Effects of inhaled and intravenous furosemide on bronchial hyperresponsiveness in patients with chronic congestive heart failure]

We studied the effects of inhaled and intravenous furosemide (40 mg) on bronchial responsiveness to acetylcholine (ACh) in patients with chronic congestive heart failure. The measurement of bronchial responsiveness was performed by inhaling doses of ACh and calculating the provocative concentration of ACh needed to cause a 20% fall in FEV1.0 (PC20-ACh). Intravenous furosemide (N = 11) had a marked diuretic effect (urine output 1014 ml (SEM 156) in 2 hours), but had no effect on resting pulmonary function and PC20-ACh. In contrast, inhaled furosemide (N = 10) had no effect on urine output and resting pulmonary function, but caused significant increase in PC20-ACh from 2.74 (GSEM 1.28) to 8.47 (GSEM 1.22) mg/ml (p less than 0.05). We conclude that inhaled furosemide, but not intravenous furosemide reduces bronchial hyperresponsiveness to ACh in patients with chronic congestive heart failure. The mechanism of this effect appears to be related to the ion transport system of airway epithelium.     

N-omega-nitro-L-arginine methyl ester increases airway responsiveness to serotonin but not to acetylcholine in cats in vivo.

BACKGROUND: We previously reported that N(omega)-nitro-L-arginine methyl ester (L-NAME) enhances airway responsiveness to inhaled serotonin in cats treated with atropine and propranolol. OBJECTIVE: To further elucidate the role of nitric oxide (NO) in airway responsiveness, we investigated whether L-NAME induces airway hyperresponsiveness to serotonin and acetylcholine (ACh) in animals with intact innervation. METHODS: Cats were anesthetized with pentobarbital sodium (50 mg/kg, i.p.), and mechanically ventilated. To assess airway responsiveness, we measured increase in total pulmonary resistance (RL) produced by delivering serotonin or ACh aerosol to the airway, and determined PC200 (the concentration which caused a 200% increase in RL). RESULTS: The following results were obtained: (1) Airway responsiveness to serotonin was significantly enhanced by the administration of L-NAME (100 mg/kg) in animals treated with atropine and propranolol. (2) Airway responsiveness to serotonin was also significantly enhanced by L- NAME in animals with intact innervation. (3) In contrast, airway responsiveness to ACh was not changed by the addition of L-NAME in cats with intact innervation. CONCLUSION: These results suggest that NO modulates nonspecific airway responsiveness in animals with intact innervation, presumably by a reflex mechanism.     

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.     

Airway hyperresponsiveness to cigarette smoke in ovalbumin-sensitized guinea pigs

This study was carried out to determine if the bronchoconstrictive effect of cigarette smoke (CS) is enhanced when airway hyperresponsiveness is induced by ovalbumin (Ova) sensitization, and if so, whether an increase in endogenously released tachykinins is involved. The bronchoconstrictive effects of an acute CS inhalation challenge (15 ml; 50% concentration) were compared between guinea pigs sensitized with aerosolized Ova and matching control animals (receiving saline aerosol). In Ova-sensitized animals, there were marked increases in the numbers of eosinophils and neutrophils in the bronchoalveolar lavage fluid (BALF), which was accompanied by an elevated bronchomotor response to acetylcholine (ACh). The baseline lung resistance (RL) and dynamic pulmonary compliance (Cdyn) were not significantly different between the two groups; however, the same CS inhalation challenge evoked a significantly more intense bronchoconstriction in the Ova-sensitized group (control group: DeltaRL = 68 +/- 8%, DeltaCdyn = -26 +/- 6%; Ova group: DeltaRL = 425 +/- 76%; DeltaCdyn = -47 +/- 8%). The levels of substance P-like immunoreactivity (SP-LI) and calcitonin gene-related peptide-like immunoreactivity (CGRP-LI) measured in the bronchoalveolar lavage (BAL) collected after CS inhalation challenge were also significantly greater in Ova-sensitized animals than in control animals. Furthermore, pretreatment with SR-48968, a selective antagonist of neurokinin-2 (NK(2)) receptor, inhibited more than 85% of the enhanced bronchomotor responses to CS challenge, but did not significantly reduce the airway hyperresponsiveness to ACh in Ova-sensitized guinea pigs. These results show that Ova sensitization induces airway hyperresponsiveness to inhaled CS, and that the endogenous tachykinins evoked by CS-induced activation of lung C fibers play a primary role in this augmented response.     

Canine parainfluenza type 2 bronchiolitis increases histamine responsiveness in beagle puppies

Histamine hyperresponsiveness with viral bronchiolitis may depend on previous exposures to viruses or to other pathogens. We studied 32 outbred beagle puppies 80 to 155 days of age who were raised in isolation and who were specific pathogen-free. Puppies were inoculated with canine parainfluenza type 2 (CPI2, n = 8), Bordetella bronchiseptica (Bb, n = 7), or both CPI2 and Bb (CPI2-Bb, n = 9). Control puppies (C, n = 8) were not inoculated. The puppies were anesthetized with sodium thiopental (5 mg/kg) and chloralose (80 mg/kg) and were ventilated mechanically. Lung resistance (RL), dynamic lung compliance (Cdyn), functional residual capacity (FRC), and responsiveness to aerosolized histamine were measured 3 days prior to inoculation (Day -3), on the day of inoculation (Day 0), and on Days 3-4, 6, 8-10, and 12-14 after inoculation. Histamine responsiveness was measured as: (1) the concentration of histamine base that increased RL to 150% (PC 150% RL) or decreased Cdyn to 75% (PC 75% Cdyn) of the response to saline (RL sal and Cdyn sal, respectively), and (2) the change in RL or Cdyn after inhalation of 11 mg/ml of histamine when compared with RL sal and Cdyn sal. On Day 0 there were no significant (p greater than 0.05) differences among groups with regard to age-corrected weights, FRC, RL, Cdyn, or histamine responsiveness. Control puppies remained healthy, and their pulmonary function and histamine responsiveness did not change. CPI2-Bb puppies increased RL and decreased FRC on Day 3-4, and were moderately ill and histamine-hyperresponsive on Day 3-4 and on Day 6.(ABSTRACT TRUNCATED AT 250 WORDS)     

Bronchial hyperresponsiveness in patients with chronic congestive heart failure

To investigate the relationship between pulmonary congestion and bronchial responsiveness, we measured bronchial responsiveness to acetylcholine in 51 patients with left heart disorders. The measurement of bronchial responsiveness was performed by inhaling doses of acetylcholine chloride (0.08 to 20 mg/ml) and calculating the PC20-FEV1. The median value for PC20-FEV1 was above 20 mg/ml in the subjects without history of congestive heart failure (n = 18), was 5.29 mg/ml in the subjects with clinical evidence of congestive heart failure in the past days (n = 18; p less than 0.01), and was 5.74 mg/ml in the subjects with clinical evidence of congestive heart failure at the time of study (n = 15; p less than 0.01). The hemodynamic variables by cardiac catheterization and the clinical symptoms were not correlated with the grade of bronchial responsiveness. These results suggest that the bronchial responsiveness was increased in most of the patients with chronic congestive heart failure. We concluded that continuous pulmonary congestion may contribute to the pathogenesis of bronchial hyperresponsiveness.     

Airway responsiveness to intravenous and inhaled acetylcholine in the guinea pig after cigarette smoke exposure

Exposure of conscious guinea pigs to cigarette smoke results in bronchial hyperresponsiveness. To examine the mechanisms involved, we measured airway responses to increasing doses of intravenous or inhaled acetylcholine in guinea pigs exposed to cigarette smoke (n = 20) or to air (n = 20). After exposure the guinea pigs were anesthetized, paralyzed, and studied in a pressure-sensitive body plethysmograph while ventilated through a tracheostomy. Two and 6 puffs of an aerosol of increasing concentrations (0.05 to 500 micrograms/ml) of acetylcholine were delivered via the tracheostomy. Intravenous acetylcholine was delivered in boluses of 0.1 ml of increasing concentrations (0.5 to 50,000 micrograms/ml) via a catheter in an external jugular vein. Pulmonary resistance (RL), dynamic compliance (Cdyn), and heart rate (HR) were measured at baseline (after aerosolized or intravenous saline) and after each dose of acetylcholine. The peak responses to both inhaled and intravenous acetylcholine were rapid in onset (less than 15 s), short-lived (3 to 4 breaths), and were noncumulative. The baseline RL, Cdyn, and HR were not different in the smoke and air exposure groups. In the intravenous acetylcholine group, there were no differences in RL, Cdyn, and HR responses between the air and smoke exposure groups. In the inhaled acetylcholine group, the dose-response curve was shifted to the left (p less than 0.05) and reached a higher maximal response (p less than 0.01) after smoke exposure.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of leukotriene E on pulmonary mechanics in the guinea pig

The effects of intravenously infused 5(S)hydroxy-6(R)-S-cysteinyl-7,9,-trans,11,14,-cis eicosatetraenoic acid (leukotriene E) (LTE), one of the leukotriene constituents of slow-reacting substance of anaphylaxis (SRS-A), on pulmonary resistance (RL) and dynamic compliance (Cdyn), breathing frequency, and mean systemic arterial pressure were determined in both anesthetized and unanesthetized guinea pigs. The LTE caused a dose-dependent increase of RL and decrease in Cdyn over the range of doses from 100 to 10,000 ng/kg with significance effects at the highest doses. The onset of effect after a significant dose occurred within 30 s and was maximal 1 to 3 min after infusion. The LTE elicits a significantly greater effect on RL for a given change in Cdyn than occurs with LTC or LTD indicating that LTE is a less selective peripheral airway agonist than LTC or LTD. The LTD infusion resembled LTC or LTD in evoking a systemic arterial hypotension that was preceded by a brief initial period of hypertension in unanesthetized animals.     

Bronchial hyperresponsiveness to inhaled methacholine in subjects with chronic left heart failure at a time of exacerbation and after increasing diuretic therapy

Cough and wheezing are common findings in left heart failure. However, it is still questionable whether nonallergic bronchial hyperresponsiveness, the hallmark of asthma, is also associated with this condition. In 12 subjects with acute decompensation of chronic postischemic LV failure, we assessed the PC20 methacholine during an episode of acute LV failure and after five to 15 days of intensive diuretic therapy. Weight, arterial blood gases, plethysmographic lung volumes, and expiratory flows were also measured on both visits. Extravascular lung water was estimated indirectly with a radiologic score. During acute decompensation, six subjects had significant airway obstruction and eight had a PC20 less than or equal to 16 mg/ml (significant bronchial hyperresponsiveness). After diuretic therapy, subjects improved significantly, losing an average of 2.2 kg, but they still had chronic LV failure and evidence of an obstructive breathing defect. Although mean PC20 was unchanged, three subjects had significantly improved PC20 after treatment. We conclude that: (1) left ventricular failure is often associated with mild bronchial hyperresponsiveness, although it is not excluded that smoking and the resulting possibility of bronchial obstruction can also play some role; and (2) acute treatment does not generally alter bronchial responsiveness to methacholine, suggesting that chronic LV failure can cause chronic changes to the airways.     

The effect of a respiratory tract infection on histamine-induced changes in lung mechanics and irritant receptor discharge in dogs

The effects of intravenously administered histamine on total lung resistance (RL), dynamic lung compliance (Cdyn), and the discharge of lung irritant receptors have been measured in normal dogs and in dogs whose upper respiratory tract was naturally infected with the organism Bordetella bronchiseptica. The resting values for RL and irritant receptor discharge were similar for the infected and control dogs, but Cdyn was significantly lower in the infected group of dogs. Intravenous administration of 20 microgram of histamine/kg of body weight produced significantly greater direct and reflex changes in RL in the infected dogs than in the control animals. The changes in Cdyn in both groups of animals were similar. Intravenous administration of histamine (20 microgram/kg) produced a significantly greater increase in the rate of discharge of lung irritant receptors found in infected dogs than in control dogs. A possible mechanism responsible for the hyperreactivity to histamine is seen in the hypersensitivity of the irritant receptors introduced by the epithelial lesions observed in the infected dogs.     

Endogenous sensory neuropeptide release enhances nonspecific airway responsiveness in guinea pigs.

To test whether endogenous sensory neuropeptide release results in airway hyperresponsiveness to exogenous bronchoconstrictor stimuli, male Camm-Hartley guinea pigs were exposed either to capsaicin aerosol for 10 min (CAP-AER) or to saline aerosol (SAL-AER) as a control condition. The following day, animals were anesthetized, tracheostomized, and beta-adrenergically blocked with propranolol, and their bronchoconstrictor responses to intravenously administered acetylcholine (ACh), neurokinin A (NKA), or capsaicin were measured. The bronchoconstriction induced by isocapnic dry gas hyperpnea also was assessed. Compared with the SAL-AER control group, the CAP-AER-treated animals exhibited augmented bronchoconstrictor responses to ACh and NKA. In contrast, the SAL-AER and CAP-AER groups had equivalent bronchoconstrictor responses to dry gas hyperpnea and to intravenously administered capsaicin. CAP-AER treatment caused neutrophilic airway inflammation, as reflected in increased numbers of neutrophils in bronchoalveolar lavage fluid obtained from CAP-AER-treated animals. Ablation of airway c-fiber neuron function (by chronic pretreatment with capsaicin prior to capsaicin aerosol inhalation) eliminated the ACh hyperresponsiveness observed in the CAP-AER-treated animals, demonstrating that sensory nerve products play a key role in the development of this nonspecific hyperresponsiveness. Our results demonstrate that sensory nerve stimulation with capsaicin aerosol leads to nonspecific bronchoconstrictor hyperresponsiveness and cellular airway inflammation, and thus disclose another potentially important role of sensory nerves in regulating airway function.(ABSTRACT TRUNCATED AT 250 WORDS)     

Contribution of the vagal nerve on histamine-induced bronchoconstriction in guinea-pigs

Recently, it has been suggested that the peripheral vagal nerve might participate in the bronchoconstriction locally in addition to the concept of "vagal reflex". We investigated the contribution of the vagal nerve on the modulation of airway responses to histamine (8 micrograms/kg, iv) in anesthetized and mechanically ventilated guinea-pigs. Airway responses were assessed by measurement of pulmonary resistance (RL). To determine whether the vagal nerve mediates excitatory effects by "vagal reflex" in guinea-pigs, we investigated the effects of vagotomy or hexamethonium (2 mg/kg, iv). Increase in RL induced by histamine was significantly enhanced after the vagotomy or the treatment of hexamethonium. Histamine-induced bronchoconstriction was also enhanced by the vagotomy in the animals after the administration of propranolol (1 mg/kg, iv). To determine whether the peripheral vagal nerve may play any role in the vagotomized animals, we investigated the effect of atropine (1 mg/kg, iv). Atropine reduced histamine-induced bronchoconstriction significantly in the vagotomized guinea-pigs or in the animals treated with hexamethonium. We conclude that the vagal nerve mainly exerts on inhibitory role through the central nervous system, and that the peripheral vagal nerve distal to ganglion plays an excitatory effects by releasing acetylcholine from the terminals in histamine-induced bronchoconstriction in guinea-pigs.     

Treatment of massive hemoptysis by combined occlusion of pulmonary and bronchial arteries.

Massive, life-threatening hemoptysis occurred in a patient with left upper lobe bronchiectasis secondary to old tuberculosis. Selective left bronchial arteriography showed extravasation of contrast medium in the bronchiectatic area. A marked decrease in hemoptysis occurred after selective left bronchial arterial embolization. Complete cessation of bleeding followed the inflation of a Swan-Ganz balloon catheter that had been placed in the left main pulmonary artery.     

Mechanisms of late hemodynamic and airway dynamic responses to endotoxin in awake sheep

The mechanism of sustained alterations in pulmonary hemodynamics and lung mechanics after endotoxin infusion in sheep remains unclear. We examined the effects of metaproterenol, propranolol, atropine, and ibuprofen on pulmonary artery pressure (Ppa), dynamic compliance (Cdyn), resistance to airflow across the lungs (RL), specific airway conductance (SGaw), and alveolar-arterial oxygen difference (delta AaPO2) (room air) given 2.5 h after endotoxemia (except for propranolol, which was given 1 h after metaproterenol) in awake sheep. Atropine infusion had no effect on any of the variables measured. Ibuprofen infusion immediately reduced mean Ppa from 31 +/- 2 (mean +/- SEM) to 24 +/- 2 cm H2O (p less than 0.05). Metaproterenol and ibuprofen immediately increased Cdyn and SGaw and decreased RL to near baseline (p less than 0.05). No intervention affected delta AaPO2 (p greater than 0.05). In sheep treated with metaproterenol, propranolol immediately returned lung mechanics (p less than 0.05) to premetaproterenol levels without affecting delta AaPO2 (p greater than 0.05). Ibuprofen reduced lung lymph thromboxane-B2 towards baseline levels (p less than 0.05). We conclude that endotoxemia causes prolonged bronchoconstriction and pulmonary hypertension in sheep, which is largely mediated by constrictor prostanoids rather than by cholinergic mechanisms and is reversible with ibuprofen given 2.5 h after endotoxin.     

Studies of an antiendotoxin antibody in preventing the physiologic changes of endotoxemia in awake sheep

In sheep, endotoxin (LPS) causes pulmonary hypertension, hypoxemia, leukopenia, exudation of protein-rich lung lymph, reduced dynamic compliance (Cdyn), and increased resistance to airflow (RL), changes similar to those seen in human sepsis and sepsis-induced ARDS. We used well-described methods in the awake sheep-endotoxin model to evaluate the effectiveness of a commercially manufactured antibody to prevent the physiologic changes of endotoxemia. In awake sheep with chronic lung lymph fistulas, we used a whole-body plethysmograph to measure Cdyn, RL, and FRC. Pulmonary artery, left atrial, and systemic arterial pressures were recorded continuously. Arterial blood gases (for calculating AaPO2), leukocyte counts, and lymph samples were collected every 30 min. Animals received a 30-min (2 mg/kg) infusion of antiendotoxin antibody 4 h before LPS (0.75 micrograms/kg) challenge (n = 4), or were given a mixture of LPS (0.75 micrograms/kg) and antibody (2 mg/kg) that had been incubated in vitro at 37 degrees C for 30 min before infusion (n = 6). A control group given only 2 mg/kg of antibody (n = 4) showed no change in any measured parameter, whereas control animals receiving LPS alone (n = 6) exhibited a typical endotoxin response. In all animals receiving endotoxin, Cdyn declined by approximately 50% within 30 to 60 min, and RL increased approximately sixfold over a similar time course. Accompanying the abnormalities in lung mechanics were pulmonary hypertension, leukopenia, and widening of the AaPO2.(ABSTRACT TRUNCATED AT 250 WORDS)     

Variability of pulmonary responsiveness to aerosolized histamine in normal rabbits

Considerable between-subject variability in pulmonary responsiveness to histamine has been reported in normal human subjects, dogs, guinea pigs, and rhesus monkeys, but rabbits have not been studied. We determined the between- and within-rabbit variability of pulmonary histamine responsiveness in 34 anesthetized and mechanically ventilated New Zealand White rabbits. In 30 rabbits, 5 breaths of aerosolized histamine were delivered in 9 increasing concentrations ranging from 0.01 to 100 mg/ml. Eleven of 30 rabbits were rechallenged with histamine on 1-4 additional occasions over a 3-week period. In the remaining 4 rabbits, 9 doses of distilled H2O were aerosolized to determine the degree of spontaneous variability in measurements of lung resistance (RL) and dynamic lung compliance (Cdyn). We defined an increase in RL of greater than 50% of baseline (TD50RL) and a decrease in Cdyn of greater than 25% of baseline (TD25Cdyn) as being significant based on observations in these 4 rabbits. These limits exceeded the 99.9 percentile of spontaneous variability in RL and Cdyn. Pulmonary responsiveness to histamine varied widely, with a greater than 10,000-fold range in TD50RL and a 1,000-fold range in TD25Cdyn between the most and least sensitive rabbits. The variability of this responsiveness was log-normally distributed. It was not correlated with age, sex, or baseline RL and Cdyn. In contrast, within-rabbit responses to histamine challenge were quite reproducible. Five of 30 rabbits were killed at the conclusion of their histamine challenges for pathologic examination of their lungs. No evidence of airway inflammation was found.(ABSTRACT TRUNCATED AT 250 WORDS)     

Airway responsiveness in isolated perfused rat lungs: effect of thoracic irradiation

We developed techniques for assessing airway reactivity in isolated perfused rat lungs by measuring the lung mechanics changes produced by injection of ACh into the pulmonary circulation. Lung resistance (RL) and dynamic compliance (Cdyn) changed in a dose-response fashion after ACh. We used the preparation to examine the effect of thoracic irradiation on airway responsiveness and pulmonary inflammation. Groups of rats were studied after sham irradiation or 24 h or 72 h after a single dose of 1500 rads. Thoracic irradiation did not alter baseline lung mechanics, but did increase the responsiveness of rat lungs to ACh 72 h after radiation. Radiation was not associated with an increase in neutrophils in lung lavage, airways or peripheral lung tissue. We conclude that thoracic irradiation alters airways reactivity without causing overt pulmonary inflammation, and that isolated perfused lungs can be useful for measurement of airway reactivity.     

Airway responsiveness to acetylcholine or capsaicin in immature and mature guinea pigs in vivo

Non-specific airway hyperresponsiveness is a characteristic feature of bronchial asthma. Airway reactivity to cholinergics may change with age during childhood. The present paper describes tests to see if the airway responsiveness induced by acetylcholine (ACh) or capsaicin, which causes a release of endogenous tachykinins from the sensory nerve, changes with age in guinea pigs. Changes in lung resistance (RL) were measured to monitor airflow obstruction caused by intravenous ACh or capsaicin in anesthetized immature guinea pigs (aged 2 weeks), and to compare with those of adult guinea pigs (aged 11 weeks). It was shown that both ACh and capsaicin induced a rapid and dose-dependent increase in RL both in immature and adult animals. The two age groups had similar responsiveness to ACh or capsaicin in terms of potency or sensitivity. The response induced by capsaicin was not affected by atropine. In addition, capsaicin caused no extravasation of Evans Blue dye as an index of airway plasma exudation in both age groups. The airflow obstruction induced by i.v. capsaicin is mainly due to a cholinergic-unrelated smooth muscle contraction. These results suggest that airway smooth muscle responsiveness to cholinergics or capsaicin is comparable in both immature and adult guinea pigs in vivo.     

The role of sensory nerves in propranolol-induced bronchial hyperresponsiveness in the guinea-pig

The racemic mixture propranolol (RS-(+/-)-, and the S-(-)- and R-(+)-) isomers of propranolol have been shown to induce bronchial hyperresponsiveness in the guinea-pig unrelated to beta-adrenoreceptor occupancy, that is attenuated by vagal section and mediated via the generation of 5-lipoxygenase metabolites of arachidonic acid. We have investigated the role of sensory nerves in propranolol-induced bronchial hyperresponsiveness in guinea-pigs. Airways responsiveness to acetylcholine, bradykinin and bombesin was determined before and 10 min after intravenous infusion with RS-(+/-)-, S-(-)- and R-(+)-propranolol (1 mg/kg) in vehicle and capsaicin-treated guinea-pigs. Propranolol (1 mg/kg, iv) significantly augmented the bronchoconstrictor response to acetylcholine, bradykinin and bombesin (P<0.001), an effect that was observed for RS-(+/-)-, S-(-)- and R-(+)-propranolol. In capsaicin-treated animals, the increased airways responsiveness to acetylcholine following intravenous infusion of S-(-)-propranolol was significantly inhibited. Capsaicin treatment tended to reduce the increase in airways responsiveness to bradykinin following infusion with R-(+)-propranolol, but was only significant for the highest dose used. Similarly, capsaicin treatment had no effect on the ability of RS-(+/-)-, S-(-)- and R-(+)-propranolol to enhance the bronchoconstrictor response to bombesin. Our results suggest that propranolol-induced bronchial hyperresponsiveness to certain spasmogens is in part mediated by the action of capsaicin-sensitive nerves.     

Physiological responses of the airway wall and lung in hyperresponsive pigs.

Airway hyperresponsiveness (AHR) might be driven by mechanisms inherent to the airway wall, and/or by factors arising from outside the airways. A porcine model of allergen-induced AHR was utilized to investigate physiological responses in intact airways in vitro and their contribution to responsiveness in vivo. Responsiveness to acetylcholine (ACh) was measured in eight ovalbumin (OA)-sensitized/challenged pigs (tests) and eight saline-challenged controls. In vivo responsiveness to ACh was determined from pulmonary resistance (RL). In vitro responsiveness to ACh was determined from airway pressure in isovolumic bronchial segments, after exposure via the adventitial or the luminal surface. Test pigs had lung (255+/-26% increase in RL, p<0.0001) and skin responses to OA, and AHR to ACh (p<0.0001). In vitro, test bronchi were less sensitive than controls to ACh applied to the airway adventitia (negative log of the ACh concentration producing half the maximum response (pD2)=4.18 and 4.58 respectively, p<0.01), but not the lumen. Test bronchi had an increased amount of smooth muscle normalized for airway size versus controls (p<0.05). Maximum responses to lumenal ACh in vitro showed a weak positive correlation with maximum changes to ACh in vivo (r=0.599, p=0.05). This study concludes that the effect of antigen challenge on bronchial responsiveness varies with the route of exposure to acetylcholine. In vitro responses to lumenal acetylcholine are increased despite a possible reduction in responsiveness of airway smooth muscle. Responsiveness of the bronchial wall only partially explains responsiveness of the lungs in vivo.