Cyclic GMP affecting the tracheal nonadrenergic noncholinergic inhibitory system

An association between guanosine 3',5'-monophosphate (cyclic GMP) and the nonadrenergic noncholinergic inhibitory system (NANCIS) has been demonstrated in the isolated bovine tissue (Bowman and Drummond, 1984). In order to investigate this association in the guinea pig trachea, we used cyclic GMP derivatives, guanylate cyclase activators (N-methylhydroxylamine (NMH) and nitroglycerin (NG)] and inhibitors [oxyhemoglobin (HbO2) and methylene blue (MB)]. Under general anesthesia paralysis, the animals were ventilated and hourly injected with atropine (0.2 mg/kg) and propranolol (1 mg/kg). Cervical segment of the trachea was converted to a closed tracheal pouch and then filled with Kreb's solution augmented with atropine (1 microM) and propranolol (3.5 microM). A decrease in the pouch pressure (Pp) reflected NANCIS nerve transmural stimulation (TS)--or drug-induced relaxation. Pharmacological agents were applied intravenously. At 2-11 min after injection, NMH and NG decreased baseline Pp and reduced TS-induced relaxation. NMH, which is more potent than NG in activating particulate guanylate cyclase activity, potentiated the TS-induced relaxation at high frequencies, but NG did not. HBO2 inhibited the TS-induced relaxation at high but not at low frequencies. In contrast, MB inhibited the relaxation at low but not high frequencies. The results suggest that activation of particulate or membrane bound guanylate cyclase potentiates NANCIS-induced decrease in Pp. Therefore, there is a possible association between cyclic GMP and the NANCIS in the guinea pig trachea.     

Dysfunction of nonadrenergic noncholinergic inhibitory system after antigen inhalation in actively sensitized cat airways.

We have investigated whether proteases released during antigen inhalation cause dysfunction of the nonadrenergic noncholinergic inhibitory nervous system (NANCIS). Frequency-response (F-R) studies of NANCIS were performed before and after Ascaris antigen (ASC) inhalation using actively sensitized cats. NANC dilatatory effects were obtained by stimulating bilateral cervical vagi under cholinergic and beta-adrenergic blockade and serotonin-induced bronchoconstriction, and assessed by maximal percent relaxation (rmax) and the frequency causing 50% of maximal relaxation (EF50). ASC inhalation caused a transient increase in pulmonary resistance in all animals. One hour after ASC inhalation, pulmonary resistance returned to the baseline value, but ASC inhalation significantly attenuated NANC inhibitory activities: rmax decreased from 82.2 +/- 4.7 (mean +/- SE) to 64.3 +/- 11.2% (p less than 0.05), and the geometric mean of EF50 increased from 1.7 to 4.3 Hz (p less than 0.05). Dilatatory effects of infused VIP, a possible neurotransmitter of NANCIS, was also attenuated after ASC inhalation. Pretreatment with leupeptin (3 mg/kg) abolished ASC-induced impairment of NANC inhibitory activities. By contrast, dilatatory effects of adrenergic nerve stimulation were not affected by ASC inhalation. These results suggest that NANC inhibitory activities can be impaired after ASC inhalation, and that this impairment of NANCIS may be due to effects of proteases released during allergic reaction.     

Difference in bronchoprotective effects of bronchodilators on postallergic propranolol-induced bronchoconstriction.

Administration of propranolol provokes bronchoconstriction only in asthmatic patients. It is unknown whether bronchodilator therapy can prevent the propranolol-induced bronchoconstriction (PIB). We previously reported an animal model of PIB in which bronchoconstriction is caused by propranolol when inhaled 20 minutes after an antigen provocation in passively sensitized guinea pigs. Our goal was to evaluate the bronchoprotective effects of bronchodilators on the PIB in our animal model. Propranolol was inhaled 20 minutes after an antigen challenge in passively sensitized, anesthetized, and artificially ventilated guinea pigs. Atropine (5 mg/kg) and equipotent doses of salbutamol (0.6 microgram/kg) and aminophylline (25 mg/kg), which were determined by the dose-response curves for inhibition of histamine-induced bronchoconstriction, were intravenously administered 5 minutes before the propranolol inhalation. Treatment of the animals with 25 mg/kg of aminophylline, but not with 0.6 microgram/kg of salbutamol or 5 mg/kg of atropine, significantly prevented the PIB. These results show that our animal model is an experimental model of PIB which is resistant to beta 2-agonists or anticholinergics and suggest that aminophylline may be useful to prevent and treat PIB resistant to beta 2-agonists.     

The effects of parasympathectomy on serotonin-induced bronchoconstriction in the cat

We studied the contribution of neural influences, in particular, the nonadrenergic, noncholinergic inhibitory system, on the modulation of airway responses to serotonin (5-HT) in the anesthetized and mechanically ventilated cat. Airway responses were assessed by measurement of pulmonary resistance (RL). Parasympathectomy (PS) caused a variable increase in bronchoconstriction in 9 of 10 cats (n = 10) that had received pretreatment intravenously with atropine (3 mg/kg) and propranolol (2 mg/kg); PS performed following pretreatment with phentolamine (2 mg/kg), propranolol, and atropine led to an increase in bronchoconstriction in only 2 of 6 cats. Dose-response curves to aerosolized 5-HT were performed in one group of cats (n = 5) before and 30 min after PS and in control group (n = 6). Both groups of animals were pretreated intravenously with atropine, propranolol, and phentolamine. The concentration of aerosolized 5-HT that was necessary to double pulmonary resistance (ED200RL) was significantly reduced from 0.117 to 0.062 mg/ml (p less than 0.01) by PS, in contrast to control cats in which ED200RL during 2 consecutive dose-response curves (0.076 and 0.087 mg/ml, respectively) did not change significantly. We conclude that there is neural modulation of airway responses to infused 5-HT through an alpha-adrenergic pathway and that an additional inhibitory nonadrenergic, noncholinergic neural influence is demonstrable in the response to aerosolized 5-HT.     

Effect of nonadrenergic noncholinergic inhibitory nerve stimulation on the allergic reaction in cat airways

To examine the effect of nonadrenergic noncholinergic (NANC) inhibitory nerve stimulation on the antigen inhalation with allergic animals, changes in pulmonary resistance (RL) and arterial plasma histamine concentration ([H]) caused by inhalation of Ascaris suum antigen were studied in five control (Group A) and five nerve-stimulated (Group B) cats, which were anesthetized and mechanically ventilated. All animals were actively sensitized with Ascaris antigen before the experiment. After cholinergic and beta-adrenergic blockade with intravenously administered atropine (3 mg/kg) and propranolol (2 mg/kg), inhalation of the antigen (1:100 dilution) was performed for 3 min. For Group B, bilateral cervical vagi were stimulated electrically for 1 min before the antigen inhalation and successively every 30 s until 5 min had passed from the onset of inhalation. RL and [H] were determined before, during, and after antigen inhalation in both groups. Baseline RL and [H] did not differ significantly between groups (16.3 +/- 2.2 (mean +/- SE) cm H2O/L/s and 14.0 +/- 0.7 ng/ml, respectively, for Group A; 14.4 +/- 1.3 and 15.6 +/- 2.7, respectively, for Group B). Increases in RL and [H] of Group B after the antigen inhalation were significantly depressed, compared with Group A (p less than 0.01 and p less than 0.05, respectively, two-way ANOVA). The increase in RL 5 min after antigen inhalation was 113 +/- 19% for Group A and 28 +/- 8% for Group B, and the increase in [H] at the same point was 36.3 +/- 9.1 ng/ml for Group A and 4.4 +/- 1.4 ng/ml for Group B.(ABSTRACT TRUNCATED AT 250 WORDS)     

Antigen-induced airway inflammation and hyper-responsiveness does not enhance airway responses to a subsequent antigen challenge in rats

Brown-Norway (BN) rats develop airway hyper-responsiveness and lung eosinophilia 18-24 h after ovalbumin (OA) challenge. We hypothesized therefore that allergen-induced airway inflammation would further enhance airway responses to a subsequent antigen challenge. Animals were sensitized to both OA and bovine serum albumin (BSA) and, 14 days later, challenged by aerosols with both antigens 24 h apart. Measurements of pulmonary resistance (RL) were made for 8 h after the second antigen challenge and bronchoalveolar lavage (BAL) was performed. Animals were divided into three groups and received two challenges as follows: saline-BSA (n=9), OA-saline (n=8) and OA-BSA (n=10). Sensitization was confirmed by measurements of specific OA-IgE and BSA-IgE. Early responses [determined as the highest value of RL within the first 30 min after the challenge] were absent in all study groups. The late responses [determined from the area under the RL versus time curve from 120 to 480 min after the challenge] were significantly greater in animals challenged with BSA (15.16+/-3.86) compared to saline (3.76+/-4.09; P<0.05). However previous exposure to OA did not further increase the late response in animals subsequently challenged with BSA (20.11+/-3.67) despite enhanced airway responsiveness to LTD4 at this time point. BAL eosinophils and lymphocytes were significantly increased following BSA challenge in previously OA-challenged animals, compared to numbers retrieved from animals previously exposed to saline (P<0.05). These data indicate that previous exposure to OA did not further increase the LR to a second antigen challenge despite substantial increases in airway inflammatory cells and airway hyper-responsiveness to LTD4.     

Reflex activation of the nonadrenergic noncholinergic inhibitory nervous system in feline airways

Experiments were undertaken to learn if the nonadrenergic noncholinergic inhibitory nervous system (NANCIS) in feline airways could be activated reflexly either by mechanically stimulating the laryngeal mucosa or by inducing acute bronchospasm with boluses of 5-hydroxytryptamine (5HT) injected intravenously. Mechanical stimulation of the dorsal laryngeal mucosa evoked a biphasic bronchomotor response in anesthetized cats that had received intravenously an infusion of 5HT to raise their basal airway smooth muscle tone. The response consisted of a transient augmentation of bronchoconstriction followed by a prolonged bronchodilation. After muscarinic cholinergic receptor blockade with atropine, the constriction phase of the response disappeared, but the relaxation phase persisted. Bronchodilation elicited by laryngeal stimulation was resistant to beta-adrenergic receptor blockade with propranolol but was abolished by autonomic ganglionic blockade with hexamethonium and blocked reversibly by vagal cooling. The latter interventions, when imposed between successive dose-response curves generated by intravenous 5HT in animals pretreated with atropine and propranolol, did not alter the positions or slopes of the curves. These findings support the conclusion that mechanical stimulation of the larynx reflexly activates not only the well-known vagal cholinergic excitatory pathway to the airways but also the more recently described vagal, nonadrenergic noncholinergic inhibitory pathway. The results further indicate that bronchoconstriction is neither a prerequisite for the bronchodilator component of the laryngeal bronchomotor reflex nor an independent initiating stimulus for NANCIS-mediated reflex bronchodilation.     

Tracheal responsiveness to both isoprenaline and beta2-adrenoreceptor blockade by propranolol in cigarette smoke exposed and sensitized guinea pigs

OBJECTIVE: Airway hyperresponsiveness is the main feature of asthma and also exists in cigarette smokers. In previous studies we have shown increased airway responsiveness to isoprenaline in asthmatic patients and smokers. In this study, tracheal responsiveness to isoprenaline and beta-adrenergic receptor blockade was investigated in animals exposed to cigarette smoke (AECS) with or without sensitization by ovalbumin (OA). METHODOLOGY: Guinea pigs were exposed to cigarette smoke over a 3-month period with or without sensitization by injection and inhalation of OA. Tracheal responses in AECS, AECS + sensitized and control animals (n = 7 for each group) to isoprenaline in the absence and presence of 20 nmol/L propranolol were measured and EC(50) was established. The propranolol blockade (concentration ratio minus one (CR-1)) was calculated (post-propranolol EC(50)/EC(50)) - 1. RESULTS: The tracheal response of AECS and AECS + sensitized guinea pigs to isoprenaline was significantly higher than that of control animals (EC(50): 4.24 +/- 0.54, 3.66 +/- 0.53 and 7.71 +/- 0.68.79 micromol for AECS, AECS + sensitized and control animals, respectively) (P < 0.001). There was no significant difference in EC(50) between AECS and AECS + sensitized. CR-1 was also significantly higher in the trachea of AECS and AECS + sensitized compared with controls (13.39 +/- 2.22 and 15.35 +/- 2.95 vs. 3.10 +/- 0.6, P < 0.05 in both cases). There was no significant difference in CR-1 between AECS and AECS + sensitized. There was a significant correlation between the tracheal response to isoprenaline (EC(50)) and CR-1 (r =-0.731, P < 0.001). There was no significant difference in tracheal maximum response to isoprenaline between the three groups of animals. CONCLUSIONS: The results of this study indicate an increased tracheal response to a beta(2)-adrenergic stimulating drug and enhanced beta(2)-adrenergic blockade by propranolol in both AECS and AECS + sensitized. These results suggest similar increase in airway responsiveness to beta(2)-adrenergic agonists and beta(2)-receptor blockade in AECS and AECS + sensitized guinea pigs.     

Endogenous tachykinins in antigen-induced acute bronchial responses of guinea pigs.

Because tachykinins (TKs) cause severe bronchoconstriction in humans and animals, this study was carried out to examine whether depletion of TKs can prevent or ameliorate antigen-induced immediate bronchial constriction. Forty-five guinea pigs were randomly divided into six groups: control, antigen challenge, TK depletion + antigen challenge, ganglionic (Ggl) blockade, Ggl blockade + antigen challenge, and TK depletion + Ggl blockade + antigen challenge. Control animals received no treatment. Animals of all antigen challenge groups were sensitized with ovalbumin 10 days before the study. TK depletion was performed via 5-day pretreatment of capsaicin, which began 11 days before the study. On the day of the study, pulmonary resistance (RI), dynamic compliance (Cdyn), and breathing patterns were measured for 15 min just before (baseline) and for 30 min after intravenous injection of either saline (control) or ovalbumin (antigen challenge). In controls, saline injection did not produce any significant change within 30 min, whereas antigen challenge significantly increased RL at 4-15 min and significantly decreased Cdyn at 6-15 min, suggesting antigen-induced bronchoconstriction. Following TK depletion, antigen challenge produced pulmonary changes similar to those without depletion. Ggl blockade reduced RL and breathing frequency, and increased Cdyn and tidal volume; the blockade, however, did not significantly alter (in terms of % baseline) antigen challenge-induced changes in RL, Cdyn, or breathing patterns. These results suggest that TKs and reflexes via Ggl do not appear to be important contributing factors for antigen-induced immediate bronchial constriction in this animal model.     

Type I hypersensitivity reactions in intestinal mucosae from rats infected with Fasciola hepatica

Type I hypersensitivity reactions in the intestinal tract of sensitized animals may contribute to resistance to reinfection with Fasciola hepatica. Colonic mucosae isolated from previously infected rats were voltage clamped in Ussing chambers. Antigen was prepared as a crude homogenate from adult liver fluke. Assay of serum antibodies against fluke antigen confirmed sensitization. Antigen challenge evoked a rapid onset, transient inward current in sensitized but not in control preparations. Chloride secretion accounted for at least part of the response since the loop diuretic bumetanide reduced the effect of antigen by 61%. Anti-rat IgE mimicked the response to antigen and desensitized tissues to subsequent antigen challenge. Local synthesis of eicosanoids may mediate the response to antigen since the cyclo-oxygenase inhibitor piroxicam reduced the response by 76%. In contrast, mepyramine which is a histamine receptor antagonist did not alter the ion transport response evoked by antigen. Tetrodotoxin reduced the response to antigen by 53% implicating intrinsic neurons within the lamina propria as effector cells in the responses of this tissue to antigen. We propose that antigen stimulation of electrogenic chloride movement and consequent fluid secretion in vivo may contribute to a local effector mechanism in prevention of reinfection of previously sensitized hosts.     

Vaccination of rhesus monkeys against Plasmodium knowlesi with aqueous suspension of MDP as an adjuvant.

In these investigations two types of antigen preparations were used: (i) Whole Antigen (WAg), and (ii) Soluble Antigen (SAg). For immunization, Muramyl Dipeptide (MDP) was employed as an adjuvant. Highest reciprocal antibody titre values were recorded in ELISA and IHA tests from animals immunized by WAg-MDP. Skin reactions in animals sensitized with WAg-MDP combination showed a well developed zone of erythema with induration after 24 hours of intradermal injection. Animals immunized with WAg-MDP showed a maximum leukocyte migration inhibition. All the animals in experimental and control groups showed patent infection following challenge with live parasites. Animals belonging to the control groups showed 100% mortality. On the basis of these experiments it could be concluded that MDP preparation afforded some protection to the test animals.     

Colonic and jejunal motor disturbances after colonic antigen challenge of sensitized rat

BACKGROUND & AIMS: Inflammation in the colon may alter motility in the proximal gut and potentiate clinical symptoms. The aim of this study was to characterize the effect of colonic anaphylaxis on local (colonic) and remote (small intestinal) motility and identify the mechanism and mediators involved. METHODS: Rats were sensitized by intraperitoneal injection of 10 microg egg albumin and surgically prepared with electrodes in jejunum and colon and a colostomy tube. Colonic and jejunal myoelectric activity were recorded in fasted animals before and after colonic antigen challenge without and then after pretreatment with specific antagonists. RESULTS: Colonic antigen challenge of sensitized rats was associated with significant (1) increase in colonic myoelectric spike activity, (2) disruption of fasting jejunal motility and initiation of aborally propagating spike complexes, and (3) increase in plasma rat mast cell protease II levels with a decrease in granulated mast cells in colon but not jejunum. The myoelectric disturbance in both colon and jejunum was inhibited significantly by pretreatment with atropine and hexamethonium, doxantrazole, cyclooxygenase, and lipoxygenase inhibitors. Methysergide inhibited only the jejunal disturbance. CONCLUSIONS: Colonic antigen challenge of sensitized animals results in local mast cell activation and the release of mediators that modulate neural pathways to initiate both a local colonic and a remote jejunal myoelectric disturbance. (Gastroenterology 1997 Jun;112(6):1996-2005)     

Effect of histamine H1 receptor antagonists on antigen-induced increase of cough sensitivity in guinea pigs

Eosinophilic airway inflammation and increased cough sensitivity without bronchial hyperresponsiveness are the pathologic and physiologic features of bronchodilator-resistant non-productive cough-associated global atopic tendency, abbreviated herein as atopic cough. Histamine H₁ receptor antagonists are effective in relieving the cough in nearly 60% of patients with atopic cough. However, there is no direct evidence that histamine H₁ receptor antagonists can reduce cough hypersensitivity associated with eosinophilic airway inflammation. The purpose of the present study was to clarify this issue. The number of coughs caused by inhalation of increasing concentrations of capsaicin (10^− 8, 10^− 6 and 10^− 4 mol/L) was counted 24 h after the administration of an aerosolized antigen in actively sensitized conscious guinea pigs and then bronchoalveolar lavage (BAL) was performed. Azelastine (0.1 or 1 mg/kg) or terfenadine (0.2 or 2 mg/kg) was given intraperitoneally 60 min before capsaicin provocation 24 h after the antigen challenge in sensitized guinea pigs. In addition, azelastine (0.1 or 1 mg/kg) was administered 90 min before the capsaicin challenge in naïve guinea pigs. The cough response to capsaicin and the number of eosinophils in BAL fluid (BALF) were significantly increased after antigen challenge. Azelastine and terfenadine significantly reduced the increased cough response after antigen challenge, while azelastine had no effect in naïve animals. In conclusion, histamine H₁ receptor antagonists reduce antigen-induced increases in cough sensitivity in sensitized guinea pigs without direct inhibition of a common cough reflex pathway.     

Type 1 angiotensin II receptor antagonism reduces antigen-induced airway reactions

Although the renin-angiotensin system is activated in patients with asthma during severe acute attacks and angiotensin II has been shown to cause bronchoconstriction in patients with asthma, the role of angiotensin II in patients with asthma is unclear. We investigated the effects of two specific antagonists at type 1 and type 2 angiotensin II receptors, candesartan cilexetil (TCV-116) and PD123319, on antigen-induced airway reactions in guinea pigs. Sixty minutes after intraperitoneal administration of candesartan cilexetil (0.1, 1.0, or 10 mg/kg) or PD123319 (30 mg/kg), animals received an antigen challenge. Airway responsiveness to inhaled methacholine was assessed as the dose of methacholine required to produce a 200% increase in the pressure at the airway opening (PC(200)). Differential cell counts in bronchoalveolar lavage fluids (BALF) were measured 24 h after antigen challenge. Candesartan cilexetil did not inhibit antigen-induced bronchoconstriction in sensitized guinea pigs or alter PC(200) in nonsensitized guinea pigs. Antigen inhalation significantly increased bronchoconstrictor responses to methacholine and increased airway accumulation of eosinophils; both responses showed dose-dependent prevention by candesartan but not by PD123319. These results indicate that endogenous angiotensin II promotes antigen-induced airway hyperresponsiveness and eosinophil accumulation by acting at type 1 receptors.     

Surfactant degradation activity in bronchoalveolar lavage fluid from guinea pigs challenged with antigen

BACKGROUND AND OBJECTIVE: Surfactant dysfunction is a characteristic of bronchial asthma, but mechanisms of dysfunction following antigen exposure are not understood. The aim of this study was to examine whether bronchoalveolar lavage fluid (BALF) has surfactant degradation activity after antigen challenge, using an animal model of asthma. METHODS: BALF was collected 24 h after a challenge with aerosolized antigen solution in actively sensitized guinea pigs and from non-sensitized control guinea pigs. The surface tension of BALF was measured by pulsating bubble surfactometer. Surfactant activity was expressed as the minimum surface tension of BALF after 5 min of pulsation. BALF was separated into a cellular phospholipid fraction and supernatant, and reconstituted into 'pellet + supernatant' and 'pellet + saline' fractions. RESULTS: Surfactant activity of BALF from sensitized antigen-challenged animals was reduced after 4 h of incubation at 37 degrees C but a decrease was not observed in BALF from non-sensitized control animals. The decrease of surfactant activity in BALF from challenged animals was prevented by incubation at 4 degrees C. Disappearance of surfactant activity after incubation at 37 degrees C was observed in the 'pellet + supernatant', but not in the 'pellet + saline' fraction. The decrease of surfactant activity in BALF was also partially suppressed by the secretory phospholipase A2 inhibitor, indoxam, and by a cocktail of protease inhibitors. CONCLUSION: Surfactant-degrading activity was present in the supernatant of BALF from antigen-challenged guinea pigs. This activity may be attributed to secretory phospholipase A2 and to proteases present in the antigen-challenged airway.     

Different innervation mechanisms between the lesser and greater curvature of guinea pig antrum

Transmural stimulation (TS) produced a frequency-dependent contraction of the longitudinal muscles from the lesser curvature of the guinea pig antrum, which was abolished by atropine. On the other hand, a response to TS of the strips from the greater curvature was biphasic: a rapid contraction followed by a relaxation, which was abolished by tetrodotoxin. By pretreatment with atropine, rapid contraction of the biphasic response evoked by TS in the greater curvature was abolished and relaxation was augmented. Relaxation to TS of the greater curvature was not affected by prazocine, yohimbine, phentolamine, propranolol, theophylline, apamin, -chymotrypsin, and vasoactive intestinal polypeptide receptor antagonist. Different innervation mechanisms were suggested to be present in the longitudinal muscles between the lesser curvature (innervated with excitatory cholinergic neurons) and the greater cuvature (innervated with excitatory cholinergic neurons and nonadrenergic inhibitory neurons) of the guinea pig antrum.     

Anaphylactic challenge causes eosinophil accumulation in bronchoalveolar lavage fluid of guinea pigs. Modulation by betamethasone, phenidone, indomethacin, WEB 2086, and a novel antiallergy agent, SCH 37224

Eosinophil infiltration into bronchoalveolar areas of the lung has been assessed in guinea pigs sensitized to ovalbumin (OA) and then challenged with the aerosolized antigen. Cell content, histamine, and guinea pig albumin (GPA) have been measured in bronchoalveolar lavage (BAL) fluid from these animals. Extensive eosinophil accumulation resulted from sensitization followed by OA challenge; monocytes that initially accounted for greater than 80% of the BAL cells remained essentially constant, and neutrophils comprised less than 3% of the population throughout. Eosinophils were elevated at 3 h, peaked with a fivefold increase at 24 h, and remained elevated for at least 7 days. Histopathologic changes observed in lungs taken from sensitized guinea pigs 24 h after OA challenge confirm this eosinophilia. Increased histamine and GPA were detected only at 5 min. Oral treatment with betamethasone (ED50 = 0.4 mg/kg), phenidone (ED50 = 15 mg/kg), Sch 37224 (ED50 = 0.5 mg/kg), and WEB 2086 (ED50 = 4 mg/kg) decreased eosinophil accumulation in the BAL fluid, indicating roles for 5-lipoxygenase products and PAF in this multimediator-dependent model of allergic inflammation. On the other hand, 4 mg/kg of indomethacin increased total cells with no effect on eosinophils, precluding a major role for cyclooxygenase products. Sch 37224, an antileukotriene agent and an orally active novel antiallergy agent in sheep, guinea pigs, and humans, is as potent as betamethasone at blocking eosinophil infiltration, suggesting that it may also suppress human pulmonary inflammation.     

Effect of interleukin-2 on the airway response to antigen in the rat.

To evaluate the hypothesis that lymphocyte stimulation can modify the bronchoconstrictive response to inhalational challenge with an allergen, we administered interleukin-2 (IL-2), an important lymphokine in lymphocyte activation and proliferation, to actively sensitized rats. Brown Norway rats received either human recombinant IL-2 (n = 8) or its vehicle (n = 7) twice a day from the ninth to the fourteenth day after active sensitization to ovalbumin (OA) and were challenged with an aerosol of OA. Lung resistance (RL) during the early response increased to a maximum of 698 +/- 230% and 180 +/- 26% of baseline values in the animals receiving IL-2 and vehicle, respectively (p less than 0.025). The late response was threefold greater in IL-2-treated than in vehicle-treated animals (p = 0.01). IL-2 increased OA-specific IgG levels in the serum, but it did not significantly affect total or specific IgE levels. IL-2 caused an inflammatory infiltrate around the airways with significant increases in eosinophils, lymphocytes, and mast cells prior to antigen challenge. Our results indicate that stimulation of cell-mediated immunity can affect airway responsiveness to antigen.     

Inverse relationship between heart rate and blood pressure variabilities in rats

The interplay of heart rate variability, baroreceptor control of heart rate, and blood pressure (BP) variability was examined in chronically instrumented, unanesthetized, freely moving rats in which the efferent neural influences on heart rate were pharmacologically altered. In each rat, BP was recorded continuously for 90 minutes in the control condition and in one or more of the following conditions: 1) beta-adrenergic receptor blockade by propranolol, 1 mg/kg; 2) cholinergic blockade by atropine, 0.75 mg/kg, and 3) combined blockade by propranolol plus atropine. Each BP recording was analyzed beat-to-beat by a computer that calculated heart rate and BP variabilities, both expressed as variation coefficients. In addition, under each condition the sensitivity of the arterial baroreceptor control of heart rate was assessed by measuring the reflex changes in pulse interval in response to BP changes induced by bolus i.v. injections of phenylephrine and nitroprusside. As compared with the control condition, 1) propranolol (n = 10) reduced heart rate variability by 23 +/- 4% (p less than 0.01), only slightly impaired baroreceptor reflex sensitivity, and did not significantly modify BP variability (+11 +/- 7%); 2) atropine (n = 11) reduced heart rate variability by 30 +/- 7% (p less than 0.01), drastically impaired baroreceptor reflex sensitivity, and increased BP variability (+40 +/- 8%, p less than 0.01); 3) combined blockade (n = 10) caused variability and baroreceptor reflex changes similar to those induced by atropine alone. Thus, heart rate variability depends on both vagal and sympathetic influences. However, only the former component affects BP variability, that is, it plays an antioscillatory role.(ABSTRACT TRUNCATED AT 250 WORDS)     

Antigen-induced bronchial hyperreactivity and bronchopulmonary inflammation in rats: effect of TNF receptor binding protein

The effect of a receptor binding protein for tumor necrosis factor (TNFrbp) on cell infiltration, bronchial hyperreactivity, and release of inflammatory mediators were studied following antigen challenge in sensitized rats. A 3-fold increase in total cell number, mainly neutrophils and eosinophils, was noted in bronchoalveolar lavage (BAL) fluid 8 hours after antigen challenge. Antigen challenge also induced a significant hyperreactivity of the lower bronchus to carbachol and serotonin, but did not affect the reactivity of the trachea and upper bronchus. This increased responsiveness of the lower bronchus was transient, being detected 8 hours but not 24 hours after antigen challenge. Thromboxane B2 (TxB2), prostaglandin E2 (PGF2), and nitric oxide (NO) levels increased in the BAL fluid of sensitized rats 8 hours after antigen challenge by 197%, 172%, and 173%, respectively. TNFrbp treatment reduced by 83% the antigen-induced cell infiltration, with neutrophils being the cells most affected. The bronchial hyperreactivity induced by antigen challenge was also significantly inhibited by TNFrbp, whereas TxB2, PGE2, and NO levels in the BAL fluid were not affected. In our animal model, the cell infiltration and bronchial hyperreactivity appear to be mediated to some extent by TNF, but not by prostanoids nor NO.