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Biomedical subjects

J M Drazen

Publications and source records attributed to J M Drazen.

At least 163 records · Page 9Linked to original sources
PubMed1993

The effect of inhibition of 5-lipoxygenase by zileuton in mild-to-moderate asthma.

OBJECTIVE: To evaluate the effectiveness of inhibiting the formation of the 5-lipoxygenase products of arachidonic acid by the 5-lipoxygenase inhibitor zileuton in the treatment of mild-to-moderate asthma. DESIGN: Randomized, double-blind, placebo-controlled study. SETTING: University hospitals and private allergy and pulmonary practices. PATIENTS: A total of 139 persons with asthma who had a forced expiratory volume in 1 second (FEV1) of 40% to 75% of the predicted value and who were not being treated with inhaled or oral steroids. INTERVENTION: Zileuton, 2.4 g/d or 1.6 g/d, or placebo for 4 weeks. MEASUREMENTS: Airway function, beta-agonist use, and symptoms; inhibition of 5-lipoxygenase assessed by measurement of urinary leukotriene E4 (LTE4). RESULTS: Zileuton produced a 0.35-L (95% CI, 0.25 to 0.45 L) increase in the FEV1 within 1 hour of administration (P < 0.001 compared with placebo), equivalent to a 14.6% increase from baseline. After 4 weeks of zileuton therapy, airway function and symptoms improved, with the greatest improvements occurring in the 2.4 g/d group: This group's FEV1 increased by 0.32 L (CI, 0.16 to 0.48 L), a 13.4% increase, compared with a 0.05-L (CI, -0.10 to 0.20 L) increase in patients taking placebo (P = 0.02). Symptoms and frequency of beta-agonist use also decreased with zileuton, 2.4 g/d. The mean urinary LTE4 level decreased by 39.2 pg/mg creatinine (CI, 18.1 to 60.4 pg/mg creatinine) and 26.5 pg/mg creatinine (CI, 6.6 to 46.5 pg/mg creatinine) in the 2.4 g/d and 1.6 g/d groups, respectively, compared with a slight increase in the placebo group (P = 0.007 and P = 0.05). No difference was noted in the number of adverse events among treatment groups. CONCLUSIONS: Inhibition of 5-lipoxygenase can improve airway function and decrease symptoms and medication use in patients with asthma, suggesting that this inhibition can be useful therapy for asthma. Also, 5-lipoxygenase products may mediate part of the baseline airway obstruction in patients with mild-to-moderate asthma.

Adult↗
PubMed1993

Human lung expresses unique gamma-glutamyl transpeptidase transcripts.

gamma-Glutamyl transpeptidase (EC 2.3.2.2, gamma GT) is a membrane-bound ectoenzyme that plays an important role in the metabolism of glutathione. It is composed of two subunits, both of which are encoded by a common mRNA. We examined the expression of gamma GT in human lung tissue by Northern blot analysis and screening a cDNA library made from human lung poly(A)+ RNA. Our results show that there are two gamma GT mRNA populations in human lung tissue. We define these as group I (2.4 kb) and group II (approximately 1.2 kb) transcripts. In the present communication, we characterize the unique lung transcript. Sequence analysis of representative clones shows that group I transcripts are virtually identical to those previously isolated from liver and placenta but possess a unique 5' untranslated region. In marked contrast, group II transcripts appear to be human-lung-specific. Group II transcripts appear on Northern blots probed with full-length or 3'-biased gamma GT cDNA. Sequence analysis of group II clones shows them to be homologous with group I clones in the region that encodes the reading frame for the light chain; however, they possess a series of unique 5' untranslated regions, which suggests that they arise from lung-specific message processing. Additionally, approximately 50% of the isolated group II clones contain 34 nt substitutions compared with the "wild-type" gamma GT transcripts. These data indicate that human lung expresses unique gamma GT transcripts of unknown function as well as the classical form. The abundant group II transcripts may encode part of a heterodimer related to gamma GT or represent processed lung-specific pseudogenes.

Amino Acid Sequence↗
PubMed1993

Mast cells contribute to the changes in heart rate, but not hypotension or death, associated with active anaphylaxis in mice.

The mast cell is widely thought to contribute importantly to the cardiopulmonary changes associated with anaphylaxis, but much of the evidence for this is indirect. We, therefore, performed a detailed assessment of heart rate and pulmonary function during active anaphylaxis in genetically mast cell-deficient W/Wv or S1/S1d mice, the congenic normal (+/+) mice, and W/Wv mice repaired of their mast cell deficiency by transplantation of bone marrow from the congenic +/+ mice (+/+ BM-->W/Wv mice). For all five groups of mice, Ag challenge resulted in the death of more than two-thirds of the sensitized animals, whereas none of the nonsensitized control mice died as a result of Ag infusion. Sensitized normal (WBB6F1(-)+/+ or WCB6F1(-)+/+) mice and +/+BM-->W/Wv mice developed increases in heart rate that were significantly greater than those of nonsensitized +/+ mice or those of sensitized mast cell-deficient mice, indicating that mast cells contribute to the tachycardia observed in this form of active anaphylaxis. By contrast, even though some of the pulmonary changes associated with active anaphylaxis were more severe in +/+ than in mast cell-deficient mice, it was not clear to what extent this difference was mast cell dependent. W/Wv mice undergoing active anaphylaxis developed decreases in systemic arterial blood pressure that occurred more rapidly and were more severe than those observed in the congenic +/+ mice, indicating that the hypotension associated with this model of anaphylaxis also can occur by mast cell-independent mechanisms. We conclude that in this model of anaphylaxis mast cells: 1) are required for the development of the tachycardia response; 2) may contribute to, but are not essential for, production of decreases in lung function; and 3) are not necessary for the development of hypotension or death.

Age Factors↗
PubMed1993

Bronchoconstrictor activities of NP gamma and NPK in anaesthetized guinea-pigs: effect on NEP inhibition.

The effects of rapid intravenous infusions of gamma-preprotachykinin-(72-92)-peptide amide (neuropeptide gamma) or beta-preprotachykinin-(72-107)-peptide amide (neuropeptide K), two N-terminally extended forms of neurokinin A (NKA), on pulmonary mechanics were examined in anaesthetized mechanically ventilated guinea-pigs. Neuropeptide gamma (NP gamma) and neuropeptide K (NPK) each caused dose-related decreases in pulmonary conductance (GL). The rank order of potency as bronchoconstrictors for the three peptides was NPK > NP gamma > NKA. Pretreatment of guinea-pigs with the neutral endopeptidase (NEP) inhibitor SCH32615 (1 mg/kg iv) decreased the doses of NP gamma and NKA required to cause a 50% decrease in GL by 3.8- and 4.9-fold respectively, but did not significantly alter NPK-induced bronchoconstriction. In animals without SCH32615, the time course of bronchoconstriction was similar for NKA and NP gamma, but NPK caused significantly more prolonged changes in GL. SCH32615 did not alter the time course of bronchoconstriction induced by NKA or NPK, but prolonged the changes in GL induced by NP gamma. The results indicate that post-translational processing of gamma- and beta-preprotachykinin mRNAs to yield NP gamma and NPK instead of NKA results in an enhanced duration of effect and an increase in bronchoconstrictor potency.

Amino Acid Sequence↗
PubMed1993

Pulmonary mechanical responses to intravenously administered capsaicin in guinea-pigs: effect of peptidase inhibitors.

In order to examine the role of peptidases in modulating bronchoconstrictor responses to i.v. administered capsaicin, a potent C-fiber stimulant, we measured changes in pulmonary conductance (GL) and dynamic compliance (Cdyn) in anesthetized mechanically ventilated guinea-pigs. Control guinea-pigs, and guinea-pigs treated with the neutral endopeptidase (NEP) inhibitors thiorphan (1.7 mg/kg) or SCH32615 (1 mg/kg), the angiotensin converting enzyme (ACE) inhibitor captopril (5.7 mg/kg), or combinations of NEP and ACE inhibitors, were given increasing doses of capsaicin by rapid i.v. injection. The doses of capsaicin required to cause a 50% decrease in GL and Cdyn (ED50GL and ED50Cdyn respectively) were computed for each animal. None of the peptidase inhibitors, when given alone, had any effect on the changes in pulmonary mechanics induced by capsaicin. However, combined administration of thiorphan and captopril, or SCH32615 and captopril, caused a decrease in ED50Cdyn for capsaicin, and prolonged the time during which the peak changes in GL induced by capsaicin persisted. These data support the hypothesis that substances whose degradation is inhibited by combined NEP and ACE inhibitors contribute to the bronchoconstriction induced by iv administered capsaicin. This profile of enzymatic degradation is consistent with the tachykinin, substance P.

Airway Resistance↗
PubMed1993

Agonist-induced lipoxin A4 generation: detection by a novel lipoxin A4-ELISA.

Lipoxin A4 (LXA4) possesses potent bioactions. To facilitate its detection, an enzyme-linked immunosorbent assay (ELISA) was developed that proved sensitive and selective. Quantitation by ELISA of LXA4 generated from cellular sources strongly correlated (r = 0.99) with values obtained by high-pressure liquid chromatography (HPLC). We used this LXA4-ELISA to examine parameters influencing LXA4 generation from endogenous substrates during human platelet-neutrophil (PLT-PMN) interactions in vitro. Agonist-induced LXA4 production was clearly evident at a PLT-PMN ratio of 10:1, and recombinant human granulocyte/monocyte colony stimulating factor-priming of PMN augmented LXA4 generation 5-6 fold. The chemotactic peptide formylmethionyl-leucyl-phenylalanine, platelet-derived growth factor and arachidonic acid (20:4n-6) each stimulated formation of immunoreactive LXA4 (iLXA4) in these co-incubations. The presence of iLXA4 was also evaluated in vivo in aspirin-sensitive asthmatic patients who, in a randomized, double-blind crossover design, underwent nasal lavage after they each ingested a predetermined threshold dose of aspirin or placebo. Aspirin challenge provoked statistically significant increases in iLXA4 in each patient (P < 0.005). These results validate the use of a solid-phase ELISA for detection of LXA4. Furthermore, the use of this ELISA has allowed the first documentation of iLXA4 formation in human subjects with aspirin-sensitive asthma following specific antigenic challenge.

Adult↗
PubMed1993

Modulation of vasoactive intestinal peptide pulmonary relaxation by NO in tracheally superfused guinea pig lungs.

The mechanism of vasoactive intestinal peptide (VIP)-induced pulmonary relaxation in tracheally perfused guinea pig lungs was defined with the use of inhibitors of nitric oxide synthase (NOS) and by direct measurement of nitric oxide (NO) equivalents recovered from lung perfusion fluid. Lungs treated with 200 microM NG-nitro-L-arginine were resistant to the relaxant effects of VIP in these lungs; the 50% inhibitory dose (ID50) for VIP was 32 nmol/kg (95% confidence interval, 16-79), which was approximately 100-fold greater than the ID50 of control lungs which was 0.39 nmol/kg, (0.16-0.79, P < 0.0001). This inhibitory effect could be overcome with excess L- but not D-arginine. In contrast, VIP-induced relaxation of isolated guinea pig trachea was not modified by inhibitors of NOS. To confirm that VIP infusion resulted in NO generation in whole lungs, we measured NO equivalents in lung effluent by two distinct technologies. We found that VIP injection caused a significant increase in NO equivalents from 0.11 +/- 0.04 microM to 0.78 +/- 0.15 microM (P < 0.05) and that this increase preceded VIP-induced pulmonary relaxation. Lungs pretreated with the putative guanylyl cyclase inhibitor methylene blue were less responsive to VIP [ID50 4.0 nmol/kg (1.5-10), P < 0.005 compared with control lungs], consistent with a physiologically significant guanosine 3',5'-cyclic monophosphate-dependent mechanism. Our data demonstrate that VIP has the capacity to relax whole lungs in part by stimulating the generation of NO.

Animals↗
PubMed1993

Construction and uses of a concentric catheter for gas sampling in lung airways.

A catheter for intra-airway sampling of gas concentrations was constructed from concentric polyethylene tubes. The internal tube (0.58 mm ID, 0.91 mm OD) was connected to a gas analyzer while the external tube (1.20 mm ID, 1.75 mm OD) was constantly flushed by air or a calibration gas, except during sampling. Injection and sampling dead spaces were 0.35 and 0.28 ml, respectively. Delay at 4-ml/min sampling rate was 4.0 +/- 0.2 s. The 0-90% step response to a sudden change in gas composition was 0.24 s when connected to a mass spectrometer. This catheter was used to assess tracer gas dispersion during oscillatory flow (1-20 Hz) in a straight long tube. Local concentrations measured through the catheter, after a small bolus of tracer gas was injected through the external tube, compared favorably with direct measurements through needles inserted via the tube wall and with theoretical predictions. The catheter was also used to measure intra-airway gas concentrations in dog airways during spontaneous breathing, conventional mechanical ventilation, high-frequency ventilation, high-frequency vibration ventilation, and constant-flow ventilation. It ws placed by a fiber-optic bronchoscope and used to measure local quasi-steady concentrations of CO2 and local dispersion with the bolus method. The occurrence of catheter clogging with secretions was substantially reduced with flow through the external tube. Transmitting a calibration gas through the external tube facilitated in situ recalibration of the gas analyzer without removing the catheter. The use of this catheter improved the efficiency and accuracy of measurements of gas concentrations inside lung airways.

Animals↗
PubMed1993

The pivotal role of 5-lipoxygenase products in the reaction of aspirin-sensitive asthmatics to aspirin.

A subset of persons with asthma develop bronchospasm, naso-ocular, gastrointestinal, and/or dermal reactions after ingesting aspirin (ASA) or agents with the capacity to inhibit cyclooxygenase. The bronchopulmonary reactions have been associated with a rise in urinary LTE4. We examined the effects of an inhibitor of 5-lipoxygenase, zileuton, in a group of eight asthmatic patients with known sensitivity to ASA accompanied by LTE4 hyperexcretion. We first confirmed ASA sensitivity and an increase in urinary LTE4 after ASA ingestion in these patients using a placebo-controlled ASA challenge. Subjects were then randomized to a double-blind, crossover trial to examine the effects of zileuton versus placebo on the response to ASA. Zileuton treatment decreased baseline urinary LTE4 excretion from a mean of 469 +/- 141 pg/mg creatinine to 137 +/- 69 pg/mg creatinine (p < 0.02) and blunted the maximum increase in urinary LTE4 after ingestion of ASA (3,539 +/- 826 pg/mg creatinine versus 1,120 +/- 316 pg/mg creatinine [p < 0.01]). The pre-ASA challenge FEV1 was unchanged by zileuton (3.41 +/- 0.15 L versus 3.35 +/- 0.17 L, zileuton versus placebo). Zileuton prevented the fall in FEV1 in response to ingestion of ASA; post-ASA ingestion the mean of the minimal FEV1 fell to 2.72 +/- 0.18 L on the placebo day while there was no significant fall on the zileuton day (3.26 +/- 0.17 L; p < 0.014). Zileuton also prevented the development of the nasal, gastrointestinal (p < 0.006 and p < 0.025, respectively), and dermal symptoms which developed after ASA ingestion.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Peptidase modulation of vasoactive intestinal peptide pulmonary relaxation in tracheal superfused guinea pig lungs.

The effects of enzyme inhibitors on vasoactive intestinal peptide (VIP)-induced decreases in airway opening pressure (PaO) and VIP-like immunoreactivity (VIP-LI) recovery were studied in isolated tracheal superfused guinea pig lungs. In the absence of inhibitors, VIP 0.38 (95% CI 0.33-0.54) nmol/kg animal, resulted in a 50% decrease in PaO and 33% of a 1 nmol/kg VIP dose was recovered as intact VIP. In the presence of two combinations of enzyme inhibitors, SCH 32615 (S, 10 microM) and aprotinin (A, 500 tyrpsin inhibitor units [TIU]/kg) or S and soybean trypsin inhibitor (T, 500 TIU/kg), VIP caused a significantly greater decrease in PaO and greater quantities of VIP were recovered from lung effluent (both P < 0.001). The addition of captopril, (3 microM), leupeptin (4 microM), or bestatin (1 microM) failed to further increase pulmonary relaxation or recovery of VIP-LI. When given singly, A, T, and S did not augment the effects or recovery of VIP. The efficacy of S (a specific inhibitor of neutral endopeptidase [NEP]) and A and T (serine protease inhibitors) thus implicated NEP and at least one serine protease as primary modulators of VIP activity in the guinea pig lung. We sought to corroborate this finding by characterizing the predominant amino acid sites at which VIP is hydrolized in the lung. When [mono(125I)iodo-Tyr10]VIP was offered to the lung, in the presence and absence of the active inhibitors, cleavage products consistent with activity by NEP and a tryptic enzyme were recovered. These data demonstrate that NEP and a peptidase with an inhibitor profile and cleavage pattern compatible with a tryptic enzyme inactivate VIP in a physiologically competitive manner.

Animals↗
PubMed1993

Mast cell activation enhances airway responsiveness to methacholine in the mouse.

Mast cell-deficient mutant mice and their normal littermates were used to determine whether activation of mast cells by anti-IgE enhances airway responsiveness to bronchoactive agonists in vivo. Pulmonary conductance was used as an index of airway response as the mice were challenged with increasing intravenous doses of methacholine (Mch) or 5-hydroxytryptamine (5-HT). Mast cell activation with anti-IgE enhanced pulmonary responsiveness to Mch in both types of normal mice (P < 0.0001 by analysis of variance) but not in either genotype of mast cell-deficient mouse. Additionally, anti-IgE pretreatment of genetically mast cell-deficient W/Wv mice whose mast cell deficiency had been repaired by infusion of freshly obtained bone marrow cells or bone marrow-derived cultured mast cells from congenic normal mice led to significant (P < 0.0001) enhancement of Mch responsiveness. 5-HT responsiveness was not significantly influenced by anti-IgE pretreatment in any of the mice studied. The data support the hypothesis that IgE-mediated activation of mast cells enhances pulmonary responsiveness to cholinergic stimulation.

Analysis of Variance↗
PubMed1993

CD10/neutral endopeptidase 24.11 regulates fetal lung growth and maturation in utero by potentiating endogenous bombesin-like peptides.

Bombesin-like peptides (BLPs) are mitogens for bronchial epithelial cells and small cell lung carcinomas, and increase fetal lung growth and maturation in utero and in organ cultures. BLPs are hydrolyzed by the enzyme CD10/neutral endopeptidase 24.11 (CD10/NEP) which is expressed in bronchial epithelium and functions to inhibit BLP-mediated growth of small cell lung carcinomas. To determine whether CD10/NEP regulates peptide-mediated lung development, we administered a specific CD10/NEP inhibitor, SCH32615, to fetal mice in utero from gestational days e15-17. Fetal lung tissues were evaluated on e18 for: (a) growth using [3H]thymidine incorporation into nuclear DNA; and (b) maturation using: [3H]-choline incorporation into surfactant phospholipids, electron microscopy for type II pneumocytes, and Northern blot analyses for surfactant apoproteins A, B, and C. Inhibition of CD10/NEP stimulated [3H]thymidine incorporation into DNA (70% above baseline, P < 0.005), [3H]choline incorporation into surfactant phospholipids (38% above baseline, P < 0.005), increased numbers of type II pneumocytes (36% above baseline, P = 0.07), and fivefold higher surfactant protein A transcripts (P < 0.05). CD10/NEP-mediated effects were completely blocked by the specific bombesin receptor antagonist, [D-Phe12, Leu14]bombesin. These observations suggest that CD10/NEP regulates fetal lung growth and maturation mediated by endogenous BLPs.

Animals↗
PubMed1993

Peptidase modulation of airway effects of neuropeptides.

SP and NKA are potent endogenous bronchoconstrictors, whereas VIP is a potent endogenous bronchodilator. There is abundant evidence that these neuropeptides are released in the lung in a variety of conditions and that they have the capacity to modulate the bronchoactivity of the same stimuli that release them. On many occasions, their bronchoactive effects are masked by their degradation at or near the site of their release. However, when the microenvironment is modified to decrease their cleavage, they can express enhanced physiologic effects. Although it appears that the human asthmatic lung may be an environment in which the effects of neuropeptides can be amplified, the role of neuropeptides in the pathogenesis of airway obstruction remains speculative.

Amino Acid Sequence↗
PubMed1992

Exon 16 del: a novel form of human neutral endopeptidase (CALLA).

The enzyme neutral metalloendopeptidase (E.C. 3.4.24.11), also known as the common acute lymphocytic leukemia antigen, neutral endopeptidase, or enkephalinase, functions as an inactivator of a wide variety of signaling oligopeptides such as substance P, neurokinin A, enkephalins, endothelin, atrial natriuretic factor, and formyl chemotactic peptides. A cDNA clone isolated from a human lung library encodes a fragment of neutral metalloendopeptidase containing an internal 81 base pair deletion when compared with the human placental cDNA for this enzyme. Comparison of the deleted cDNA sequence with the intron-exon structure recently determined as the common acute lymphocytic leukemia antigen reveals that the 81 base pairs corresponds precisely with exon 16. RNA analysis using splice junction oligonucleotides indicates that the 16 del form constitutes a minor but significant fraction of the RNA species present in human lung. Expression of constructs containing "wild type" and "exon 16 del" neutral endopeptidases in COS-7 cells reveals that deletion of this 27 amino acid segment reduces enzymatic activity toward the synthetic substrate glutaryl-alanyl-alanyl-phenyl-alanyl-4-methoxy-2-naphthylamide to barely detectable levels.

Amino Acid Sequence↗
PubMed1992

Effect of the NEP inhibitor SCH32615 on airway responses to intravenous substance P in guinea pigs.

We examined the effects of the selective neutral endopeptidase (NEP) inhibitor SCH32615 on airway responses to rapid intravenous infusions of substance P (SP) and neurokinin A (NKA) and on recovery of administered tachykinins from arterial blood in anesthetized mechanically ventilated guinea pigs. SCH32615, in doses that cause a marked increase in the magnitude of bronchoconstriction induced by infused NKA, had little effect on the changes in pulmonary conductance (GL) or dynamic compliance induced by SP. In animals in which SCH32615 (1 mg/kg) was administered in combination with the angiotensin-converting enzyme (ACE) inhibitor captopril (5.7 mg/kg), the dose of SP required to decrease GL by 50% was fourfold less than in animals that received captopril alone (P < 0.005). SP measured in arterial blood withdrawn within 45 s of intravenous administration of this tachykinin was not different in control and SCH32615-treated animals, whereas captopril caused an approximately threefold increase in SP concentrations (P < 0.005). When SCH32615 and captopril were administered together, significantly more SP was recovered than when captopril or SCH32615 was administered alone (P < 0.0005). Our results are consistent with the hypothesis that both NEP and ACE contribute to the degradation of intravenously infused SP. ACE degradation of SP is sufficient to limit SP-induced bronchoconstriction even in the presence of specific NEP inhibition.

Airway Resistance↗
PubMed1992

Recovery of leukotriene E4 from the urine of patients with airway obstruction.

The urinary excretion of leukotriene E4 (LTE4) was measured in subjects presenting for emergency treatment of airway obstruction. A total of 72 subjects presenting with airway obstruction performed peak flow determinations before and after three treatments with nebulized albuterol given at 20-min intervals. Of these subjects, 22 more than doubled their peak flow rates, while 19 failed to increase their peak flow rates more than 25% during the treatment period. These groups were designated "responders" and "nonresponders," respectively. Urinary LTE4 excretion was determined in 16 of the 22 responders and 12 of the 19 nonresponders as well as 13 normal subjects by precolumn extraction, analytic reversed-phase high-performance liquid chromatography, and enzyme immunoassay. In the normal subjects the urinary LTE4 excretion was significantly (p less than 0.0001) less than the urinary LTE4 measured in the responder subjects, but not less than the urinary LTE4 excretion in the nonresponder group (p = 0.071). The enhanced recovery of LTE4 from the urine of subjects with acutely reversible airway narrowing is consistent with a bronchoconstrictor role for the cysteinyl leukotrienes in spontaneous acute asthma.

Acute Disease↗
PubMed1992

Changes in cross-sectional airway areas induced by methacholine, histamine, and LTC4 in asthmatic subjects.

To examine whether leukotrienes, histamine, and methacholine have different sites of bronchoconstrictor action, we studied 8 stable asthmatic subjects (mean age +/- SD, 26 +/- 5 yr) on 3 different days. On each day, a randomized challenge with LTC4, methacholine, or histamine was performed until the dose that provoked a fall of 20% in FEV1 (PC20) was obtained. Complete and partial flow-volume curves as well as area-distance profiles generated by the acoustic reflection technique (ART) at a fixed lung volume were obtained in all subjects before and after each inhalation challenge. No significant differences were found in pulmonary function or baseline cross-sectional airway areas for the different study days. The three agonists provoked significant (p less than 0.05) bronchoconstriction at the level of the main bronchi when identical falls of FEV1 were achieved. Similarly, equal reductions of V30p were elicited by the three agonists. However, LTC4 and methacholine induced additional tracheal constriction but histamine inhalation did not. These differences in the degree of tracheal constriction were statistically significant (p less than 0.05; ANOVA). These results may be explained by distinct pharmacologic properties of the agents used and may have relevance in the understanding of the pathophysiology of asthma.

Analysis of Variance↗