Depression Of Respiratory Activity Research Articles

Синтетические каннабиноиды: распространённость, механизмы формирования зависимости, психические нарушения, связанные с употреблением. Современное состояние проблемы

According to the authors among the new psychoactive substances, the number of which is growing every year, despite the measures aimed at the obstacles to their dissemination there discovered the most frequent violations of psychotic conditions associated with use of synthetic cannabinoid in clinical practice. On the black market, they are distributed through online shops, under the guise of herbal mixtures for Smoking. When ingested, this group of drugs at the peak of intoxication raises a number of mental (different according to the depth of impaired consciousness, auditory and visual hallucinations, panic attacks, acute psychotic paranoid disorders, catatonic stupor, polar affective disorders, acute polythematic delusional symptoms) and somatic disorders (disorders of heart rhythm and conduction, acute ischemic disorders, hypertension, depression of respiratory activity, violation of thermoregulation, development of acute renal failure, vomiting, expressed cephalgia, clinic of hypokalemia). In the reviewed literature and authors own observations there have been discovered some cases of mental addiction development to synthetic cannabinoids. The analysis of new literature data and own clinical observations helped the authors to compare the psychotropic effects caused by this group of drugs, relative to other known surfactants. The toxic effects of CSC on the body greatly exceeds the use of plant cannabinoids, and it has almost the same effects as the synthetic cathinone’s. The speed of formation of psychological dependence is lower compared to synthetic cathinone. Developing current strategies for diagnosis, treatment, and rehabilitation of patients who use synthetic cannabinoids remains an important task for practical healthcare.

Relevance of Mitochondrial Genetics and Metabolism in Cancer Development

Cancer cells are characterized in general by a decrease of mitochondrial respiration and oxidative phosphorylation, together with a strong enhancement of glycolysis, the so-called Warburg effect. The decrease of mitochondrial activity in cancer cells may have multiple reasons, related either to the input of reducing equivalents to the electron transfer chain or to direct alterations of the mitochondrial respiratory complexes. In some cases, the depression of respiratory activity is clearly the consequence of disruptive mitochondrial DNA (mtDNA) mutations and leads as a consequence to enhanced generation of reactive oxygen species (ROS). By acting both as mutagens and cellular mitogens, ROS may contribute directly to cancer progression. On the basis of our experimental evidence, we suggest a deep implication of the supercomplex organization of the respiratory chain as a missing link between oxidative stress, energy failure, and tumorigenesis. We speculate that under conditions of oxidative stress, a dissociation of mitochondrial supercomplexes occurs, with destabilization of complex I and secondary enhanced generation of ROS, thus leading to a vicious circle amplifying mitochondrial dysfunction. An excellent model to dissect the role of pathogenic, disassembling mtDNA mutations in tumor progression and their contribution to the metabolic reprogramming of cancer cells (glycolysis vs. respiration) is provided by an often underdiagnosed subset of tumors, namely, the oncocytomas, characterized by disruptive mutations of mtDNA, especially of complex I subunits. Such mutations almost completely abolish complex I activity, which slows down the Krebs cycle, favoring a high ratio of α-ketoglutarate/succinate and consequent destabilization of hypoxia inducible factor 1α (HIF1α). On the other hand, if complex I is partially defective, the levels of NAD(+) may be sufficient to implement the Krebs cycle with higher levels of intermediates that stabilize HIF1α, thus favoring tumor malignancy. The threshold model we propose, based on the population-like dynamics of mitochondrial genetics (heteroplasmy vs. homoplasmy), implies that below threshold complex I is present and functioning correctly, thus favoring tumor growth, whereas above threshold, when complex I is not assembled, tumor growth is arrested. We have therefore termed "oncojanus" the mtDNA genes whose disruptive mutations have such a double-edged effect.

Disparate purinergic modulation of respiration in rats and mice

Disparate purinergic modulation of respiration in rats and mice

A mapping study of cardiorespiratory responses to chemical stimulation of the midline medulla oblongata in ventilated and freely breathing rats.

The aim of this study was to examine the cardiorespiratory effects of chemically stimulating neurons in the midline medulla oblongata (MM) of artificially ventilated and freely breathing anesthetized rats. Earlier studies reported that stimulation of the MM elicits increases or decreases in mean arterial pressure (MAP) and phrenic nerve activity, depending on the mode and site of stimulation, anesthetic, and species. In the first series of experiments, rats were anesthetized with urethane, artificially ventilated, paralyzed, and bilaterally vagotomized. The rostrocaudal extent of the MM was mapped by microinjections of DL-homocysteic acid or L-glutamate (both 100 mM, 100 nl), and, in line with previous studies, most injections produced only small responses in MAP, heart rate, and splanchnic sympathetic nerve activity. Increases in respiratory parameters were evoked in caudal regions. However, activation of a discrete region of the MM at the level of the caudal pole of the facial nucleus (CP7) consistently caused a dramatic reduction in phrenic nerve amplitude and/or frequency and, in six rats, produced a prolonged apnea. The second series of experiments was carried out on freely breathing pentobarbitone sodium-anesthetized rats, with a diaphragmatic electromyogram used to monitor respiratory activity. Respiratory activity could again be abolished at CP7 after microinjections of glutamate (100 mM, 50 nl); however, these responses were accompanied by large decreases in MAP and moderate reductions in heart rate. This depression of respiratory activity may be due to activation of propriobulbar inhibitory neurons that project to known respiratory centers in the brain stem.

The role of gamma-aminobutyric acid and glutamate for hypoxic ventilatory response in anesthetized rabbits.

Acute hypoxia produces an increase in ventilation. When the hypoxia is sustained, the initial increase in ventilation is followed by a decrease in ventilation. Hypoxia causes changes in brain neurotransmitters depending on its severity and durations. The purpose of this study was to investigate the role of gamma-aminobutyric acid (GABA) and glutamate for hypoxic ventilatory response in rabbits. The experiments were performed in peripheral chemoreceptors intact and denervated rabbits anesthetized with Na-pentobarbitate. For intracerebroventricular (ICV) injections of reagents in each animal, cannula was placed in left lateral cerebral ventricle by stereotaxic method. After ICV injection of GABA (0.48 mg/kg), air breathing in both groups caused a depression of respiratory activity. On the other hand, after ICV injection of GABA, breathing of hypoxic gas mixture (8% O(2)-92% N(2)) in both groups produced the hypoxic hyperventilation. After ICV injection of GABA, blockade of GABA(A) receptors with bicuculline (0.2 mg/kg) did not prevent the hypoxic hyperventilation. In contrast, after ICV GABA injection, blockade of glutamate NMDA receptors with MK-801 (0.09 mg/kg) completely abolished the hypoxic hyperventilation observed while the animals were breathing hypoxic gas mixture. Our findings suggest that ICV injection of GABA causes respiratory depression in normoxic conditions, and that it increases ventilation in hypoxic conditions with or without peripheral chemoreceptor impulses by increasing glutamate.

The herbicide dicamba (2-methoxy-3,6-dichlorobenzoic acid) interacts with mitochondrial bioenergetic functions.

The effects of dicamba, a widely used broad-leaf herbicide, on rat liver mitochondrial bioenergetic activities were examined. The results obtained for state 4 respiration indicate not only an uncoupling effect, the result of an increase on the permeability of inner mitochondria membrane to protons, but also a strong inhibitory effect on the redox complexes. State 3 and respiration uncoupled by FCCP (carbonylcyanide p-trifluoromethoxyphenylhydrazone) were inhibited to approximately the same extent, i.e. by about 70%. Depression of respiratory activity is essentially mediated through partial inhibition of mitochondrial complexes II and III. ATPase activity was much less depressed by dicamba than ATP synthase activity. Therefore, a considerable part of the inhibition observed on ATP synthase is the result of an inhibition on the redox complexes. The loss of phosphorylation capacity, induced by dicamba, was in the last analysis not only the result of a direct effect of dicamba on the enzymatic complex (F(0)-F(1) ATPase) but also the result of a deleterious effect on the integrity of the mitochondrial membrane, which can promote an inhibition of the respiratory complexes and an increase of the proton permeability of the inner membrane.

Respiratory Activity of Isolated Rat Hepatocytes Following Cold Storage and Subsequent Rewarming: A Comparison of Sucrose-Based and University of Wisconsin Solutions

Investigations were carried out on the respiratory function of isolated rat hepatocytes after cold storage alone for periods up to 48 h in either sucrose-based solution (SBS) or University of Wisconsin (UW) solution and after subsequent normothermic preincubation. In both SBS and UW, cold storage for 24 h depressed respiratory function (to 21 ± 3 and 23 ± 3 nmol O2/min/106 cells, respectively) compared to control cell values (31 ± 3 and 33 ± 5 nmol O2/min/106 cells; P < 0.01 in each case). However, normothermic preincubation for 60 min returned respiratory activity to control values (for SBS and UW storage: 41 ± 6 and 40 ± 5 nmol O2/min/106 cells; for control cells: 43 ± 5 and 46 ± 6 nmol O2/min/106 cells). Storage for 48 h in both SBS and UW allowed further depression of respiratory activity, with no recovery after preincubation. Stimulation of respiration by succinate in hepatocytes stored for longer periods was suggestive of increased membrane permeability. Both SBS and UW are effective storage solutions for isolated hepatocytes for up to 24 h as judged by aerobic metabolism, but significant damage was expressed in both solutions when preservation was extended.

Effect of hypoxia on the activity of respiratory and non-respiratory modulated retrotrapezoid neurons of the cat

The retrotrapezoid nucleus (RTN), a part of the rostral ventrolateral medulla, is involved in the control of breathing. A recent immunohistological study suggested a possible involvement of the RTN in hypoxic chemoreflex loop. The present electrophysiological study performed in the cat demonstrates that 23 out of 24 RTN neurons were stimulated during the biphasic respiratory response to hypoxia, which consists of a reinforcement followed by a depression of respiratory activity. This confirms the previous immunohistological study. While 15 RTN neurons might integrate either phase I ( n=7) or phase II ( n=8) O 2-chemosensitive inputs, the remaining eight RTN neurons stimulated by hypoxia are susceptible to integrate both phase I and phase II O 2-chemosensitive inputs. In conclusion, our results suggest that the different subsets of RTN neurons may influence respiratory output by conveying signals originating from peripheral and/or central chemoreceptors stimulated during hypoxia.

Mitochondrial bioenergetics is affected by the herbicide paraquat

The potential toxicity of the herbicide paraquat (1,1-dimethyl-4,4′-bipyridylium dichloride) was tested in bioenergetic functions of isolated rat liver mitochondria. Paraquat increases the rate of State 4 respiration, doubling at 10 mM, indicating uncoupling effects. Additionally, State 3 respiration is depressed by about 15%, at 10 mM paraquat, whereas uncoupled respiration in the presence of CCCP is depressed by about 30%. Furthermore, paraquat partially inhibits the ATPase activity through a direct effect on this enzyme complex. However, at high concentrations (5–10 mM), the ATPase activity is stimulated, probably as consequence of the described uncoupling effect. Depression of respiratory activity is mediated through partial inhibitions of mitochondrial complexes III and IV. Paraquat depresses Δψ as a function of herbicide concentration. In addition, the depolarization induced by ADP is decreased and repolarization is biphasic suggesting a double effect. Repolarization resumes at a level consistently higher than the initial level before ADP addition, for paraquat concentrations up to 10 mM. This particular effect is clear at 1 mM paraquat and tends to fade out with increasing concentrations of the herbicide.

Role of supernumerary subunits in mitochondrial cytochrome c oxidase

Role of supernumerary subunits of bovine heart cytochrome c oxidase has been investigated by examining the influence on the enzymatic activity of their removal by Chromatographic procedures or controlled digestion by trypsin. Is has been shown that partial proteolytic cleavage of subunit IV results in depression of respiratory activity and of redox-linked proton translocation. Selective removal by gel-filtration of subunit VIb has no significant influence on the redox and protonmotive activity of the oxidase.

Prolonged inhibition of respiration following acute hypoxia in glomectomized cats

Respiratory responses to several minutes exposure to hypoxia (Pa O 2 < 30 torr) were determined in anesthetized, paralyzed, vagotomized and glomectomized cats end-tidal P CO 2 and body temperature were kept constant. Respiratory activity was quantified from phrenic nerve activity. Animals breathed 100% O 2 during the control period. The study reaffirmed that in glomectomized animals hypoxia causes depression of respiratory activity. The new findings was that phrenic activity remained significantly depressed below the original control level for more than one hr after return to the hyperoxic state. Medullary ECF pH was measured in 3 cats. There was an acid shift of pH during hypoxia that persisted for more than one hour after return to hyperoxic state. We pretreated another group (n = 5) of animals with theophylline, a specific antagonist of the inhibitory neurotransmitter adenosine. Hypoxia caused depression of respiratory activity, but it was less severs than in untreated animals. Upon return to the hyperoxic state, respiratory activity returned to the original control level within 10 min. We conclude that the long-lasting depression of respiration following hypoxia is mediated by adenosine. Furthermore, adenosine appears to be partially responsible for the acute depression of respiration during the hypoxic exposure.

Respiratory depression produced by activation of GABA receptors in hindbrain of cat.

Respiratory responses to activation of gamma-aminobutyric acid (GABA) receptors in the hindbrain were measured in chloralose-anesthetized cats using a Fleisch pneumotachograph. GABA receptors were activated by intracisternal injections of muscimol and GABA. Muscimol (0.05--6.65 micrograms) administered to seven animals caused a depression of respiratory activity with apnea occurring in each animal. Before apnea occurred, a decrease in tidal volume was observed (from 25.7 +/- 0.9 to 14.7 +/- 1.1 ml). Respiratory rate and inspiratory and expiratory durations were unchanged. GABA (0.05--12.15 mg) administered to five animals produced the same effect as muscimol on respiratory activity. Apnea produced by both agents was reversed by intracisternal administration of the GABA-receptor antagonist drug, bicuculline. Administration of bicuculline to four naive animals increased tidal volume (from 31.3 +/- 1.7 to 36.5 +/- 0.7 ml) but had no effect on either respiratory rate or inspiratory duration. These results indicate that activation of GABA receptors causes respiratory depression and suggest that GABA may be an important neurotransmitter in CNS neural pathways involved in regulating respiratory activity.

Versuche zur Wirkung von Paraoxon auf Atem- und Vaguszentren und der Einflu� verschiedener Antidote

The cholinesterase inhibiting organophosphates induce a dangerous or lethal depression of respiratory activity by central and peripheral effects. In many species the laryngospasm is an important factor for death by asphyxia.

The effect of carbon monoxide inhalation on respiratory activity and blood acid-base equilibriaum of normal and chemoreceptorless rabbits.

AbstractThe respiratory response of man and animals to inhalations of various concentrations of CO in air has been found to be variable by various investigators. At the end of last century, Haldane and Haldane and L. Smith (1935), in experiments conducted on themselves for the purpose of investigating the symptoms of CO poisoning in man, observed a distinct hyperpnea at blood CO saturations of 30 % or more. Haggard and Henderson (1921) and Wright (1936) noted a long lasting initial stimulation followed by depression of respiratory activity in unanesthetized dogs and anesthetized cats and rabbits, respectively, on the inhalation of CO in air. The reaction was entirely abolished on sectioning of the vagi (Haggard and Henderson, 1921) while merely the final depressive effect of CO inhalation was observed after the denervation of the chemoreceptor zones (Wright, 1936). On the other hand, Chiodi et al. (1941) failed to note any hyperpnea in man and in one unanesthetized dog on the inhalations of 0.1–0.35 % CO ...

Oxygen for acute respiratory depression due to administration of thiopental sodium.

It is a well-recognized fact that barbiturates produce respiratory depression when administered intravenously, since their action as anesthetics is associated with depression of respiratory activity. For this reason it seemed worthwhile to compare the effects of thiopental (Pentothal) sodium on arterial blood oxygen of 18 patients undergoing a simple surgical procedure with the effects of administering oxygen simultaneously with the thiopental sodium to another group of 10 patients. In this group of 28 female patients, between the ages of 19 and 37, all had a diagnosis of incomplete abortion and were brought to surgery for a therapeutic dilation and curettage. Except for the presence of mild to severe anemias there were no other complicating medical conditions. PROCEDURE All patients were given 1/150 grain (0.4 mg.) of atropine as premedication one hour before surgery. Under local anesthesia a Cournand needle was placed in either the radial or brachial artery. There were

THE TREATMENT OF HEMOPTYSIS IN PULMONARY TUBERCULOSIS

Hemoptysis of known pulmonary origin in tuberculosis is now treated at North Reading in a rather original manner. The plan in use was selected for its superiority after three years of gradual elimination of various forms of treatment. Many methods commonly employed to cope with pulmonary hemorrhage were discarded after a fair trial on account of inefficiency and harmful sequelae. For instance, morphin, generally advocated and no doubt extensively used in the treatment of this complication, has fallen decidedly out of favor with us. The text-books offer it for use by reason of the indication for the depression of respiratory activity, the allaying of excitement, and the suppression of cough. The idea is that all efforts should cooperate toward quieting the patient, but this seems to be without due regard for the alleviation of the trouble which causes the disturbance. Let one who prescribes morphin in such instances remain at the patient's bedside to observe the