Bronchoconstriction In Humans Research Articles

Smooth muscle in the maintenance of increased airway resistance elicited by methacholine in humans.

Airway narrowing is maintained for a prolonged period after acute bronchoconstriction in humans in the absence of deep inspirations (DIs). To determine whether maintenance of airway smooth muscle (ASM) shortening is responsible for the persistence of airway narrowing in healthy subjects following transient methacholine (MCh)-induced bronchoconstriction. On two separate visits, five healthy subjects underwent MCh challenges until respiratory system resistance (Rrs) had increased by approximately 1.5 cm H2O/L/s. Subjects took a DI either immediately after or 30 minutes after the last dose. The extent of renarrowing following the bronchodilator effect of DI was used to assess the continued action of MCh (calculated as percent change in Rrs from the pre-DI Rrs). We then used human bronchial rings to determine whether ASM can maintain shortening during a progressive decrease of carbachol concentration. The increased Rrs induced by MCh was maintained for 30 minutes despite waning of MCh concentration over that period, measured as attenuated renarrowing when the DI was taken 30 minutes after compared with immediately after the last dose (7 min post-DI, -36.2 ± 11.8 vs. 14.4 ± 13.2%; 12 min post-DI, -39.5 ± 9.8 vs. 15.2 ± 17.8%). Ex vivo, ASM shortening was largely maintained during a progressive decrease of carbachol concentration, even down to concentrations that would not be expected to induce shortening. The maintenance of airway narrowing despite MCh clearance in humans is attributed to an intrinsic ability of ASM to maintain shortening during a progressive decrease of contractile stimulation.

Suppression of the cough reflex byα2-adrenergic receptor agonists in the rabbit

The α2-adrenergic receptor agonist clonidine has been shown to inhibit citric acid-induced cough responses in guinea pigs when administered by aerosol, but not orally. In contrast, oral or inhaled clonidine had no effect on capsaicin-induced cough and reflex bronchoconstriction in humans. In addition, intravenous administration of clonidine has been shown to depress fentanyl-induced cough in humans. We investigated the effects of the α2-adrenergic receptor agonists, clonidine and tizanidine, on cough responses induced by mechanical and chemical (citric acid) stimulation of the tracheobronchial tree. Drugs were microinjected (30–50 nL) into the caudal nucleus tractus solitarii (cNTS) and the caudal ventral respiratory group (cVRG) as well as administered intravenously in pentobarbital sodium-anesthetized, spontaneously breathing rabbits. Bilateral microinjections of clonidine into the cNTS or the cVRG reduced cough responses at 0.5 mmol/L and abolished the cough reflex at 5 mmol/L. Bilateral microinjections of 0.5 mmol/L tizanidine into the cNTS completely suppressed cough responses, whereas bilateral microinjections of 5 mmol/L into the cVRG only caused mild reductions in them. Depressant effects on the cough reflex of clonidine and tizanidine were completely reverted by microinjections of 10 mmol/L yohimbine. Intravenous administration of clonidine (80–120 μg/kg) or tizanidine (150–300 μg/kg) strongly reduced or completely suppressed cough responses. These effects were reverted by intravenous administration of yohimbine (300 μg/kg). The results demonstrate that activation of α2-adrenergic receptors in the rabbit exerts potent inhibitory effects on the central mechanism generating the cough motor pattern with a clear action at the level of the cNTS and the cVRG.

GPR17 Regulates Immune Pulmonary Inflammation Induced by House Dust Mites

Antagonists of the type 1 cysteinyl leukotriene receptor (CysLT(1)R) are efficacious for bronchoconstriction in humans with bronchial asthma; however, the clinical response to these drugs is heterogeneous. In particular, how CysLT(1)R expression and function are constitutively regulated in vivo is not known. In this study, we show that a seven-transmembrane receptor, GPR17, negatively regulates the CysLT(1)R-mediated inflammatory cell accumulation in the bronchoalveolar lavage fluid and lung, the levels of IgE and specific IgG1 in serum, and Th2/Th17 cytokine expression in the lung after intranasal sensitization and challenge with the house dust mite (extract of Dermatophagoides farinae [Df]) in mice. Sensitization of naive wild-type recipients with Df-pulsed bone marrow-derived dendritic cells of each genotype or sensitization of each genotype with Df-pulsed wild-type bone marrow-derived dendritic cells and Df challenge revealed markedly increased pulmonary inflammatory and serum IgE responses for GPR17-deficient mice as compared with wild-type mice and reduced responses in the genotypes lacking CysLT(1)R. These findings reveal a constitutive negative regulation of CysLT(1)R functions by GPR17 in both the Ag presentation and downstream phases of allergic pulmonary inflammation.

Wasabi and a Volatile Anesthetic

Wasabi and a Volatile Anesthetic

Marcos F. Vidal Melo, M.D., Ph.D., Recipient of the 2007 Presidential Scholar Award

Marcos F. Vidal Melo, M.D., Ph.D., Recipient of the 2007 Presidential Scholar Award

Is the upregulation of bradykinin B2 receptors by TGF-β1 one of the missing pieces in the “airway hyperresponsiveness” puzzle?

transforming growth factor (TGF)-β1 belongs to the TGF-β family of proteins corresponding to a set of pleiotropic secreted signaling molecules with unique and potent immunoregulatory properties ([10][1]). TGF-β1 is produced by every leukocyte lineage, including lymphocytes, macrophages, and

Intravenous nicorandil prevents thiamylal-fentanyl–induced bronchoconstriction in humans*

Nicorandil has a hybrid property between nitrates and potassium channel openers and has been reported to cause a concentration-dependent relaxation of isolated guinea pig trachealis. Experimental asthma in a guinea pig model was also inhibited by nicorandil. However, no clinical data on the bronchorelaxant effects of this drug have been published. The aim of this study was to investigate whether intravenous nicorandil prevents thiamylal-fentanyl-induced bronchoconstriction. Double-blind, prospective, placebo-controlled, randomized study. A total of 36 patients were randomly allocated to two groups: a control group (n = 18) and a nicorandil group (n = 18). Intravenous administration of nicorandil or a placebo (normal saline). Anesthesia was induced with 5 mg/kg thiamylal and 0.3 mg/kg vecuronium. A continuous infusion of 15 mg x kg(-1) x hr(-1) thiamylal was then used to maintain the anesthesia. Controlled ventilation was maintained, delivering 50% nitrous oxide in oxygen. At 20 mins after the induction of anesthesia, the control group patients were given a 6 mL/hr continuous infusion of normal saline and the nicorandil group patients were given a 6 mg x hr(-1) (6 mL/hr) continuous infusion of nicorandil for 60 mins. At 30 mins after the start of the study, both groups received a 5-microg/kg dose of fentanyl. Systolic and diastolic arterial pressure, heart rate, mean airway resistance, expiratory airway resistance, and dynamic lung compliance were measured for the baseline condition, just before the administration of fentanyl (T30), at three consecutive 6-min intervals after the fentanyl injection (T36, T42, and T48) and 30 mins after the fentanyl injection (T60). Both groups had comparable baseline values for mean airway resistance, expiratory airway resistance, and dynamic lung compliance. In the control group, both mean airway resistance and expiratory airway resistance increased significantly at T36-60, compared with the baseline values, and dynamic lung compliance decreased significantly at T36-60, compared with the baseline value. In the nicorandil group, no changes in mean airway resistance, expiratory airway resistance, or dynamic lung compliance occurred at T36-60. Our observations suggest that the intravenous administration of nicorandil has a bronchodilator effect in humans.

Heparin inhibits hyperventilation-induced late-phase hyperreactivity in dogs.

Inhalation of heparin attenuates hyperventilation-induced bronchoconstriction in humans and dogs. The purpose of this study was to determine whether heparin inhibits the late-phase response to hyperventilation, which is characterized by increased peripheral airway resistance (RP), eicosanoid mediator production, neutrophilic/ eosinophilic inflammation, and airway hyperreactivity (AHR) at 5 h after dry air challenge (DAC). Fiberoptic bronchoscopy was used to record RP and airway reactivity (DeltaRP) to aerosol and intravenous histamine before and 5 h after DAC. Bronchoalveolar lavage fluid (BALF) cells and eicosanoid mediators were also measured approximately 5 h after DAC. DAC of vehicle-treated bronchi resulted in late-phase airway obstruction (approximately 120% increase over baseline RP), inflammation, increased BALF concentrations of leukotriene (LT) C(4), LTD(4), and LTE(4) and prostaglandin (PG)D(2), and AHR. Pretreatment with aerosolized heparin attenuated late-phase airway obstruction by approximately 50%, inhibited eosinophil infiltration, reduced BALF concentrations of LTC(4), LTD(4), and LTE(4) and PGD(2), and abolished AHR. We conclude that heparin inhibits hyperventilation-induced late-phase changes in peripheral airway function, and does so in part via the inhibition of eosinophil migration and eicosanoid mediator production and release.

Total and respirable airborne dust endotoxin concentrations in three equine management systems.

The concentrations of total and respirable airborne endotoxin in the breathing zone of a pony in 3 different management systems, on 8 occasions, are reported. Airborne endotoxin concentrations in all 3 systems were lower than those reported for many other agricultural environments. However, total airborne endotoxin concentrations in many of the conventional stables exceeded those which can induce pulmonary inflammation and bronchial hyper-responsiveness in normal human subjects, and exceeded those which can induce bronchoconstriction in humans with pre-existing pulmonary inflammation. Therefore, airborne endotoxin may contribute to the development of airway inflammation and dysfunction in conventionally stabled horses. Potentially detrimental effects of airborne endotoxins on the welfare and exercise performance of stabled horses can be reduced by maintaining horses in 'low dust' stables or at pasture, since these environments had significantly lower airborne dust and endotoxin concentrations.

Hypoxia, hypocapnia and spirometry at altitude.

1. Both hypoxia and hypocapnia can cause broncho-constriction in humans, and this could have a bearing on performance at high altitude or contribute to altitude sickness. We studied the relationship between spirometry, arterial oxygen saturation and end-tidal carbon dioxide (ETCO2) concentration in a group of healthy lowland adults during a stay at high altitude, and then evaluated the response to supplementary oxygen and administration of a beta 2 agonist. 2. We collected spirometric data from 51 members of the 1994 British Mount Everest Medical Expedition at sea level (barometric pressure 101.2-101.6 kPa) and at Mount Everest Base Camp in Nepal (altitude 5300 m, barometric pressure 53-54.7 kPa) using a pocket turbine spirometer. A total of 205 spirometric measurements were made on the 51 subjects during the first 6 days after arrival at Base Camp. Further measurements were made before and after inhalation of oxygen (n = 47) or a beta 2 agonist (n = 39). ETCO2 tensions were measured on the same day as spirometric measurements in 30 of these subjects. 3. In the first 6 days after arrival at 5300 m, lower oxygen saturations were associated with lower forced expiratory volume in 1 s (FEV1; P < 0.02) and forced vital capacity (FVC; P < 0.01), but not with peak expiratory flow (PEF). Administration of supplementary oxygen for 5 min increased oxygen saturation from a mean of 81%-94%, but there was no significant change in FEV1 or FVC, whilst PEF fell by 2.3% [P < 0.001; 95% confidence intervals (CI) -4 to -0.7%]. After salbutamol administration, there was no significant change in PEF, FEV1 or FVC in 35 non-asthmatic subjects. Mean ETCO2 at Everest Base Camp was 26 mmHg, and a low ETCO2 was weakly associated with a larger drop in FVC at altitude compared with sea level (r = 0.38, P < 0.05). There was no correlation between either ETCO2 or oxygen saturation and changes in FEV1 or PEF compared with sea-level values. 4. In this study, in normal subjects who were acclimatized to hypobaric hypoxia at an altitude of 5300 m, we found no evidence of hypoxic broncho-constriction. Individuals did not have lower PEF when they were more hypoxic, and neither PEF nor FEV1 were increased by either supplementary oxygen or salbutamol. FVC fell at altitude, and there was a greater fall in FVC for subjects with lower oxygen saturations and probably lower ETCO2.

Neuroeffector mechanisms: The interface between inflammation and neuronal responses

There is a complex relation between inflammation and neural control of the airways. Cholinergic neurotransmission may be enhanced by inflammatory mediators; cholinergic nerves are the dominant neural pathway for bronchoconstriction in humans. Anticholinergic drugs are more effective in acute severe asthma than in chronic asthma, suggesting that cholinergic mechanisms may be important in exacerbations. Several possible abnormalities in adrenergic control in asthma have been proposed and may be caused by the inflammatory process. Adrenergic nerves do not have direct control of airway smooth muscle but may influence bronchomotor tone in several ways, such as adrenergic neural control of the bronchial vasculature or a secondary effect on cholinergic neurotransmission. Nonadrenergic noncholinergic (NANC) mechanisms mediate both bronchoconstriction and bronchodilation, and a defect in NANC bronchodilatation has been suggested to operate in severe asthma. Relatively little is known about the properties of airway sensory (afferent) nerves in human beings. They are thought to be involved in symptoms of cough and chest tightness, and the threshold for their activation is lowered in conditions of chronic inflammation. In addition, retrograde activation of sensory nerves by a local axon reflex, resulting in the release of peptides, may contribute to inflammation of the airways. Neurogenic inflammation is probably not relevant to mild asthma, however, but it may be more important in severe disease such as brittle asthma. (J A LLERGY C LIN I MMUNOL 1996;98:S73-83.)

Maximal bronchoconstriction in humans. Relationship to deep inhalation and airway sensitivity.

We hypothesized that maximal bronchoconstriction can be predicted from the bronchomoter effect of deep inhalation (DI) and the degree of airway sensitivity to methacholine (MCh). We studied 26 healthy or mildly asthmatic subjects with limited response to MCh (maximal FEV1 decrease, 23 +/- 9 SD%; Group 1) and 26 subjects with moderate to severe asthma with exaggerated response (maximal FEV1 decrease > 40%, Group 2). The effect of DI was quantified as the linear regression coefficient of the percent decrements of maximal (Vm50) versus partial (Vp50) forced expiratory flow at 50% of FVC over the initial steps of challenge (MP slope). Airway sensitivity was inferred from the MCh doses (PDs) causing Vm50 or Vp50 to decrease by 40% or FEV1 by 15%. The absence of limit to bronchonstriction was predicted by either MP slope or any PD with accuracies between 71 and 81%, but with an accuracy of 87% by a discriminant function including MP slope and PD40Vp50. Within Group 1, the maximal FEV1 decrease correlated linearly with MP slope (r2 = 0.41); but it was better predicted by a multiple regression including MP slope and PD40Vp50 (In mg) (r2 = 0.54). We conclude that the magnitude of the bronchodilator effect of DI during induced bronchoconstriction and airway sensitivity predict the level of maximal bronchoconstriction in vivo. We speculate that these parameters reflect some of the mechanisms modulating the response to bronchoconstrictor stimuli such as airway wall structure, airway-to-parenchymal interdependence, and contractile properties of airway smooth muscle.

Prevention of bronchoconstriction by an orally active local anesthetic.

Stimulation of airway irritant receptors produces reflex bronchoconstriction that can be prevented by pretreatment with anticholinergic drugs or local anesthetics delivered by aerosol or intravenously. We compared therapeutic doses of an orally administered local anesthetic, mexiletine hydrochloride, and intravenously administered lidocaine at blocking histamine-induced bronchoconstriction in five basenji-greyhound dogs, using high-resolution computed tomography (HRCT) to directly measure changes in airway size. In the dogs given placebo, a histamine infusion decreased airway area to 61 +/- 2% (mean +/- SEM) of control (p < 0.01). Mexiletine pretreatment completely prevented histamine-induced airway constriction, with an airway area that was 94 +/- 4% of the control value during the histamine infusion (p = 0.07 compared with baseline). Mexiletine serum levels were therapeutic (1.7 +/- 0.3 mg/L). Similarly, pretreatment with lidocaine significantly blunted the airway constriction provoked by intravenous histamine. In lidocaine-pretreated dogs, histamine decreased airway area to 79 +/- 4% of baseline (p < 0.01). As in the case of mexiletine, lidocaine serum levels were also therapeutic (2.4 +/- 0.3 mg/L). Mexiletine was more effective than lidocaine at preventing histamine-induced bronchoconstriction (p = 0.02). These data suggest that orally administered local anesthetics may be useful in preventing irritant-induced bronchoconstriction in humans.

Stimulation of guinea-pig tracheal afferent fibres by non-isosmotic and low-chloride stimuli and the effect of frusemide.

1. Inhalation of low-chloride or non-isosmotic solutions evokes cough or reflex bronchoconstriction in humans that is inhibited by frusemide (furosemide), whilst capsaicin-evoked cough is unaffected. Here we have examined the responses of single vagal afferent fibres innervating the isolated guinea-pig trachea to these stimuli, and tested the effect of frusemide on fibre responses. 2. Both distilled water and hypertonic saline applied for 30 s onto identified receptive fields produced marked excitation of all A delta and C fibres tested. Isotonic glucose, a low-chloride solution, was a less potent stimulant and caused excitation in 37% of A delta fibres and 69% of C fibres. There was no difference in the distribution of low-chloride sensitive and insensitive receptive fields. 3. In the presence of frusemide, responses of A delta fibres to isotonic glucose were significantly inhibited to 34.2 +/- 6.2% of the pre-drug control level. However, frusemide was without effect either on responses of A delta fibres to distilled water or hypertonic saline, or on responses of C fibres to capsaicin. 4. These data support a role for tracheo-bronchial A delta and C fibres in airway reflexes evoked by hypotonic, hypertonic and low-chloride stimuli. The protective effect of frusemide against airway responses to low-chloride but not to non-isosmotic solutions may reflect an action on sensory nerve endings.

Effect of clonidine on induced cough and bronchoconstriction in guinea pigs and healthy humans

We examined the effects of the alpha 2-receptor agonist clonidine, administered orally and by inhalation, on citric acid- and capsaicin-induced reflexes in guinea pigs and healthy human subjects. In groups (n = 8-10) of conscious guinea pigs, oral clonidine (10 and 100 micrograms/kg) was without effects, whereas inhaled clonidine (10-1,000 microM) caused a concentration-dependent inhibition of citric acid-induced cough (coughs during 3 min: control, 6.5 +/- 0.9; 1,000 microM clonidine, 1.7 +/- 1.0; P < 0.05) and reflex bronchoconstriction (time to onset of bronchoconstriction: control, 191 +/- 24 s; 1,000 microM clonidine, 317 +/- 33 s; P < 0.05). The inhibitory effect of inhaled clonidine on both reflexes was completely reversed by pretreatment with yohimbine but not with prazosin. In 12 healthy human volunteers, oral clonidine (150 mg) caused a significant fall in supine and erect systolic blood pressure and a significant increase in drowsiness as measured on a visual analogue scale 1 and 2 h after administration. Despite these effects, oral clonidine had no effect on capsaicin-induced cough or reflex bronchoconstriction in humans. In contrast to the effects in guinea pigs, inhaled clonidine (281 microM) had no effect on capsaicin-induced cough or reflex bronchoconstriction in humans. These data suggest that peripheral alpha 2-receptors exert an inhibitory effect on sensory neurotransmission in the guinea pig but not in the healthy human airway, indicating an important difference between the two species.

Histamine N‐methyltransferase Modulates Human Bronchial Smooth Muscle Contraction

To elucidate the modulatory role of histamine-degrading enzymes in airway constrictor responses, human bronchial strips were studied under isometric conditions in vitro. Pretreatment of tissues with the histamine N-methyltransferase (HMT) inhibitor SKF 91488 specifically potentiated the contractile responses to histamine, causing a leftward displacement of the concentration response curves, whereas the diamine oxidase inhibitor aminoguanidine had no effect. This potentiation was attenuated by mechanical removal of the epithelium. The HMT activity was detected in the human bronchi, which was less in the epithelium-denuded tissues than the epithelium-intact tissues. These results suggest that HMT localized to the airway epithelium may play a protective role against histamine-mediated bronchoconstriction in humans.

Effect of cetirizine, a potent H1 antagonist, on platelet activating factor induced bronchoconstriction in asthma

Effect of cetirizine, a potent and specific H1 receptor antagonist, was examined on platelet activating factor-induced bronchoconstriction in 10 patients (5 male, mean [s.e.m.] aged 37.4 [3.6] years) with mild asthma in a placebo controlled, double-blind cross-over study. Airway responses were assessed by measuring specific airway conductance (SGaw). Patients were challenged with a single dose (12-96 micrograms) of PAF that had previously produced a 35% fall in SGaw. PAF challenges were performed after single dose (15 mg) and 1 week's treatment (15 mg twice daily) of cetirizine. There was no significant difference in pre- and post-treatment baseline values of SGaw on different study days and the percentage changes after cetirizine were 38.7 (7.01) and 45.6 (5.52) compared to 50.2 (2.89) and 43.9 (7.26) with placebo respectively. Similarly mean (s.e.m.) area under curve (AUC-SGaw/time course response) was 391 (143) and 514 (85) with cetirizine compared to 565 (37) and 461 (94) with placebo respectively. The difference was not statistically significant. There was no difference in facial flushing and feeling of warmth between cetirizine and placebo. We conclude that PAF induced bronchoconstriction in humans is not mediated by histamine release and that H1 receptor antagonists do not modify PAF induced bronchoconstriction.

Pharmacology of Furosemide in the Horse: A Review

Furosemide, a diuretic, is frequently administered to horses for the prophylaxis of exercise-induced pulmonary hemorrhage and the treatment of a number of clinical conditions, including acute renal failure and congestive heart failure. Furosemide increases the rate of urinary sodium, chloride, and hydrogen ion excretion. Plasma potassium concentration decreases after furosemide administration but urinary potassium excretion in horses is minimally affected. Renal blood flow increases after furosemide administration. Systemically, furosemide increases venous compliance and decreases right atrial pressure, pulmonary artery pressure, pulmonary artery wedge pressure, and pulmonary blood volume. The systemic hemodynamic effects of furosemide are only manifest in the presence of a functional kidney, but can occur in the absence of diuresis, emphasizing the importance of the renal-dependent extra-renal effects of furosemide. The renal and systemic hemodynamic effects of furosemide are modified by prior administration of nonsteroidal anti-inflammatory drugs. Furosemide administration attenuates exercise-induced increases in right atrial, aortic, and pulmonary artery pressures in ponies. Furosemide prevents exercise and allergen-induced bronchoconstriction in humans and decreases total pulmonary resistance in ponies with recurrent obstructive airway disease. These pharmacologic effects are frequently used to rationalize its questionable efficacy in the prevention of exercise-induced pulmonary hemorrhage. Neither the effect of furosemide on athletic performance nor its efficacy in the prevention of exercise-induced pulmonary hemorrhage has been convincingly demonstrated.

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.

The Role of Pirenzepine-sensitive (M1) Muscarinic Receptors in Vagally Mediated Bronchoconstriction in Humans

In a double-blind randomized study, we compared the effects of the M1-selective muscarinic receptor antagonists pirenzepine and the nonselective antagonist ipratropium bromide on bronchoconstriction induced by inhaled sulfur dioxide (SO2) and methacholine in atopic volunteers. Both inhaled pirenzepine (70 micrograms) and ipratropium bromide (7 micrograms) significantly inhibited vagally mediated bronchoconstriction by SO2 to the same extent (p less than 0.02). However, at this dose, pirenzepine had no effect on methacholine-induced bronchoconstriction, whereas ipratropium bromide gave significant protection (p less than 0.02). This indicates that vagally mediated bronchoconstriction in humans can be inhibited by blockade of pirenzepine-sensitive (M1) muscarinic receptors probably present on a different site from muscarinic receptors at the neuromuscular junction and presumably localized to parasympathetic ganglia. Pirenzepine may be useful in investigating ganglionic function and could be beneficial therapeutically in airway disease.