Folic acid, riboflavin, thiamine, and vitamin B-6 status of a group of first-time blood donors

Chronic hypoxia has been shown to augment the production of antioxidants in rat lungs and to reduce airway hyperreactivity in patients with asthma. This study investigated indirectly whether this increase in antioxidants occurs in guinea-pig lungs and whether the increased antioxidants affect hyperpnoea-induced bronchoconstriction (HIB). Guinea-pigs were divided into four groups: control (n=8); chronic hypoxia (n=7); capsaicin pretreatment (n=7); and capsaicin pretreatment plus chronic hypoxia (n=8). Control animals were not treated. Animals in the hypoxia group were intermittently exposed to an ambient pressure of 380 mmHg for 7 days. A five day pretreatment of capsaicin was used to deplete tachykinins. In the last group, animals were pretreated with capsaicin, followed by a seven day hypoxic exposure. On the day of the study, airway function was examined in the anaesthetized and paralysed animal. Fifteen minutes of hyperpnoea caused marked decreases in the maximal expiratory flow rate at 15% vital capacity, forced expiratory volume in one second, and dynamic respiratory compliance, indicating HIB. This HIB and plasma substance P levels were significantly attenuated by chronic hypoxia, capsaicin pretreatment, and capsaicin pretreatment plus chronic hypoxia. Furthermore, chronic hypoxia attenuated airway constriction induced by xanthine-xanthine oxidase. The results suggest that chronic hypoxia attenuates hyperpnoea-induced bronchoconstriction via a decrease in the oxygen radical-mediated release of tachykinins.     

Effect of epidural anesthesia on airway constriction induced with methacholine or capsaicin in cats

The choice of epidural anesthesia for patients with bronchial asthma is controversial. We studied the effect of epidural anesthesia on airway constriction induced by methacholine or capsaicin in cats. Cats were anesthetized with pentobarbital and mechanically ventilated. Peak airway pressure and compliance, as well as cardiac sympathetic and vagal nerve activity were recorded. We sprayed 0.2% methacholine of 0.2% capsaicin into the trachea to produce airway constriction, and 15 min after drug spray we injected 2% lidocaine 1.0 ml into the epidural space. Methacholine increased peak airway pressure by 25% and decreased compliance by 26%. Capsaicin increased peak airway pressure 20% and decreased compliance 22%. After epidural anesthesia, cardiac sympathetic nerve activity decreased to 40% and 44%, vagal nerve activity decreased to 92% and 61% of control values in methacholine and capsaicin groups, respectively. However, here were no changes in the peak airway pressure and compliance in the two groups. These results suggest that epidural anesthesia, even if epidural anesthesia decrease sympathetic nerve activity, has no effect on the airway constriction induced with methacholine or capsaicin.     

Elastase in hyperpnea-induced guinea pig airway constriction

Aerosolized elastase has been shown to produce airway constriction in guinea pigs. In this study, we examined whether endogenous elastase plays a role in isocapnic hyperpnea-induced airway constriction using an elastase inhibitor, eglin-c. The study was divided into three experiments. In the first experiment, we used an elastase inhibitor, eglin-c, to suppress hyperpnea-induced bronchoconstriction. Twenty-two young male Hartley guinea pigs were divided into three groups: control (n=8), eglin-c(1) (a lower dose of eglin-c, n=7), and eglin-c(2) (a higher dose of eglin-c, n=7). In the second experiment, we tested whether eglin-c affects pulmonary function following 15 min of normal air ventilation in two groups of animals: control (n=8) and eglin-c (n=8). In the third experiment, animals were divided into two groups: control (n=7) and compound 48/80 (a mast cell degranulating agent, n=7). Airway function was examined in the anesthetized-paralyzed animal. In the first and third experiments, 15 min of isocapnic hyperpnea caused marked decreases in dynamic respiratory compliance, forced expiratory flow at 0.1 s and maximal expiratory flow at 50% total lung capacity, demonstrating hyperpnea-induced airway constriction. This bronchoconstriction was significantly attenuated by eglin-c and by pretreatment with compound 48/80. In the second experiment, eglin-c did not significantly affect bronchial function following normal air ventilation. These data suggest that elastase released from mast cells directly or indirectly induces hyperpnea-induced bronchoconstriction.     

Impaired sensorineural function after allergen-induced mediator release

We tested the hypothesis that allergen-induced mediator release augments the magnitude of isocapnic dry gas hyperpnea-induced bronchoconstriction in sensitized guinea pigs. Male Hartley guinea pigs were sensitized by spontaneous inhalation of ovalbumin (OA) aerosol on days 0 and 7 of the study. On day 14, sensitized animals again breathed OA aerosol and were prospectively divided into a group that exhibited labored breathing (LB), presumably reflecting OA-induced inflammatory mediator release, and a group that did not exhibit LB at this time. Control guinea pigs breathed saline aerosol on days 0, 7, and 14. Bronchoalveolar lavage on day 17 disclosed relative eosinophilia in OA+LB, but not in OA-LB, animals. On day 17, the bronchoconstrictor responses to increasing intravenous (i.v.) doses of acetylcholine (ACh), substance P (SP), neurokinin A (NKA), and capsaicin, as well as dry gas hyperpnea, were measured in vivo in animals from each group. Control and OA-LB guinea pigs exhibited similar responses, but OA+LB animals demonstrated augmented bronchoconstriction induced by i.v. administration of ACh, SP, or NKA. However, despite their augmented responsiveness to these exogenous constrictor agonists, OA+LB animals displayed no greater bronchoconstriction after dry gas hyperpnea or i.v. capsaicin administration. It is known that both dry gas hyperpnea and i.v. capsaicin cause bronchoconstriction in guinea pigs by releasing endogenous tachykinins from airway sensory C-fibers. Thus, our results suggest that allergen-induced mediator release impairs endogenous tachykinin release from airway sensory C-fibers in guinea pigs.     

The relationship of HIV status, type of coagulation disorder, and school absenteeism to cognition, educational performance, mood, and behavior of boys with hemophilia

Apnoea, bradycardia and hypotension were elicited by right atrial injections of capsaicin in anaesthetized monkeys. At the threshold dose (2.5 +/- 0.3 microgram/kg), tachypnoea was elicited (latency 1.6 +/- 0.2 s) which got replaced by apnoea with higher doses of capsaicin. These responses persisted (1) after cooling the cervical vagi to 6-8 degrees C, and (2) after instilling xylocaine into the pericardial sac. Tachypnoea and apnoea were elicited after bilateral cervical vagotomy also, but only with higher doses and after a longer latency (5.0 +/- 0.3 s). Right atrial injection of capsaicin and insufflation of halothane stimulated vagal pulmonary C-fibre receptors with a latency of 1.7 +/- 0.7 s and 0.2 +/- 0.1 s, respectively. Tachypnoea/apnoea, bradycardia and hypotension were elicited by left atrial injection of capsaicin also (threshold dose: 5.0 +/- 1.2 micrograms/kg). The respiratory responses persisted (1) after instilling xylocaine into the pericardial sac, and (2) after bilateral cervical vagotomy suggesting that they were due to stimulation of non-cardiac receptors with sympathetic afferents. It is concluded that the initial respiratory responses elicited by right atrial injection of capsaicin were due to stimulation of pulmonary C-fibre receptors with vagal afferents.     

Vagal efferent nerve-dependent inhibitory action of pancreatic polypeptide and peptide YY in conscious rats: comparison with somatostatin

The release of pancreatic polypeptide (PP) and peptide YY (PYY) is regulated by the vagal nerve, and the inhibitory effect of these peptides on pancreatic exocrine secretion shows indirectly via a neural mechanism. To determine the role of the vagal nerve on the inhibitory action of these peptides on the pancreas, we compared the effect on the pancreatic response to bile and pancreatic juice diversion in conscious rats with and without vagotomy. We also studied this response in rats treated with capsaicin, because bile-pancreatic juice diversion is the most potent endogenous stimulation of pancreatic secretion in conscious rats. In addition, since somatostatin potently inhibits of pancreatic enzyme secretion, the effects of PP and PYY were compared with somatostatin. An intravenous infusion of 2.5 nmol/kg per h of PP and PYY significantly inhibited the pancreatic responses of bile and pancreatic juice diversion in animals with an intact vagal nerve and in those treated with capsaicin, whereas the same dose of peptides failed to inhibit pancreatic secretion in vagotomized rats. Somatostatin inhibited pancreatic secretion under all conditions tested. We concluded that the inhibitory action of PP and PYY on pancreatic secretion is fully mediated by the vagal efferent nerve although other multiple mechanisms are involved for the inhibitory action of somatostatin.     

Nisin resistance in Listeria monocytogenes ATCC 700302 is a complex phenotype

The constriction of pulmonary airways is limited by the tethering effect exerted by parenchymal attachments. To characterize this tethering effect at the scale of intraparenchymal airways, we studied the pattern of parenchymal distortion due to bronchoconstriction in a rat lung explant system. First, we measured the elastic modulus under tension for 2% (wt/vol) agarose alone (37.6 +/- 1.5 kPa) and for agarose-filled lung (5.7 +/- 1.3 kPa). The latter is similar to the elastic modulus of air-filled lung at total lung capacity (4.5-6 kPa) (S. J. Lai-Fook, T. A. Wilson, R. E. Hyatt, and J. R. Rodarte. J. Appl. Physiol. 40: 508-513, 1976), suggesting that explants can be used as a model of lung tissue distortion. Subsequently, confocal microscopic images of fluorescently labeled 0.5-mm-thick explants prepared from agarose-filled rat lungs inflated to total lung capacity (48 ml/kg) were acquired. Images were taken before and after airway constriction was induced by direct application of 10 mM methacholine, and the pattern of parenchymal distortion was measured from the displacement of tissue landmarks identified in each image for 14 explants. The magnitude of the radial component of tissue displacement was calculated as a function of distance from the airway wall and characterized by a parameter, b, describing the rate at which tissue movement decreased with radial distance. The parameter b was 0.994 +/- 0.19 (SE), which is close to the prediction of b = 1 of micromechanical modeling (T. A. Wilson. J. Appl. Physiol. 33: 472-478, 1972). There was significant variability in b, however, which was correlated with the fractional reduction in airway diameter (r = 0.496). Additionally, parenchymal distortion showed significant torsion with respect to the radial direction. This torsion was similar in concentric zones around the airway, suggesting that it originates from inhomogeneity in the parenchyma rather than inhomogeneous airway constriction. Our results demonstrate the significance of the nonlinear mechanical properties of alveolar walls and the anisotropy of the parenchyma in determining the nature of airway-parenchymal interdependence.     

How inhomogeneities and airway walls affect frequency dependence and separation of airway and tissue properties

It has been proposed that during mild-to-moderate bronchoconstriction one can partition airway and tissue properties on the basis of input impedance (Zin) acquired from 0.1 to 5 Hz (K.R. Lutchen, B. Suki, Q. Zhang, F. Peták, B. Daróczy, and Z. Hantos. J. Appl. Physiol. 77: 373-385, 1994). The approach is to apply a homogeneous lung model that contains airway resistance and viscoelastic tissue damping and elastance parameters. The tissue parameters account for the frequency dependence in lung resistance (RL) and elastance (EL). We present an anatomically consistent asymmetrically branching airway model to address two key questions: 1) How will lung inhomogeneities, airway wall shunting, and tissue viscoelasticity contribute to increased frequency dependence and levels of RL and EL during lung constriction? and 2) How much can lung inhomogeneities and airway wall shunting contribute to our assessment of airway, tissue, and overall lung properties derived from Zin? The model incorporates nonrigid airway walls and allows for explicit control over the type and degree of inhomogeneous airway constriction or tissue changes. Our results indicate that, from 0.1 to 5 Hz, airway wall shunting does not become important unless the entire lung periphery experiences significant constriction. Mild-to-moderate inhomogeneous peripheral airway constriction produces a relatively minor additional frequency dependence in RL and EL beyond that due to the tissues alone. With more extreme constriction, however, there is a marked frequency-dependent increase in EL. This phenomenon may render it impossible to distinguish from a single frequency measurement whether an increase in EL during bronchoconstriction is a consequence of a true increase in tissue stiffening or simply a consequence of airway phenomena. Finally, Zin from 0.1 to 5 Hz can be used to provide a reasonable separation of airway and tissue properties for mild-to-moderate homogeneous or inhomogeneous lung constriction. However, during more severe disease, inhomogeneities and/or wall shunting will produce substantial overestimation of tissue damping and hysteretic properties. In fact, the only reliable indicator of a real change in the tissues may be a change in the estimate of tissue elastance that is based on data extending to a sufficiently low frequency.     

Effect of vagotomy on airway hyperreactivity to endogenously released neurotransmitters at 18-24 h after inhaled antigen

Airway reactivity was examined in anaesthetized guinea-pigs 18-24 h after inhalation challenge of ovalbumin-sensitized animals with ovalbumin. Bronchoconstrictor responses were measured from the increases in pulmonary inflation pressure. The study was undertaken to examine whether ovalbumin challenge induced airway hyperreactivity to neurotransmitters released endogenously by vagal nerve stimulation. Stimulation parameters were selected to cause release of either acetylcholine (0.3 ms pulse width for 3 s, 20 V, 2-40 Hz), both acetylcholine and neuropeptide (5 ms pulse width for 15 s, 20 V, 0.5-8 Hz) or neuropeptide only, using the latter parameters in the presence of atropine. The vagi were paired for stimulation and in some experiments were cut central to the stimulation point. Frequency-response curves for acetylcholine- and neuropeptide-mediated bronchoconstrictor responses to vagal stimulation when the nerves were intact revealed no airway hyperreactivity after ovalbumin challenge. The presence of atropine failed to reveal airway hyperreactivity. However, when the vagi were cut, the frequency-response curves were displaced to the left after ovalbumin challenge compared with saline challenged animals, indicating airway hyperreactivity. This airway hyperreactivity was significant after atropine and suggests an increase in sensitivity to endogenously released neuropeptides rather than acetylcholine. It also indicates that the airway hyperreactivity is dependent on removal of the afferent vagal pathways. Frequency-response curves for cholinergic stimulation (0.3 ms) with intact vagi revealed no airway hyperreactivity after antigen challenge. Comparisons of exogenously administered 5-hydroxytryptamine (5-HT, 300 ng/100 g i.v.) and a single vagal stimulation of 0.3 ms pulse width (cholinergic) revealed no airway hyperreactivity to either stimulus after ovalbumin challenge. However if the vagi were cut, airway hyperreactivity was observed, again suggesting that removal of afferent pathways is important for revealing airway hyperreactivity in the anaesthetized guinea-pig. Ovalbumin challenge caused significant increases in the bronchoconstrictor responses to a single dose of capsaicin (50 microg/100 g i.v.) or dose-response curves to bradykinin. Since these agents release neuropeptides from sensory C-fibres, this is further support for a raised sensitivity to endogenously released neuropeptides.     

Role of tachykinins in distilled water-induced bronchoconstriction in guinea-pigs

BACKGROUND: An inhalation of ultrasonically nebulized distilled water (UNDW) induces bronchoconstriction only in asthmatics, but the mechanism underlying the response is not fully understood. We recently showed that bronchoconstriction occurs immediately after UNDW is inhaled 20min after an aerosolized antigen challenge in passively sensitized guinea-pigs. OBJECTIVE: This study was conducted to examine the role of tachykinins in this response. METHODS: Passively sensitized animals were anaesthetized and artificially ventilated, and changes in pressure at the airway opening (Pao) were measured as an overall index of airway narrowing. A tachykinin NK1 and NK2 dual receptor antagonist, FK224, and a tachykinin NK1 selective antagonist, FK888, were intravenously administered 15 min after the antigen challenge. The effects of capsaicin desensitization and a neutral endopeptidase inhibitor, phosphoramidon, were also examined. RESULTS: FK224 and FK888 significantly (P < 0.05 and P < 0.05, respectively) reduced the time course curve of the increase in Pao caused by UNDW inhalation in a dose-dependent manner. The percentage increase in Pao from the preantigen challenge value at 1 min after the UNDW inhalation was 267.4+/-17.1, 358.0+/-33.7 and 412.4+/-27.6% with 10 mg/kg of FK224, 1.0 mg/kg of FK224 and vehicle, respectively, (P<0.01 between 10 mg/kg of FK224 and vehicle) and the value was 254.4+/-48.5% with 10 mg/kg of FK888, 327.1+/-57.6% with 1.0 mg/kg of FK888 and 418.5+/-39.0% with vehicle, respectively (P < 0.05 between 10 mg/kg of FK888 and vehicle). The capsaicin desensitization, but not phosphoramidon, significantly reduced the UNDW-induced increase in Pao. CONCLUSION: These results suggest that tachykinins, at least substance P, are involved in a part of the UNDW-induced bronchoconstriction in our guinea-pig model.     

Increased levels of GMAP, VIP and nitric oxide synthase, and their mRNAs, in lumbar dorsal root ganglia of the rat following systemic resiniferatoxin treatment

Using in situ hybridization, the expression of mRNA encoding galanin, vasoactive intestinal polypeptide (VIP), neuropeptide Y (NPY), and nitric oxide synthase (NOS), respectively, was studied in lumbar dorsal root ganglia of rats given a single s.c. dose of 300 micrograms kg-1 resiniferatoxin (RTX), an ultrapotent capsaicin analogue. In control animals, 10% of the DRG neurones were positive for galanin mRNA, whereas no message for VIP, NPY or NOS could be detected. One week after RTX treatment, a markedly increased number (approximately 30%) of the neurones expressed galanin mRNA. Simultaneously, VIP and NOS mRNA became detectable in 6-8% of the neurones. The number of galanin-positive neurones declined after 2 weeks and returned to control levels by 8 weeks. The increase in number of VIP-, or NOS-positive neurones persisted up to 4 weeks after RTX treatment and declined thereafter. Also, there was a small increase in NPY mRNA-positive neurones. In parallel immunohistochemical experiments, similar increases were observed for galanin message-associated protein (GMAP)-, VIP- and NOS-like immunoreactivities. Our findings suggest that RTX can cause changes (messenger plasticity) in galanin, VIP and NOS expression in capsaicin-sensitive sensory neurones of the rat, similar to those described following axotomy.     

Specific binding of [3H]resiniferatoxin by human and rat preoptic area, locus ceruleus, medial hypothalamus, reticular formation and ventral thalamus membrane preparations

Specific [3H]resiniferatoxin (RTX) binding detects the vanilloid (capsaicin) receptors and provides a biochemical means for exploring their pharmacology. In the present study we demonstrate specific vanilloid (RTX) binding sites in various brain areas not known to be innervated by primary afferent neurons. Specific high-affinity binding of [3H]RTX could be detected in membrane preparations of the posterior ("hypothalamic") and anterior ("septal") parts of the preoptic area, locus ceruleus, medial hypothalamus, brainstem reticular formation and ventral thalamic nuclei from naive rats. The determined levels of binding at 4 nM [3H]RTX were 23.0 +/- 4.5, 7.1 +/- 1.6, 29.9 +/- 2.3, 23.5 +/- 2.4, 9.9 +/- 2.2 and 8.1 +/- 1.9 fmol/mg, respectively; unfortunately, the high levels of non-specific binding (higher than 80%) in the present experiments made it impossible for us to characterize fully the binding properties of the receptors. However, no detectable specific [3H]RTX binding was present in membranes of brain nuclei from rats pretreated with 300 mg/kg capsaicin, a treatment which causes loss of response to capsaicin. Significant specific [3H]RTX binding was also absent in membrane preparations of the midbrain central gray matter, somatosensory cortex and cerebellum either from naive or capsaicin treated rats. In human brain specific [3H]RTX binding measured at 4 nM [3H]RTX showed a pattern of distribution similar to that in the rat brain. The corresponding levels of specific [3H]RTX binding in the preoptic area, locus ceruleus, medial hypothalamus, reticular formation and ventral thalamus were 44.9 +/- 2.4, 50.6 +/- 3.0, 36.1 +/- 2.9, 9.4 +/- 2.8 and 8.4 +/- 2.4 fmol/mg, respectively. Our findings corroborate previous biological evidence that vanilloid receptors are present in brain as well as in sensory afferent neurons.     

A controlled evaluation of a lifts and transfer educational program for nurses

The role of the parasympathetic autonomic nervous system (ANS) in digoxin intoxication was investigated in atropine pretreated conscious rabbits. Both the electrocardiographic registration and the histologic analysis indicated possible prevention of lethal arrhythmias by atropine pretreatment. The hearts of animals pretreated with atropine appeared less damaged, since they presented only a light cytoplasmic vacuolization. It was evident that the administration of digoxin without atropine pretreatment provoked dramatic signs of digitalis intoxication followed by animal death. Myocardia of these rabbits were highly damaged. On the other hand, our experimental data indicated that the abolishment of the vagal tone by atropine blockade caused only signs (i.e. inversion of the T wave) due to myocardial ischemia, to which the light cytoplasmic vacuolation could be correlated. Myocardial ischemia could be caused by constriction of coronary blood vessels, which could be consequential to both the prevalent activity of the orthosympathetic ANS, following parasympathetic blockade, and direct digoxin effects on vascular fibrecells, which both produce vasoconstriction. Therefore, it is reasonable to assume that the parasympathetic ANS plays a major role in digitalis intoxication in rabbits.     

Cholecystokinin changes the duration but not the rate of licking in vagotomized rats.

Abdominal vagotomy markedly reduces or abolishes the inhibitory effect of cholecystokinin (CCK-8) on meal size. To investigate the rate and microstructure of licking underlying this phenomenon, licking was measured throughout a meal of milk in intact and vagotomized rats after intraperitoneal injections of isotonic saline or CCK-8. CCK-8 increased the slope of the decay of licking, decreased the efficiency of licking, and decreased the duration of licking in intact rats but had no effect on either the slope of the decay of licking or the efficiency of licking, but it increased the duration of licking in vagotomized rats. These results demonstrate that abdominal vagal nerves are necessary for CCK-8 to increase the rate of decay of licking, but nonvagal mechanisms mediate the effect of CCK-8 on duration of licking. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

On the causes of lung hyperinflation during bronchoconstriction

Airway obstruction in asthma and chronic obstructive pulmonary disease (COPD) is often associated with lung hyperinflation. In this review, we examine the mechanisms that may cause functional residual capacity (FRC), residual volume (RV) and total lung capacity (TLC) to increase during acute and chronic airway obstruction. Normally, FRC at rest is determined by the static characteristics of the lung and chest wall. When airways narrow, FRC may be also be determined by dynamic factors. There are data suggesting that expiratory flow limitation during tidal breathing represents the starting trigger for FRC to increase, in order to allow breathing at higher flows. Indeed, the increase in FRC during induced bronchoconstriction in asthma is closely associated with the occurrence of flow limitation, i.e. the achievement of maximum flow during tidal breathing. Conversely, the decrease in FRC following bronchodilatation in COPD is closely associated with flow limitation disappearing or occurring at lower lung volumes. In normal young people, RV is determined by the static characteristics of the chest wall. During bronchoconstriction RV may also be determined by dynamic factors; therefore, changes in flow or airway calibre at low lung volumes may modulate RV during bronchoconstriction. During acutely induced bronchoconstriction, RV achieved with an expiration from TLC is less than with an expiration from tidal breathing, and this effect appears to be linked to the bronchodilator effect of the deep inhalation. The reasons for the increase in TLC during airway narrowing are not clear, but the duration of the bronchoconstriction by itself may play a role.     

Neural modulation of glucose-dependent insulinotropic peptide (GIP) and insulin secretion in conscious dogs

Glucose-dependent insulinotropic peptide (GIP) is a potent incretin, but it remains unclear whether this effect is dependent upon intact vagal pathways. In four conscious dogs, plasma GIP, plasma insulin, and plasma glucose responses were measured after intraduodenal administration of a defined formula diet, after glucose was perfused intraduodenally, and after insulin-mediated hypoglycemia with and without bilateral cryogenic blockade of the cervical vagus nerves. Vagal blockade did not alter elevations of plasma GIP after the defined formula diet or after glucose. However, with the vagi blocked plasma insulin responses were suppressed after the enteral diet (-52 +/- 8%) and after intraduodenal glucose (-55 +/- 4%), without changes in plasma glucose. Intravenous atropine (50 micrograms/kg) did not modify the GIP responses to intraduodenal perfusions of the defined formula diet or to glucose, but did suppress plasma insulin responses to baseline values. Insulin hypoglycemia without or with vagal blockade had no effect on basal concentrations of plasma GIP. These results indicate that vagal muscarinic and nonvagal muscarinic pathways participate in the control of the intestinal phase of insulin secretion, but the regulation of GIP secretion is independent of vagal or muscarinic neural control mechanisms.     

Participation of tachykinins in experimental models of lung damage

In the present investigation a possible involvement of tachykinins during sulfur dioxide-(SO2) and metabisulfite-(MBS) induced bronchoconstriction, and paraquat (PQ)-induced mortality was studied. SO2 (250ppm) inhalation and MBS (3mM) perfusion induced a marked decrease of compliance and conductance in the isolated and perfused lung. SO2-induced bronchoconstriction was associated with release of Calcitonin Gene Related Peptide, suggesting activation of capsaicin sensitive sensory nerves. Pretreatment of animals with capsaicin, in order to deplete the tachykinin content of sensory nerves, significantly reduced SO2- and MBS-induced bronchoconstriction. PQ (25mg/Kg) treatment induced high mortality (75%) after 3 weeks. Pretreatment with capsaicin significantly protected versus PQ induced mortality (25%). The results suggest that tachykinin content in the respiratory airways participate to SO2- and MBS-induced bronchoconstriction and PQ mortality.     

Cigarette smoke-inhibition of neurogenic bronchoconstriction in guinea-pigs in vivo: involvement of exogenous and endogenous nitric oxide

1. We investigated the effect of acute inhalation of cigarette smoke on subsequent non-adrenergic, non-cholinergic (NANC) neural bronchoconstriction in anaesthetized guinea-pigs in vivo by use of pulmonary insufflation pressure (PIP) as an index of airway tone. The contribution of endogenous nitric oxide (NO) was investigated with the NO synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME). The contribution of plasma exudation to the response was investigated with Evans blue dye as a plasma marker. 2. Inhalation of 50 tidal volumes of cigarette smoke or air had no significant effect on baseline PIP. In the presence of propranolol and atropine (1 mg kg(-1) each), electrical stimulation of the vagus nerves in animals given air 30 min previously induced a frequency-dependent increase in PIP above sham stimulated controls (16 fold increase at 2.5 Hz, 24 fold increase at 10 Hz). In contrast, in smoke-exposed animals, the increase in subsequent vagally-induced PIP was markedly less than in the air controls (90% less at 2.5 Hz, 76% less at 10 Hz). 3. L-NAME (10 mg kg[-1]), given 10 min before air or smoke, potentiated subsequent vagally-induced (2.5 Hz) NANC bronchoconstriction by 338% in smoke-exposed animals, but had no significant effect in air-exposed animals. The inactive enantiomer D-NAME (10 mg kg[-1]) had no effect, and the potentiation by L-NAME was partially reversed by the NO-precursor L-arginine (100 mg kg[-1]). Vagal stimulation did not affect the magnitude of vagally-induced bronchoconstriction 30 min later. 4. Cigarette smoke exposure reduced the magnitude of subsequent bronchoconstriction induced by neurokinin A (NKA) by 37% compared with the effect of NKA in air-exposed animals. L-NAME had no significant effect on the smoke-induced inhibition of NKA-induced bronchoconstriction. 5. Vagally-induced plasma exudation in the main bronchi was greater in smoke-exposed animals compared with air-exposed animals (120% greater at 2.5 Hz, 82% greater at 10 Hz). 6. We conclude that cigarette smoke-induced inhibition of subsequent NANC neurogenic bronchoconstriction is not associated with inhibition of airway plasma exudation and is mediated in part via exogenous smoke-derived NO, or another bronchoprotective molecule, and by endogenous NO.     

Neuropeptide Y stimulates bile secretion via Y1 receptor in the left dorsal vagal complex in rats

Neuropeptide Y (NPY) injected into the cerebrospinal fluid and the left dorsal vagal complex enhances bile acid-independent and bicarbonate-dependent bile secretion through vagal muscarinic pathways in animal models. NPY binds to and activates six different receptor subtypes, and NPY Y1 and Y2 receptors are distributed in the dorsal vagal complex. We sought to determine which NPY receptor subtypes are involved in central stimulation of bile secretion by examining the effect of microinjection of specific NPY receptor agonists into the dorsal vagal complex. The bile duct was cannulated in urethane-anesthetized and bile acid-compensated rats. After measuring basal secretion, NPY, peptide YY (PYY), [Leu31, Pro34]NPY, NPY(13-36), or NPY(3-36) was microinjected into the either right or left dorsal vagal complex and bile secretion was observed for 100 minutes. Hepatic branch vagotomy was performed 2 hours before the peptide injection. Microinjection of NPY and PYY (8 pmol) into the left dorsal vagal complex increased bile secretion. [Leu31, Pro34]NPY microinjected into the left dorsal vagal complex also dose-dependently (1-8 pmol) stimulated bile acid-independent and bicarbonate-dependent bile secretion. Microinjection of NPY(13-36) into the left dorsal vagal complex did not stimulate and NPY(3-36) dose-dependently inhibited bile secretion. Stimulation of bile secretion by [Leu31, Pro34]NPY was abolished by hepatic branch vagotomy. NPY acts in the left dorsal vagal complex to stimulate bile acid-independent and bicarbonate-dependent bile secretion via Y1 receptor subtype.     

Effects of airway inflammation on cough response in the guinea pig

We have developed a guinea pig model for cough related to allergic airway inflammation. Unanesthetized animals were exposed to capsaicin aerosols for 10 min, and cough frequency was counted during this period. The cough evaluation was performed by the following three methods: visual observation, acoustic analysis, and monitoring of pressure changes in the body chamber. These analyses clearly differentiated a cough from a sneeze. To elucidate the relationship between cough response and airway inflammation, animals were immunosensitized and multiple challenged. Sensitized guinea pigs presented no specific changes microscopically, but multiple-challenged animals showed an increased infiltration of inflammatory cells into the airway. Cough number in response to capsaicin increased significantly from 4.7 +/- 1.4 coughs/10 min in normal animals to 10.6 +/- 2.0 coughs/10 min in sensitized animals and further to 22.8 +/- 1.3 coughs/10 min in multiple-challenged animals. This augmented cough frequency was significantly inhibited by the inhalation of tachykinin-receptor antagonists and by oral ingestion, but not inhalation, of codeine phosphate. The results suggest that airway inflammation potentiates an elevation of cough sensitivity in this model.