Effects of Methylecgonidine on acetylcholine-induced bronchoconstriction and indicators of lung injury in guinea pigs

The fumarate salt of methylecgonidine (MEG; anhydroecgonine methylester), a pyrolysis product of cocaine, has previously been shown to antagonize contractions of guinea pig isolated trachea induced by acetylcholine (ACh) and other spasmogenics. We determined the effects of MEG fumarate on ACh-induced bronchoconstriction in vivo. Specific airway conductance (SGaw) was measured in guinea pigs receiving 30–300 mg/kg s.c. MEG fumarate and exposed one hour later to nebulized ACh (0.2–3.2%; by inhalation). MEG fumarate did not induce any changes in SGaw; neither did it antagonize dose-dependent decreases in SGaw induced by ACh. However, tremors, salivation, startle and increased numbers of fecal boli were observed after MEG administration. Thus, unlike antagonism of ACh-induced contractions of guinea pig isolated trachea observed in vitro, MEG fumarate does not antagonize ACh-induced bronchoconstriction in vivo, even at doses which induced changes in grossly-observable behavior. Inhalation of a condensation aerosol of MEG base induced lung damage as evidenced by the presence of blood and higher levels of protein and lactate dehydrogenase in the lung lavage fluid of MEG-treated animals than of control animals. Aerosols of MEG fumarate, on the other hand, did not induce lung damage when inhaled. These results extend previous observations that MEG base may contribute to detrimental pulmonary effects of crack smoking.     

No involvement of lipid mediators in a guinea pig model of ultrasonically nebulized distilled water-induced bronchoconstriction

An inhalation of ultrasonically nebulized distilled water (UNDW) induces bronchoconstriction only in asthmatics, but the mechanism underlying the response is not fully understood. We have reported that bronchoconstriction occurs immediately after UNDW is inhaled 20 min after an antigen challenge in guinea pigs. Our aim was to examine the role of lipid mediators in this response. Passively sensitized guinea pigs were anesthetized and artificially ventilated. A sulfidopeptide leukotriene receptor antagonist, KCA-757, and platelet-activating factor antagonists, Y-24180 and E6123, were administered i.v. 15 min after an aerosolized antigen challenge, and UNDW was inhaled 5 min later. KCA-757, Y-24180, or E6123 did not, significantly alter the UNDW-induced bronchoconstriction. Together with our previous data that thromboxane A2 receptor antagonists did not influence the UNDW-induced bronchoconstriction, the present results suggest that lipid mediators are not involved in the UNDW-induced bronchoconstriction in our guinea pig model.     

Bronchodilator Efficacy of Liposome Formulations of Metaproterenol Sulfate in the Anesthetized Guinea Pig

Abstract

Experiments were performed in anesthetized guinea pigs to determine the effects of encapsulation of the beta-2 adrenergic agonist drug metaproterenol sulfate (MPS) into various liposomes. Bronchodilator activity was measured as the ability of inhaled aerosolized MPS to reduce the bronchoconstriction resulting from repeated administration of inhaled aerosolized histamine solution. One percent MPS in saline (free MPS) reduced the airway resistance response to the inhaled histamine challenges. This bronchodilator effect returned toward control over the 2 hr study period, and had returned to control values 10-12 hr after drug administration. In addition, the free MPS caused significant tachycardia and systemic vasodilation. All three liposome-encapsulated MPS formulations caused significantly smaller cardiovascular side effects. One formation also showed immediate inhibition of the histamine bronchoconstriction similar to free drug. This effect persisted until the 10-12 hr study period, which suggests that the duration of action was greater than that for free drug. Thus, increased duration of inhaled MPS bronchodilator activity and reduction of its undesired cardiovascular side effects can be achieved by liposome encapsulation of the drug.     

The effect of ONO-3708, a novel TxA2 receptor antagonist, on U-46619-induced contraction of guinea pig and human tracheal strips in vitro and on bronchoconstriction in guinea pigs in vivo.

The effect of (9, 11), (11, 12)-didedoxa-9 alpha, 11-alpha-dimethylmethano-11,12-methano-13,14-dihydro-13-aza-14-oxo -15-cyclo-pentyl-16, 17, 18, 19, 20-pentanor-15-epi-TxA2 (ONO-3708) on 9,11-methanoepoxy-prostaglandin H2 (U-46619)-induced contraction of airway smooth muscle in the guinea pigs and human in vitro and bronchoconstriction in guinea pigs in vivo was investigated. In in vitro experiments, ONO-3708 inhibited the U-46619-induced contraction of isolated guinea pig and human tracheal smooth muscle in a dose related fashion (guinea pig; pA2=7.78, human; pA2 = 7.43). The contractions of guinea pig tracheal muscle caused by histamine and leukotriene D4 (LTD4) were not inhibited by ONO-3708. In in vivo experiments, intravenous injection of ONO-3708 at doses between 1 and 20 mg/kg inhibited the U-46619-induced increase of airway insufflation pressure as measured by Konzett-R?ssler method. In addition, ONO-3708 inhibited the U-46619-induced increase in airway reactivity to acetylcholine. These data suggest that ONO-3708 has possible therapeutic utility for asthma in which TxA2 participates.     

Dysfunction of M2-muscarinic receptors in pulmonary parasympathetic nerves after antigen challenge.

The effect of antigen challenge on the function of neuronal M2-muscarinic autoreceptors in the lungs was studied in anesthetized guinea pigs. Guinea pigs were injected intraperitoneally with saline (control group) or ovalbumin (10 mg/kg) on days 1, 3, and 5. One group of sensitized animals was challenged on days 20-25 with aerosolized ovalbumin for 5 min/day (challenged group), while another group of the sensitized animals was not challenged (sensitized group). On day 26 the animals were anesthetized, paralyzed, tracheostomized, and artificially ventilated. Pulmonary inflation pressure (Ppi), tidal volume, blood pressure, and heart rate were recorded. Both vagus nerves were cut, and electrical stimulation of the distal portions caused bronchoconstriction (measured as an increase in Ppi) and bradycardia. In the control group, pilocarpine (1-100 micrograms/kg iv) attenuated vagally induced bronchoconstriction by stimulating inhibitory M2-muscarinic receptors on parasympathetic nerves in the lungs. Conversely, blockade of these receptors with the antagonist gallamine (0.1-10 mg/kg iv) produced a marked potentiation of vagally induced bronchoconstriction. These results confirm previous findings. In the challenged guinea pigs, pilocarpine did not inhibit vagally induced bronchoconstriction. Furthermore, gallamine did not potentiate vagally induced bronchoconstriction to the same degree as in the controls. In the group of animals that was sensitized but not challenged, the potentiation of vagally induced bronchoconstriction by gallamine was identical to the controls. There was no increase in baseline Ppi in the sensitized or challenged animals compared with the controls.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacology of L-660,711 (MK-571): a novel potent and selective leukotriene D4 receptor antagonist

L-660,711 (3-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl) ((3-dimethyl amino-3-oxo propyl)thio)methyl)thio)propanoic acid is a potent and selective competitive inhibitor of [3H]leukotriene D4 binding in guinea pig (Ki value, 0.22 nM) and human (Ki value, 2.1 nM) lung membranes but is essentially inactive versus [3H]leukotriene C4 binding (IC50 value in guinea pig lung, 23 microM). Functionally it competitively antagonized contractions of guinea pig trachea and ileum induced by leukotriene (LT) D4 (respective pA2 values, 9.4 and 10.5) and LTE4 (respective pA2 values, 9.1 and 10.4) and contractions of human trachea induced by LTD4 (pA2 value, 8.5). L-660,711 (5.8 x 10(-8)M) antagonized contractions of guinea pig trachea induced by LTC4 in the absence (dose ratio = 28) but not in the presence of 45 mM L-serine borate (dose ratio less than 2). L-660,711 (1.9 x 10(-5)M) did not block contractions of guinea pig trachea induced by histamine, acetylcholine, 5-hydroxytryptamine, PGF2 alpha, U-44069, or PGD2. In the presence of atropine, mepyramine, and indomethacin, L-660,711 (1.9 x 10(-5)M) inhibited a small component of the response to antigen on guinea pig trachea but completely blocked anti-IgE-induced contractions of human trachea. L-660,711 (i.v.) antagonized bronchoconstriction induced in anesthetized guinea pigs by i.v. LTC4, LTD4, and LTE4 but did not block bronchoconstriction to arachidonic acid, U-44069, 5-hydroxytryptamine, histamine, or acetylcholine. Intraduodenal L-660,711 antagonized LTD4 (0.2-12.8 micrograms/kg)-induced bronchoconstriction in guinea pigs, and p.o. L-660,711 blocked LTD4- and Ascaris-induced bronchoconstriction in conscious squirrel monkeys and ovalbumin-induced bronchoconstriction in conscious sensitized rats treated with methysergide (3 micrograms/kg). The pharmacological profile of L-660,711 indicates that it is a potent, selective, orally active leukotriene receptor antagonist which is well suited to determine the role played by LTD4 and LTE4 in asthma and other pathophysiologic conditions.     

Tachykinins mediate bronchoconstriction elicited by isocapnic hyperpnea in guinea pigs

We tested the hypothesis that tachykinins mediate hyperpnea-induced bronchoconstriction (HIB) in 28 guinea pigs. Stimulus-response curves to increasing minute ventilation with dry gas were generated in animals depleted of tachykinins by capsaicin pretreatment and in animals pretreated with phosphoramidon, a neutral metalloendopeptidase inhibitor. Sixteen anesthetized guinea pigs received capsaicin (50 mg/kg sc) after aminophylline (10 mg/kg ip) and terbutaline (0.1 mg/kg sc). An additional 12 animals received saline (1 ml sc) instead of capsaicin. One week later, all animals were anesthetized, given propranolol (1 mg/kg iv), and mechanically ventilated (6 ml/kg, 60 breaths/min, 50% O2 in air fully water saturated). Phosphoramidon (0.5 mg iv) was administered to five of the noncapsaicin-treated guinea pigs. Eucapnic dry gas (95% O2-5% CO2) hyperpnea "challenges" were performed by increasing the tidal volume (2-6 ml) and frequency (150 breaths/min) for 5 min. Capsaicin-pretreated animals showed marked attenuation in HIB, with a rightward shift of the stimulus-response curve compared with controls; the estimated tidal volume required to elicit a twofold increase in respiratory system resistance (ES200) was 5.0 ml for capsaicin-pretreated animals vs. 3.7 ml for controls (P less than 0.03). Phosphoramidon-treated animals were more reactive to dry gas hyperpnea compared with control (ES200 = 2.6 ml; P less than 0.0001). Methacholine dose-response curves (10(-11) to 10(-7) mol iv) obtained at the conclusion of the experiments were similar among capsaicin, phosphoramidon, and control groups. These findings implicate tachykinin release as an important mechanism of HIB in guinea pigs.     

Temperature Effects on Legionella pneumophila Killing by and Multiplication in Phagocytes of Guinea Pigs

We examined the effects of temperature on the interaction between Legionella pneumophila and phagocytes of guinea pigs. The body temperatures of guinea pigs infected with a sublethal dose (1.2 × 10⁴ CFU) or a lethal dose (1.0 × 10⁵ CFU) of L. pneumophila elevated from 38.4±0.15 C to 40.2±0.42 C or 40.3 ± 0.62 C, respectively. The intracellular bacterial killing by and bacterial proliferation in the phagocytes were examined at 33, 37, 40, and 42 C, using in vitro culture systems of peritoneal macrophages or polymorphonuclear leukocytes (PMN) of guinea pigs. In all the macrophages incubated at different temperatures, significant intracellular bacterial killings were observed at 4 hr after in vitro phagocytosis. After 24 hr of incubation, there was about a 100-fold increase of CFU and the number reached a maximum after 48 hr of incubation in the macrophages incubated at 42 C as well as 37 and 40 C, suggesting that macrophages support the intracellular bacterial growth in hyperthermia. In the PMN, L. pneumophila CFU 4 hr or 12 hr after the infection were significantly lower at 42 C than those at 37 C (P<0.05), indicating that the bactericidal capacity of PMN was enhanced at 42 C compared to 37 C. However, in all the PMN incubated at different temperatures, there were about 10-fold increases of CFU 24 hr after the infection, suggesting that PMN as well as macrophages support intracellular bacterial growth in hyperthermia. The extracellular bacterial growth was examined at 33, 37, 40, and 42 C in buffered yeast extract (BYE) broth or RPMI 1640 medium containing 50% guinea pig serum as a permissive or non-permissive liquid medium for the bacterial growth, respectively. Inhibition of bacterial growth in BYE broth at 42 C, and a decrease of CFU in RPMI 1640 medium containing 50% guinea pig serum at 42 C were observed. In conclusion, hyperthermia may be beneficial by restricting extracellular bacterial survival, but it exerts no beneficial effect on the restriction of intracellular bacterial growth in phagocytes, though PMN showed enhanced initial killing at 42 C. These results suggest that fever, or hyperthermia itself, may not largely contribute as a nonspecific host defense early in the course of legionellosis.     

Effect of hyperimmune bovine colostrum raised against Cryptosporidium parvum on infection of guinea pigs by Cryptosporidium wrairi.

Oocysts shedding was markedly reduced in guinea pigs inoculated intraintestinally with Cryptosporidium wrairi sporozoites that had been incubated with hyperimmune bovine colostrum raised to C. parvum when compared with shedding in guinea pigs inoculated with sporozoites incubated in either non-immune bovine colostrum or buffered saline. However oocyst shedding was apparently not reduced in guinea pigs inoculated by gavage with oocysts of C. wrairi and subsequently treated twice daily per os with hyperimmune bovine colostrum. Similarly, oocyst shedding was apparently not reduced by oral treatment with hyperimmune bovine colostrum when treatment was begun simultaneously with inoculation of C. wrairi oocysts.     

Inhibition of antigen-induced airway hyperresponsiveness, but not acute hypoxia nor airway eosinophilia, by an antagonist of platelet-activating factor

The role of platelet-activating factor (PAF) in Ag-induced airway hyperresponsiveness was evaluated in a guinea pig model using the PAF antagonist SDZ 64-412. Repeated OVA challenge by aerosol (twice weekly x 4 wk) of previously sensitized guinea pigs produced striking airway hyperresponsiveness as determined by pulmonary resistance changes to increasing doses of inhaled acetylcholine given 3 days after the last OVA challenge. Each OVA challenge produced significant hypoxia that was unaffected by oral pretreatment with 20 mg/kg SDZ 64-412, 2 h before each challenge (pO2 = 35 +/- 2 mm Hg for OVA alone vs 40 +/- 6 mm Hg for SDZ and OVA groups, respectively). SDZ 64-412 pretreatment abolished the airway hyperresponsiveness resulting from repeated Ag challenge. Morphometric analysis revealed that SDZ 64-412 treatment had no effect on the increased numbers of eosinophils that infiltrated the airways of OVA-challenged guinea pigs. These results suggest that PAF may be a primary mediator of airway hyperresponsiveness, but not acute bronchoconstriction, induced by repeated Ag challenge. This activity of PAF appears independent of eosinophil recruitment to airways.     

The inhaled Rho kinase inhibitor Y-27632 protects against allergen-induced acute bronchoconstriction, airway hyperresponsiveness, and inflammation

Recently, we have shown that allergen-induced airway hyperresponsiveness (AHR) after the early (EAR) and late (LAR) asthmatic reaction in guinea pigs could be reversed acutely by inhalation of the Rho kinase inhibitor Y-27632. The present study addresses the effects of pretreatment with inhaled Y-27632 on the severity of the allergen-induced EAR and LAR, the development of AHR after these reactions, and airway inflammation. Using permanently instrumented and unrestrained ovalbumin (OA)-sensitized guinea pigs, single OA challenge-induced EAR and LAR, expressed as area under the lung function (pleural pressure, P(pl)) time-response curve, were measured, and histamine PC(100) (provocation concentration causing a 100% increase of P(pl)) values were assessed 24 h before, and at 6 and 24 h after, the OA challenge (after the EAR and LAR, respectively). Thirty minutes before and 8 h after OA challenge, saline or Y-27632 (5 mM) was nebulized. After the last PC(100) value, bronchoalveolar lavage (BAL) was performed, and the inflammatory cell profile was determined. It was demonstrated that inhalation of Y-27632 before allergen challenge markedly reduced the immediate allergen-induced peak rise in P(pl), without significantly reducing the overall EAR and LAR. Also, pretreatment with Y-27632 considerably protected against the development of AHR after the EAR and fully prevented AHR after the LAR. These effects could not be explained by a direct effect of Y-27632 on the histamine responsiveness, because of the short duration of the acute bronchoprotection of Y-27632 (<90 min). In addition, Y-27632 reduced the number of total inflammatory cells, eosinophils, macrophages, and neutrophils recovered from the BAL. Altogether, inhaled Y-27632 protects against acute allergen-induced bronchoconstriction, development of AHR after the EAR and LAR, and airway inflammation in an established guinea pig model of allergic asthma.     

Lack of adrenomedullin on antigen-induced bronchoconstriction in guinea pigs in vivo

Antigen challenge can provoke acute bronchoconstriction, recognized as immediate asthmatic response (IAR), but the evolving events in this reaction are not well defined. Recently, a novel peptide, designated adrenomedullin, was isolated from human pheochromocytoma, and has been shown to have potent systemic and pulmonary vasodilator activity.The purpose of this study was to elucidate the influence of adrenomedullin in the development of IAR. Passively sensitized guinea pigs were anesthetized and treated with diphenhydramine hydrochloride, and then artificially ventilated. Ovalbumin was inhaled after an intravenous administration of adrenomedullin. Other studies were performed in naive guinea pigs to investigate the airway responses to inhaled methacholine or histamine after an intravenous administration of adrenomedullin. Antigen challenge caused bronchoconstriction in sensitized guinea pigs. Adrenomedullin did not inhibit the antigen-induced bronchoconstriction in sensitized guinea pigs or the dose-dependent responses to inhaled methacholine or histamine in naive animals in spite of its vasodilating effect. We conclude that an intravenous administration of adrenomedullin does not influence antigen-induced bronchoconstriction or bronchial responsiveness to inhaled methacholine or histamine in vivo.     

Influence of body temperature on histamine-induced bronchoconstriction in guinea pigs

The effects of body temperature on histamine-induced bronchoconstriction were investigated in anesthetized, paralyzed, and mechanically ventilated guinea pigs. Four groups of guinea pigs were studied with constant body temperatures of 40, 38, 35, and 32 degrees C, respectively. Histamine was infused for 5 min at a rate of 50 ng.kg-1.s-1. Body cooling from 40 to 32 degrees C augmented the bronchomotor responses to histamine, which eventually rose almost fourfold. The enhancement of histamine-induced bronchoconstriction induced by body cooling was not suppressed by pretreating guinea pigs with 5 mg/kg hexamethonium or 5 mg/kg hexamethonium plus 3 mg/kg atropine; neither was the enhancement of histamine-induced bronchoconstriction suppressed in pithed guinea pigs, demonstrating that the autonomic nervous system is not involved in potentiating bronchoconstriction at low body temperatures. These results suggest that, at low body temperatures, increased airway responsiveness to histamine may be because of some direct effect of temperature on bronchial airway smooth muscle.     

Pharmacological effects of oral E6123, a novel PAF antagonist, on biological changes induced by PAF inhalation in guinea pigs.

The effects of a newly synthesized PAF antagonist E6123, (S)-(+)-6-(2-chlorophenyl)-3-cyclopropanecarbonyl-8,11-dimethyl-2, 3,4,5- tetrahydro-8H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo [4,3-a][1,4]diazepine, on in vivo inhaled PAF-induced pulmonary changes were investigated. E6123 inhibited PAF inhalation-induced bronchoconstriction in guinea pigs with an ED50 value (p.o.) of 1.3 micrograms/kg which was lower than those of other PAF-antagonists such as WEB2347 (ED50 = 26 micrograms/kg) and Y-24180 (ED50 = 12 micrograms/kg). E6123 significantly inhibited PAF inhalation-induced eosinophil infiltration into the bronchiole and trachea, and bronchial hyperreactivity in guinea pigs after oral administration at 1 and 10 micrograms/kg, respectively. E6123 inhibited the PAF-induced increase in intracellular free calcium ion concentration ([Ca2+]i) in guinea pig eosinophils with an IC50 value of 14 nM. The present results suggest that E6123 may be beneficial for the treatment of asthma, in which PAF is assumed to be involved.     

Antitussive,expectorant, and bronchodilating effects of quinazoline alkaloids (±)-vasicine,deoxyvasicine, and (±)-vasicinone from aerial parts of Peganum harmala L

BackgroundThe aerial parts of Peganum harmala L. (APP) is a well-known and effective herbal medicine in China, and has been commonly used for treating various ailments, including cough and asthma.ObjectivesTo evaluate the antitussive, expectorant, and bronchodilating effects of the quinazoline alkaloids (±)-vasicine (VAS), deoxyvasicine (DVAS) (both isolated from the alkaloid fraction of APP) and (±)-vasicinone (VAO) (synthesized from VAS).MethodsThe three quinazoline alkaloids were tested as antitussive on cough models in mice and guinea pigs. VAO was synthesized from VAS via the oxidation of hydrogen peroxide. VAS, VAO, and DVAS were orally administered at dosages of 5, 15, and 45 mg/kg. Cough in these models was induced by ammonia, capsaicin, and citric acid. Phenol red secretion experiments in mice were performed to evaluate the expectorant activity of the alkaloids. Bronchodilating effects were evaluated by using a bronchoconstrictive induced by acetylcholine chloride and histamine in guinea pigs.ResultsIn antitussive tests, VAS, VAO, and DVAS significantly inhibited coughing frequency and prolonged the cough latency period in animals. At the highest doses tested (45 mg/kg), they showed antitussive activities similar to codeine phosphate (30 mg/kg) in mice and guinea pigs. Expectorant evaluation showed that VAS, VAO, and DVAS could significantly increase phenol red secretion in mice by 0.54-, 0.79- and 0.97-fold, by 0.60-, 0.99-, and 1.06-fold, and by 0.46-, 0.73-, and 0.96-fold, respectively, at dosages of 5, 15, and 45 mg/kg compared with the control (0.5% CMC-Na, 20 ml/kg). Ammonium chloride at 1500 mg/kg increased phenol red secretion in mice by 0.97-fold compared with the control. Bronchodilation tests showed that VAS, VAO, and DVAS prolonged the pre-convulsive time for 28.59%, 57.21%, and 29.66%, respectively, at a dose of 45 mg/kg in guinea pigs, whereas aminophylline prolonged the pre-convulsive time by 46.98% compared with pretreatment.ConclusionsQuinazoline alkaloids VAS, VAO, and DVAS have significant antitussive, expectorant, and bronchodilating activities. VAS, VAO, and DVAS are the active ingredients in APP, which can be used to treat respiratory disease.     

Airway hyperresponsiveness to bronchoconstrictor challenge after wood smoke exposure in guinea pigs.

Prior airway exposure to wood smoke induces an increase in airway responsiveness to subsequent smoke inhalation in guinea pigs (Life Sci. 63: 1513, 1998; 66: 971, 2000). To further characterize this airway hyperreactivity, we investigated and compared the airway responsiveness to bronchoconstrictor challenge before and 30 min after sham air exposure or wood smoke exposure in anesthetized and artificially ventilated guinea pigs. Various doses of substance P (0.8-6.4 microg/kg), capsaicin (0.2-3.2 microg/kg), prostaglandin F2alpha (30-3000 microg/kg), histamine (1-8 microg/kg), or acetylcholine (5-20 microg/kg) were intravenously injected at 2-min intervals in successively increasing doses to obtain the dose required to provoke a 200% increase in baseline total lung resistance (ED200). Wood smoke exposure significantly lowered the ED200 of substance P, capsaicin, and prostaglandin F2alpha whereas sham air exposure failed to do so. Furthermore, wood smoke exposure did not significantly alter the ED200 of histamine or acetylcholine. Pretreatment with phosphoramidon (2 mg/kg), an inhibitor of the neutral endopeptidase (the major degradation enzyme of substance P), before smoke exposure did not significantly affect the smoke-induced reduction in ED200 of substance P. Sectioning both cervical vagi before smoke exposure did not significantly alter the smoke-induced reduction in ED200 of capsaicin or prostaglandin F2alpha. These results suggest that airway exposure to wood smoke acutely produces airway hyperresponsiveness to substance P, capsaicin, and prostaglandin F2alpha, but not to histamine or acetylcholine. Since the combination of phosphoramidon and wood smoke exposure did not result in an additive potentiation of smoke-induced airway hyperresponsiveness to substance P, it is suggested that an inhibition of the degradation enzyme of substance P may contribute to this increase in airway reactivity. Furthermore, vagally-mediated bronchoconstriction does not play a vital role in enhanced airway responsiveness to capsaicin or prostaglandin F2alpha.     

线粒体毒素诱导突发性耳聋模型血管纹损伤机制的研究

目的研究线粒体毒素诱导豚鼠突发性耳聋模型血管纹损伤的机制。方法20只杂色豚鼠随机分为3-硝基丙酸（3-NP）组和磷酸盐缓冲液（PBS）对照组,分别经圆窗膜给予0.3 mmol/L 3-NP或PBS 10min。分别检测两组豚鼠的听性脑干反应测听（ABR）,血管纹丙二醛（MDA）、超氧化物歧化酶（SOD）及边缘细胞超微结构变化。结果与PBS对照组相比较,3-NP组ABR阈移增大、幅值减小;血管纹MDA含量增高（P〈0.05）,SOD活性降低（P〈0.05）;边缘细胞超微结构改变,尤以线粒体肿胀,空泡变最为显著。结论线粒体毒素通过氧化应激反应损伤突发性耳聋豚鼠的血管纹。     

Dexamethasone prevents virus-induced hyperresponsiveness via multiple mechanisms

In the lungs, neuronal M2 muscarinic receptors inhibit acetylcholine release from the parasympathetic nerves. Parainfluenza virus infection causes loss of M2 receptor function, which increases acetylcholine release and vagally mediated bronchoconstriction. Because glucocorticoids are known to inhibit airway hyperresponsiveness, we tested whether dexamethasone (6.5 or 65 microg/kg i.p.) prevents virus-induced hyperresponsiveness and M2 receptor dysfunction in guinea pigs. In controls, pilocarpine, a muscarinic agonist, inhibited vagally induced bronchoconstriction, demonstrating functional M2 receptors. However, in virus-infected animals, pilocarpine failed to inhibit vagally induced bronchoconstriction, demonstrating M2 receptor dysfunction. Frequency-dependent bronchoconstriction was greater in virus-infected animals than in controls, indicating airway hyperresponsiveness. Low-dose dexamethasone (6.5 microg/kg i.p.) treatment prevented virus-induced airway hyperresponsiveness, ameliorated M2 receptor dysfunction, and decreased viral content in the lungs without inhibiting virus induced inflammation. High-dose dexamethasone (65 microg/kg i.p.) prevented virus-induced hyperresponsiveness, completely reversed M2 receptor dysfunction, decreased viral titers, and decreased virus-induced inflammation. This high-dose dexamethasone also increased M2 receptor function in uninfected animals. In conclusion, dexamethasone prevented virus-induced hyperresponsiveness and M2 receptor dysfunction via multiple mechanisms.     

L-649,923, sodium (beta S*, gamma R*)-4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)-propylthio)- gamma-hydroxy-beta-methylbenzenebutanoate, a selective, orally active leukotriene receptor antagonist

L-649,923, Sodium (beta S*, gamma R*)-4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)propylthio)- gamma- hydroxy-beta-methylbenzenebutanoate is a selective and competitive inhibitor of [3H]leukotriene D4 (Ki value of 400 nM) and to a lesser extent [3H]leukotriene C4 (Ki value of 8.6 microM) binding in guinea-pig lung homogenates. Functionally, it selectively antagonized contractions of guinea pig trachea induced by leukotriene C4, D4, E4, and F4 but not those induced by acetylcholine, histamine, serotonin, prostaglandin F2 alpha, or U-44069 (stable endoperoxide analogue). Schild plot analysis indicated a competitive inhibition of contractions of guinea-pig ileum induced by leukotriene D4 (pA2 8.1) and contractions of guinea-pig trachea induced by leukotrienes E4 and F4 (pA2 7.1 and 6.9, respectively). In contrast, contractions of guinea-pig trachea induced by leukotrienes C4 (pA2 7.2; slope 0.6) and D4 (pA2 7.2; slope 0.7) were inhibited in a noncompetitive fashion. In vivo, intravenously administered L-649,923 selectively blocked bronchoconstriction induced in anesthetized guinea pigs by leukotriene C4 and D4 (ED50 values i.v. 0.38 and 0.26 mg/kg, respectively) but not that induced by histamine, arachidonic acid, serotonin, U-44069, or acetylcholine. Following intraduodenal administration, L-649,923, blocked leukotriene D4 induced bronchoconstriction (5 and 10 mg/kg). The present findings indicate that selective antagonists, such as L-649,923, may be useful for defining the role of leukotrienes in diseases such as bronchial asthma.     

Pharmacological model for airway hypersensitivity produced by propranolol and reserpine in guinea pigs

Combined treatment with propranolol and reserpine enhanced acetylcholine-induced doseresponse curves for bronchoconstriction in guinea pigs in vivo. This airway hyperreactivity model was investigated pharmacologically. (1) Increased capillary permeability and increases in leukocytes in bronchoalveolar lavage fluid (BALF) were not observed after this combined treatment. (2) The increased airway sensitivity to acetylcholine produced by propranolol and reserpine was inhibited by ketotifen and theophylline, reported in clinical studies to inhibit airway hyperreactivity. (3) Two leukotriene (LT) receptor antagonists, MCI-826 and FPL-55712, clearly inhibited this increased airway reactivity. (4) A thromboxane A₂ (TXA₂) receptor antagonist, ONO-3708, and TXA₂ synthetase inhibitor, OKY-046, also inhibited this increased airway reactivity.These results suggest that the airway hyperreactivity model produced by propranolol and reserpine in guinea pigs is a valuable pharmacological tool for investigating a remedy and LT and TXA₂ may be involved in the onset of this airway hyperreactivity.