The Biological Mechanisms of Air Ion Action : I. 5-Hydroxytryptamine as the endogenous mediator of positive air ion effects on the mammalian trachea

Intravenous administration of 5-hydroxytryptamine to rabbits and guinea pigs is shown to bring about changes very similar to those produced by (+) air ions, including (1) decreased ciliary rate, (2) contraction of the posterior tracheal wall, (3) exaggerated response of the tracheal mucosa to trauma, (4) marked vasoconstriction in the tracheal wall, and (5) increased respiratory rate. These effects are reversed by (-) air ions. Iproniazid, which raises 5-hydroxytryptamine levels in the animal by blocking monamine oxidase, produces similar but non-reversible effects. Reserpine, which depletes 5-hydroxytryptamine in the animal, causes changes that resemble those produced by (-) air ions, including (1) increased ciliary rate, (2) relaxed posterior sulcus, (3) hyperemia of the tracheal mucosa, (4) lowered respiratory rate, and (5) increased volume and rate of mucus flow. On the basis of these facts, the hypothesis is advanced that (+) air ion effects are mediated by the release of free 5-hydroxytryptamine, while (-) air ion effects depend on the ability of (-) ions to accelerate the enzymatic oxidation of 5-hydroxytryptamine.     

The effects of asphyxia on 5-hydroxytryptamine metabolism in the immature rat brain

Five-day-old rats subjected to prolonged asphyxia at 37 degrees C show a slower rate of synthesis of 5-HT as measured by the accumulation of the amine after inhibition of monoamine oxidase. During recovery from asphyxia 5-HT synthesis is markedly stimulated when measured over a 50 or 90 min period. No change in 5-HT synthesis was observed in 5-day-old rats during recovery from cold exposure or immobilization. The results indicate that the persistent increase in synthesis that follows resuscitation may be related to asphyxia per se rather than to the stress component of the treatment.     

The biological mechanism of air ion action: The effect of CO2+ in inhaled air on the blood level of 5-hydroxytryptamine in mice

Mice inhaling positively ionized air exhibited a significant rise in the blood level of 5-hydroxytryptamine [5-HT]_BL. This effect was duplicated by non-ionized air to which CO₂ ⁺ was added but did not occur when the same amount of either nonionized CO₂ or CO₂ ^– replaced CO₂ ⁺. The rise in [5-HT]_BL was associated with physiological changes that parallel those appearing after the injection of 5-HT or after administration of iproniazid.Some of the animals exposed to CO₂ ⁺ in air became ill and suffered tissue damage attributable to excessive concentrations of 5-HT. A few of the mice died and at autopsy pulmonary and enteric lesions were found which also were reasonably ascribed to the increased 5-HT_BL.The physiological,pathological and biochemical changes described furnish additional support for the 5-HT hypothesis of air ion action presented in earlier publications. There is good reason to believe that some of the known biological effects of gaseous ions involve other mechanisms.

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Zusammenfassung Der 5-Hydroxytryptamin (5-TH) Spiegel im Blut von MÄusen war signifikant erhöht nach Inhalation von positiv ionisierter Luft. Der Effekt wurde bei Zugabe von CO₂ ⁺ Ionen zu nicht-ionisierter Luft verdoppelt; er fehlte, wenn der Luft anstatt CO₂ ⁺, CO₂ ^– oder nicht-ionisiertes CO₂ beigemischt wurden.Mit dem 5-HT Anstieg im Blut kam es zu den typischen physiologischen VerÄnderungen, wie sie nach Injektion von 5-TH oder Iproniazid auftreten. Ein Teil der Tiere, die Luft mit CO₂ ⁺ geatmet hatten,erkrankte an GewebsschÄden, die sonst nach 5-HT überdosierung auftreten; mehrere Tiere starben; die Lungen- und DarmverÄnderungen wurden als Folge des erhöhten 5-HT Blutspiegels gedeutet. Diese physiologischen,pathologischen und biochemischen VerÄnderungen liefern weitere Belege für die Hypothese,dass die Luftionen über das 5-HT wirken. Es sind jedoch Anzeichen vorhanden, daas in den Wirkungsmechanismus der Gasionen noch andere Funktionen einbezogen sind.

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Résumé Des souris inhalant de l'air ionisé positivement ont montré une augmentation significante du taux sanguin de 5-hydrocytryptamine [5-HT]_BL. Cet effet fut reproduit par de l'air non ionisé auquel on avait ajoute du CO₂ ⁺, mais ne se produisit pas quand la mÊme quantité de CO₂ non ionisé ou de CO₂ ^– remplaÇait le CO₂ ⁺. L'élévation de (5-HT)_BL était accompagnée de modifications physiologiques parallèles à celles qui apparaissent après injection de 5-HT ou administration d'iproniazide. Quelques animaux exposés à du CO₁₂ ⁺ dans l'air tombèrent malades et souffrirent de lésions tissulaires attribuables à un excès de 5-HT. Un petit nombre de souris moururent et les lésions pulmonaires et intestinales trouvées à l'autopsie furent attribuées à l'augmentation de (5-HT)_BL. Les observations physiologiques, pathologiques et biochimiques décrites apportent un argument de plus en faveur de l'hypothèse présentée précédemment sur le rÔle de la 5-HT dans l'action des ions gazeux. Il y a de bonnes raisons de penser que quelques effets biologiques connus des ions gazeux sont produits par d'autres mécanismes.

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Labration for rats and mice made by Rainbrook Feed Company.     

Radioprotective effect of 5-hydroxytryptamine and 5-hydroxytryptophan on mammalian cells irradiated in vitro.

The radioprotective effect in vitro of 5-hydroxytryptamine (5-HT) and 5-hydroxytryptophan (k-HTP) was studied with cultured mammalian cells of three cell lines: 5-HT-synthesizing FMA and 5-HT-non-synthesizing FM3A and B16-C2W. In these cells, the addition of 5-HT to the suspending medium induced only a weak protection or no protection at all. The increase in the 5-HT content of these cells at the time of irradiation was negligible. Pre-incubation of cells for 40 min in a 5-HTP-containing medium resulted in an elevation of the 5-HT content concomitantly with an increase in the radioresistance of FMA cells, where the DRF at 1 per cent was 1 x 8. In FM3A and B16-C2W cells such an effect was not observed. The same relationship between 5-HT content and radioresistance was also observed in FMA cells which were cultured in different densities or with reserpine. These results strongly suggest that the substance playing the main role in the induction of radioresistance in cells in vitro is the 5-HT that exists in the cells.     

The regional metabolism of 5-hydroxytryptamine in mouse brain in vitro.

The relative rates of formation of 5-hydroxytryptophol (5-HTOL) and 5-hydroxyindoleacetic acid (5-HIAA) from exogenous 5-hydroxytryptamine, showed regional variations when examined in homogenates of seven separate areas of mouse brain. 5-HTOL production was highest in the cerebellum, and lowest in the corpus striatum, whereas the production of 5-HIAA was greatest in the hypothalamus. Addition of NADPH was shown to increase the formation of the alcohol catabolite in whole brain homogenates. The production of 5-HTOL decreased in the brain homogenates of mice which had previously been injected with phenytoin sodium or oxypertine, with the latter also causing a fall in overall 5-HT metabolism.     

The effects of horseradish peroxidase on the concentration of 5-hydroxytryptamine and platelet counts in blood of rabbits and guinea pigs

Summary When HRP was injected i.v. in rabbits and guinea pigs, a rapid fall in the number of circulating platelets and the concentration of 5 HT occurred.Platelet aggregates were trapped in lung capillaries. The aggregation was reversible with the return of platelets to the circulation concomitant with a rise in blood 5 HT concentration.     

Ion transport and regulation of respiratory tract fluid output in dogs.

To investigate the regulation of respiratory tract fluid output (RTFO), we collected the RTFO in an anesthetized canine model after a series of pharmacological interventions (inhibition of Na(+)-K(+)-ATPase or Na(+)-K(+)-2Cl(-) cotransporter, 250 microl) and physiological challenges (ionic and/or osmotic perturbation in airway lumen, 250 microl). Whereas 250 microl of aerosolized 0.9% saline caused a transient increase in RTFO, a 250-microl bumetanide-induced increase in RTFO was evident for 18 min and a 250-microl acetylstrophanthidin-induced increase in RTFO persisted for at least 30 min. Dry air ventilation decreased the responses of RTFO to the saline (sham) and acetylstrophanthidin intervention but not the bumetanide intervention. Delivery of 250 mosmol/kgH(2)O ion-free mannitol (250 microl) caused marked increases in RTFO that were little affected by the administration of acetylstrophanthidin or bumetanide 30 min before these challenges. A 250-microl 550 mosmol/kgH(2)O ion-free mannitol challenge caused a more marked and prolonged increase in RTFO. Thus aerosol delivery of a low dose of a cardiac glycoside or a near-isosmotic, ion-free, impermeant osmolyte solution may be therapeutically useful by increasing the clearance of secretions from the tracheobronchial airways.     

Cell-specific expression of CYP2A5 in the mouse respiratory tract: effects of olfactory toxicants.

We performed a detailed analysis of mouse cytochrome P450 2A5 (CYP2A5) expression by in situ hybridization (ISH) and immunohistochemistry (IHC) in the respiratory tissues of mice. The CYP2A5 mRNA and the corresponding protein co-localized at most sites and were predominantly detected in the olfactory region, with an expression in sustentacular cells, Bowman's gland, and duct cells. In the respiratory and transitional epithelium there was no or only weak expression. The nasolacrimal duct and the excretory ducts of nasal and salivary glands displayed expression, whereas no expression occurred in the acini. There was decreasing expression along the epithelial linings of the trachea and lower respiratory tract, whereas no expression occurred in the alveoli. The hepatic CYP2A5 inducers pyrazole and phenobarbital neither changed the CYP2A5 expression pattern nor damaged the olfactory mucosa. In contrast, the olfactory toxicants dichlobenil and methimazole induced characteristic changes. The damaged Bowman's glands displayed no expression, whereas the damaged epithelium expressed the enzyme. The CYP2A5 expression pattern is in accordance with previously reported localization of protein and DNA adducts and the toxicity of some CYP2A5 substrates. This suggests that CYP2A5 is an important determinant for the susceptibility of the nasal and respiratory epithelia to protoxicants and procarcinogens.     

吸烟对人体呼吸道厌氧菌的影响

目的探究吸烟对人体内的呼吸道微生态的影响。方法采用细菌鉴定及药敏分析系统鉴定健康吸烟者与非吸烟者,患下呼吸道感染吸烟与非吸烟者咽后壁分泌物的细菌密度、细菌数量及种类的改变。结果在健康吸烟者与患有下呼吸道感染患者的呼吸道中,厌氧菌明显升高,其中以韦荣菌和消化链球菌为主。结论吸烟可使人体的呼吸道微生态中细菌密度,细菌数量及种类的改变,易患呼吸系统疾病。     

Role of 5-hydroxytryptamine1B receptors and 5-hydroxytryptamine uptake inhibition in the cocaine-evoked discriminative stimulus effects in rats.

Mesolimbic dopamine pathways play a critical role in the behavioural effects of cocaine in rodents. Nonetheless, research has also demonstrated involvement of 5-hydroxytryptamine (5-HT; serotonin) transmission in these effects. The present study investigated the ability of selective 5-HT1B receptor ligands and a 5-HT reuptake inhibitor to substitute for or to alter (enhance or antagonise) the discriminative stimulus effects of cocaine. Male Wistar rats were trained to discriminate cocaine (10 mg/kg, i.p.) from saline (i.p.) in a two-choice, water-reinforced fixed ratio (FR) 20 drug discrimination paradigm. In substitution tests, the selective 5-HT1B receptor agonist 3-(1,2,5,6-tetrahydro-4-pyridyl)-5-propoxypyrrolo[3,2-b]pyridine (CP 94253; 2.5-5 mg/kg, i.p.) and the 5-HT reuptake inhibitor fluoxetine (5-10 mg/kg, i.p.) elicited ca. 40 and 0% drug-lever responding, respectively. In combination experiments, CP 94253 (2.5-5 mg/kg) given with submaximal doses of cocaine (0.3-2.5 mg/kg) produced a leftward shift in the cocaine dose-response curve; pretreatment with CP 94253 (5 mg/kg) prior to a dose of cocaine (2.5 mg/kg) which elicited lower than 40% drug-lever responding, caused full substitution. Fluoxetine (5 and 10 mg/kg) given in combination with a submaximal dose of cocaine (2.5 mg/kg) produced a 100% drug-lever responding. Pretreatment with the 5-HT1B receptor antagonists N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2'-methyl-4'-(5-methyl-[1,2,4]oxadiazol-3-yl)-1,1'-biphenyl-4 carboxamide (GR 127935; 0.5-5 mg/kg, s.c.) and 3-(3-dimethylamino)-propyl)-4-hydroxy-N-[4-(4-pyridinyl)-phenyl]benzamide (GR 55562; 1 mg/kg, s.c.) failed to modulate the dose-effect curve for cocaine (0.6-5 mg/kg). On the other hand, GR 127935 (5 mg/kg) and GR 55562 (1 mg/kg) significantly attenuated the enhancement of cocaine discrimination evoked by a combination of CP 94253 (5 mg/kg) or fluoxetine (5 mg/kg) and cocaine (2.5 mg/kg). These results indicate that 5-HT1B receptors are not directly involved in the cocaine-induced discriminative stimuli in rats. On the other hand, they indicate that pharmacological stimulation of 5-HT receptors--that also seem to be a target for fluoxetine-mediated increase in 5-HT neurotransmission--can enhance the overall effects of cocaine.     

The effects of 5-hydroxytryptophan and 5-hydroxytryptamine on dopamine synthesis and release in rat brain striatal synaptosomes.

The effects of 5-hydroxytryptophan (5-HTP) and serotonin (5-HT) on dopamine synthesis and release in rat brain striatal synaptosomes have been examined and compared to the effects of tyramine and dopamine. Serotonin inhibited dopamine synthesis from tyrosine, with 25% inhibition occurring at 3 μM-5-HT and 60% inhibition at 200 μM. Dopamine synthesis from DOPA was also inhibited by 5-HT, with 30% inhibition occurring at 200 μ. At 200 μM-5-HTP, dopamine synthesis from both tyrosine and DOPA was inhibited about 70%. When just the tyrosine hydroxylation step was measured in the intact synaptosome, 5-HT, 5-HTP, tyramine and dopamine all caused significant inhibition, but only dopamine inhibited soluble tyrosine hydroxylase [L-tyrosine 3-monooxygenase; L-tyrosine, tetrahydropteridine oxygen oxidoreductase (3-hydroxylating); EC 1.14.16.2] prepared from lysed synaptosomes. Particulate tyrosine hydroxylase was not inhibited by 10 μM-5-HT, but was about 20% inhibited by 200 μM-5-HT and 5-HTP. At 200 μM both 5-HT and 5-HTP stimulated endogenous dopamine release. These experiments suggest that exposure of dopaminergic neurons to 5-HT or 5-HTP leads to an inhibition of dopamine synthesis, mediated in part by an intraneuronal displacement of dopamine from vesicle storage sites, leading to an increase in dopamine-induced feedback inhibition of tyrosine hydroxylase, and in part by a direct inhibition of DOPA decarboxylation.     

The effects of salicylic acid on metabolism and potassium ion content in yeast.

Under anaerobic conditions, at low pH and 30 degrees, commercial baker's yeast loses K+ ion in the presence of salicylic acid. Glucose utilization is inhibited. In suspensions containing no glucose, carbohydrate stores of the cell are dissimilated to carbon dioxide and alcohol. The ion loss and inhibitory effects of salicylic acid on glucose utilization are reversed by washing the cells free of salicylate. The loss of K+ appears to be due at least partly to a K+-H+ exchange process. An unexplained maximum is seen in the curves of either net K+ loss or K+ efflux versus salicylic acid concentration. At 6 degrees the effects of salicylic acid on both endogenous metabolism and net K+ loss are minimal. Furthermore, no maximum is seen in the K+ loss-salicyclic concentration curve at this temperature. It is generalized that salicylic acid or salicylate may elicit K+ leakage from many types of cells, i.e., a fundamental action of this compound may be its ability to affect (reduce) K+ content of the cell; furthermore, it appears that the salicylate effects on K+ loss may be associated in an as-yet-unknown manner with the metabolic effects of this compound. The effects of salicylate on K+ loss in yeast may not be unique for this compound, since no experiments of this nature have been done with other penetrating undissociated acids.