACS Accelerate Program (#IT10243), University of British Columbia, jointly with Cannevert Therapeutics Ltd. Dr MacLeod reports being a colleague and friend of Dr E Puil who has recorded a conflict of interest. Dr Bernard A. MacLeod is a minor shareholder in Veritas Pharma Inc which is research-based cannabis company. Dr Barr reports grants and personal fees from Cannevert Therapeutics, grants from Global Cannabis Applications Corp, Emerald Health Therapeutics, and Entourage Biosciences, and personal fees from Medipure Pharmaceuticals and Vitality Biopharma, outside the submitted work; and has been a scientific advisor to Emerald Health Therapeutics, Cannevert Therapeutics, Global Cannabis Applications Corp, Medipure Pharmaceuticals, Vitality Biopharma and Oakum Cannabis Corp. Dr Puil reports personal fees from Cannevert Therapeutics Ltd, during the conduct of the study; has been a consultant with Cannevert Therapeutics Ltd, and is a minor shareholder in Veritas Pharma Inc., a research-based cannabis company. The authors report no other potential conflicts of interest for this work., (© 2020 Rouhollahi et al.)

An α 2 -adrenoceptor agonist, clonidine, is extensively used in both anesthesia and intensive care medicine. However, clonidine may produce pronounced hemodynamic side effects such as hypotension and bradycardia which may limit its usefulness in certain conditions. Fadolmidine is a potent α 2 -adrenoceptor agonist with different physicochemical properties than clonidine. Here, the effects of fadolmidine and clonidine on analgesia (an increase in thermal skin twitch response latency), sedation, blood pressure, heart rate, respiratory rate, and body temperature were evaluated either up to 8 h after either intrathecal or epidural bolus injections or during a 24-h continuous intrathecal infusion at equipotent analgesic doses in non-anesthetized Beagle dogs. Fadolmidine and clonidine produced a dose-dependent and equipotent maximal antinociception after intrathecal bolus injection (ED 50 : 67 μg and 78 μg, respectively), but the duration of action of fadolmidine was more long-lasting. During the intrathecal infusion, fadolmidine achieved a good analgesic effect without evoking cardiovascular side effects, e.g., hypotension; these were evident during clonidine infusion. Epidurally, the antinociceptive potency of fadolmidine was weaker (ED 50 : 128 μg) than when intrathecally administered and weaker than that of epidural clonidine (ED 50 : 51 μg). At analgesic doses, fadolmidine injection induced moderate initial hypertension concomitantly with a decrease in heart rate whereas clonidine evoked hypotension and bradycardia. These results suggest that especially when non-opioid long-term pain relief is needed, an intrathecal infusion of fadolmidine can provide long-term antinociception with less of the known use-limiting adverse effects associated with clonidine.

To evaluate the sedative and physiological effects of alfaxalone intramuscular (IM) administration, 12 healthy cynomolgus monkeys were administered single IM doses of alfaxalone at 0.625 mg/kg (ALFX0.625), 1.25 mg/kg (ALFX1.25), 2.5 mg/kg (ALFX2.5), 5 mg/kg (ALFX5), 7.5 mg/kg (ALFX7.5), or 10 mg/kg (ALFX10); saline was used as the control (CONT). The sedative effects were subjectively evaluated using a composite measure scoring system in six animals. Changes in respiratory rate, pulse rate, non-invasive blood pressure, percutaneous oxygen-hemoglobin saturation (SpO 2 ), and rectal temperature were observed after IM treatments in the other six animals. All animals were allowed to lay down following the ALFX5, ALFX7.5, and ALFX10 treatments, whereas lateral recumbency was achieved in only two animals after ALFX2.5 treatment and none after the CONT, ALFX 0.625, and ALFX1.25 treatments. The median time (interquartile range) to lateral recumbency was 6.5 min (5.3-7.8), 4.0 min (4.0-4.0), and 3.0 min (3.0-3.8), and the duration of immobilization was 27.5 min (19.0-33.8), 56.0 min (42.3-60.8), and 74.5 min (62.8-78.0) after the ALFX5, ALFX7.5, and ALFX10 treatments, respectively. Endotracheal intubation was achieved in all six animals after the ALFX7.5 and ALFX10 treatments. Dose-dependent decreases in respiratory rate, non-invasive blood pressure, SpO 2 , and rectal temperature were observed, and the quality of recovery was smooth in all animals after the ALFX5, ALFX7.5, and ALFX10 treatments. Thus, alfaxalone IM induced a dose-dependent sedative effect in cynomolgus monkeys, but at higher doses, hypotension, hypoxemia, and hypothermia could be induced.

This study aimed to evaluate chromium supplementation on productive, reproductive, and metabolic parameters at lactating Girolando cows subjected to heat stress conditions in a climatic chamber. Thirty-six lactating Girolando cows were subjected to two sequential trials. In trial 1 (thermoneutral environment), the effect of chromium supplementation was evaluated (0 vs. 0.50 mg/kg of dry matter). In trial 2, the cows were fed the same diets, but they were divided into three environmental conditions: heat stress conditions in climatic chamber, fed ad libitum (HS); thermoneutral environment, fed ad libitum (TN); and thermoneutral environment, pair-fed (PF). In thermoneutral conditions, chromium supplementation did not affect productive or metabolic parameters, although supplemented cows had lower viability of oocytes (65.11 ± 0.08% vs. 76.86 ± 0.08%). During heat stress, chromium supplementation lowered plasma glucose levels (61.17 ± 1.90 vs. 67.11 ± 1.90 mg/dL), and increased the insulin:glucose ratio (0.39 ± 0.04 vs. 0.27 ± 0.04). Cows fed the control diet in the HS group had higher vaginal temperature values (39.40 ± 0.10 °C) than the cows in the TN group and PF group (38.89 ± 0.10 °C and 38.85 ± 0.11 °C, respectively). However, supplemented cows heat-stressed maintained the same vaginal temperature as cows in thermoneutral conditions. In conclusion, chromium supplementation improved glucose metabolism and prevented body temperature increases under heat stress conditions.

Background: Preclinical studies suggest that exposures of infant animals to general anesthetics cause acute neurotoxicity and affect their neurobehavioral development representing a potential risk to human infants undergoing anesthesia. Alternative or mitigating strategies to counteract such adverse effects are desirable. Dexmedetomidine (DEX) is a clinically established sedative with potential neuroprotective properties. DEX ameliorates experimental brain injury as well as neurotoxicity caused by anesthetic doses of sevoflurane (SEVO) or other general anesthetics in infant animals. However, it is unknown whether DEX also is beneficial when given together with lower doses of these drugs. Here we tested the hypothesis that DEX co-administration with a sub-anesthetic dose of SEVO reduces responsiveness to external stimuli while also protecting against SEVO-induced brain cell apoptosis., Method: Rats were exposed on postnatal day 7 for 6 h to SEVO 1.1, 1.8, or 2.5% and were given intraperitoneal injections of saline or DEX at different doses (1-25 μg/kg) three times during the exposure. Responsiveness to external stimuli, respiratory rates, and blood gases were assessed. Apoptosis was determined in cortical and subcortical brain areas by activated caspase-3 immunohistochemistry., Results: Rats exposed to SEVO 1.1% alone were sedated but still responsive to external stimuli whereas those exposed to SEVO 1.8% reached complete unresponsiveness. SEVO-induced brain cell apoptosis increased dose-dependently, with SEVO 1.1% causing a small increase in apoptosis above that in controls. Co-administration of DEX at 1 μg/kg did not alter the responsiveness to stimuli nor the apoptosis induced by SEVO 1.1%. In contrast, co-administration of DEX at 5 μg/kg or higher with SEVO 1.1% reduced responsiveness but potentiated apoptosis., Conclusions: In the neonatal rat model, co-administration of a clinically relevant dose of DEX (1 μg/kg) with a sub-anesthetic dose of SEVO (1.1%) does not affect the neurotoxicity of the anesthetic while co-administration of higher doses of DEX with SEVO 1.1% potentiates it., Competing Interests: Declaration of Competing Interest The authors report no declarations of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: To evaluate the immobilization quality and cardiopulmonary effects of etorphine alone compared with etorphine-azaperone in blesbok (Damaliscus pygargus phillipsi)., Study Design: Blinded, randomized, crossover design., Animals: A total of 12 boma-habituated female blesbok weighing [mean ± standard deviation (SD)] 57.5 ± 2.5 kg., Methods: Each animal was administered etorphine (0.09 mg kg -1 ) or etorphine-azaperone (0.09 mg kg -1 ; 0.35 mg kg -1 ) intramuscularly with 1-week intertreatment washout period. Time to first sign of altered state of consciousness and immobilization time were recorded. Physiological variables were recorded, arterial blood samples were taken during a 40-minute immobilization period, and naltrexone (mean ± SD: 1.83 ± 0.06 mg kg -1 ) was intravenously administered. Recovery times were documented, and induction, immobilization and recovery were subjectively scored. Statistical analyses were performed; p < 0.05 was significant., Results: No difference was observed in time to first sign, immobilization time and recovery times between treatments. Time to head up was longer with etorphine-azaperone (0.5 ± 0.2 versus 0.4 ± 0.2 minutes; p = 0.015). Etorphine caused higher arterial blood pressures (mean: 131 ± 17 versus 110 ± 11 mmHg, p < 0.0001), pH, rectal temperature and arterial oxygen partial pressure (59.2 ± 7.7 versus 42.2 ± 9.8 mmHg), but lower heart (p = 0.002) and respiratory rates (p = 0.01). Etorphine-azaperone combination led to greater impairment of ventilatory function, with higher end-tidal carbon dioxide (p < 0.0001) and arterial partial pressure of carbon dioxide (58.0 ± 4.5 versus 48.1 ± 5.1 mmHg). Immobilization quality was greater with etorphine-azaperone than with etorphine alone (median scores: 4 versus 3; p < 0.0001)., Conclusions and Clinical Relevance: Both treatments provided satisfactory immobilization of blesbok; however, in addition to a deeper level of immobilization, etorphine-azaperone caused greater ventilatory impairment. Oxygen supplementation is recommended with both treatments., (Copyright © 2020 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved.)

We previously reported that intracerebroventricularly (ICV) injected arachidonic acid (AA) could produce pressor and bradycardic responses on the cardiovascular system and hyperventilation effect on the respiratory system by activating cyclooxygenase (COX). We also demonstrated that centrally injected AA-induced cardiovascular and respiratory responses were mediated by COX-metabolites, such as thromboxane A 2 (TXA 2 ), prostaglandin (PG) D, PGE, and PGF 2α . Brain tissue is also able to express the lipoxygenase (LOX) enzyme and LOX-induced AA-metabolites. The current study was designed to investigate the possible mediation of the central LOX pathway in AA-induced cardiorespiratory effects in anesthetized rats. Central pretreatment with different doses of a non-selective LOX inhibitor, nordihydroguaiaretic acid (NDGA) (500 and 1000 μg; ICV) partially blocked the AA (0.5 μmol; ICV)-evoked pressor and bradycardic cardiovascular responses in male anesthetized Sprague Dawley rats. Pretreatment with different doses of NDGA (500 and 1000 μg; ICV) also reduced AA-induced hyperventilation responses, with an increase in tidal volume, respiratory rate and minute ventilation, in the rats. Moreover, AA-induced increasing pO 2 and decreasing pCO 2 responses were diminished by central NDGA pretreatment. In summary, our findings show that the central LOX pathway might mediate, at least in part, centrally administered AA-evoked cardiorespiratory and blood gases responses., (Copyright © 2020 Elsevier B.V. All rights reserved.)