Effect of sodium metabisulphite on bronchial blood flow in conscious sheep: pharmacological modulation.

1. Sodium metabisulphite (MBS) can induce bronchoconstriction in patients with asthma. We investigated the effects of MBS aerosol on bronchial blood velocity (Vbr) and pulmonary resistance in intubated conscious sheep. 2. Bronchial blood velocity was measured by implanting a 20 MHz ultrasonic Doppler flow probe on the common bronchial branch of the bronchoesophageal artery. 3. Inhaled MBS induced a dose-dependent, transient increase in Vbr lasting for a few minutes without any changes in aortic and pulmonary artery pressures. There was some tachyphylaxis of the Vbr response to successive inhalations of MBS. 4. The cholinoceptor antagonist, ipratropium bromide and the H1 and H2 histamine antagonists, chlorpheniramine and cimetidine, had no significant effect on MBS-induced increase on Vbr. The loop diuretic, frusemide, and the anti-inflammatory drug, nedocromil sodium, which both inhibit MBS-induced bronchoconstriction in patients with asthma, were also without effect. 5. We conclude that MBS induces bronchial vasodilatation in conscious sheep, and that this effect is not dependent on the release of histamine or other mediators, or an activation of cholinergic pathways.

Amoxycillin-clavulanic acid combination in bronchopulmonary infection due to beta-lactamase-producing Branhamella catarrhalis. Preliminary report.

Since 1978 we have taken an interest in lower respiratory tract infections associated with Branhamella catarrhalis in Christchurch, New Zealand. In a preliminary trial, 20 patients with bronchopulmonary infection caused by beta-lactamase-producing B. catarrhalis were treated with a combination tablet of amoxycillin 500 mg and clavulanic acid 125 mg ('Augmentin') 3 times daily for 5 days. Sputum cultures were negative for B. catarrhalis within 3 days in all patients. Two of 7 patients whose sputum cultures were positive for this organism at a review 2 to 4 weeks later were successfully treated with a further course of amoxycillin/clavulanic acid.

Peptide mediator effects on bronchial blood velocity and lung resistance in conscious sheep.

Peptide mediators or neuropeptides released from sensory nerves may induce inflammatory effects in airways, but their effects on airway blood velocity and lung resistance have not been previously studied simultaneously in awake animals. Nine adult sheep were chronically prepared for continuous measurement of blood flow velocity to the distal trachea and bronchi by surgical implantation of a 20-MHz pulsed Doppler flow probe on the common bronchial branch of the bronchoesophageal artery. Awake restrained animals were intubated and connected to a pneumotachograph to measure resistance to airflow across the lung (RL). Doubling doses of bradykinin (BK, 0.02-1.51 nmol/kg), calcitonin gene-related peptide (CGRP, 0.004-0.26 nmol/kg), or substance P (SP, 0.02-1.19 nmol/kg) were injected as a bolus into the right atrium while mean arterial pressure (MAP), bronchial blood velocity (Vbr), and RL were measured. BK at 0.76 nmol/kg caused a transient dose-related increase in Vbr from a baseline of 19.3 +/- 2.5 to 41.4 +/- 4.1 (SE) cm/s (P less than 0.05) despite a decrease in MAP from 118 +/- 6 to 80 +/- 6 mmHg. CGRP at 0.26 nmol/kg caused a transient dose-related increase in Vbr from 16.8 +/- 2.7 to 25.3 +/- 4.7 cm/s (P less than 0.05) despite a decrease in MAP from 113 +/- 5 to 87 +/- 8 mmHg. Neither BK nor CGRP affected RL. SP at 1.19 nmol/kg transiently increased Vbr from 18.3 +/- 2.3 to 45.1 +/- 8.3 cm/s (P less than 0.05), MAP from 138 +/- 9 to 162 +/- 15 mmHg, and RL from 4.5 +/- 1.0 to 106.6 +/- 62.1 cmH2O.l-1.s.(ABSTRACT TRUNCATED AT 250 WORDS)

Bronchial vasodilation by histamine in sheep: characterization of receptor subtype.

Histamine has been shown to mediate features of pulmonary allergic reactions including increased tracheobronchial blood flow. To determine whether the increase in blood flow was due to stimulation of H1- or H2-histamine receptors, we gave histamine base (0.1 micrograms/kg iv) or histamine dihydrochloride as an aerosol (10 breaths of 0.5% "low dose" or 5% "high dose") before and after H1- or H2-receptor antagonists. Blood velocity in the common bronchial branch of the bronchoesophageal artery (Vbr) was continuously measured using a chronically implanted Doppler flow probe. Pretreatment with H2-receptor antagonists cimetidine, ranitidine, or metiamide did not affect the increase in Vbr induced by intravenous histamine [106 +/- 45% (SD)]. Addition of the H1-receptor antagonists diphenhydramine or chlorpheniramine, however, reduced the Vbr response to 16 +/- 22, 21 +/- 28, 23 +/- 23, and 37 +/- 32% of the unblocked responses (P less than 0.05) when intravenous histamine was given at 3, 10, 20, and 30 min, respectively, after the H1 antagonist. At 40, 50, and 60 min the H1-receptor blockade appeared to attenuate, but subsequent continuous infusion of chlorpheniramine (2 mg.kg-1.min-1) then blocked the histamine response for 60 min. Low-dose histamine aerosol did not change mean arterial or pulmonary arterial pressures, cardiac output, or arterial blood gases but increased Vbr transiently from 15.2 +/- 3.4 to 37.6 +/- 8.4 (SE) cm/s. After chlorpheniramine, the Vbr response to histamine, 16.3 +/- 2.2 to 22.6 +/- 3.6 cm/s, was significantly reduced (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Phase V of the single-breath washout test.

A downward-deflecting phase V is often seen following the phase IV terminal rise in the single-breath N2 washout test (SB N2). This phase V was studied in eight normal nonsmoking subjects aged 27-41, using both the SB N2 test and single-breath washouts of boluses of inert tracer gas slowly inhaled from residual volume (RV). All of the subjects showed a distinct phase V in both tests. Expiratory flow rates between 0.1 and 2.0 1/s were used; at each flow rate phase V appeared shortly after expiration became flow limited. Thus the volume above RV at which phase V began increased with increasing expiratory flow rate. The difference between the exhaled volumes at which flow became limited and phase V appeared was shown to be approximately equal to the anatomic dead space. This behavior is predicted by a model of lung emptying in a gravitational field. As expiration proceeds, flow limitation occurs first in the (tracer-poor) lower lung regions and then progresses toward the (tracer-rich) upper lung regions causing phase IV. When all lung regions have finally become flow limited, the amount of flow from the upper regions decreases relative to that of the lower regions, thereby causing phase V.

Effect of formoterol, a long-lasting beta 2-adrenoceptor agonist, against methacholine-induced bronchoconstriction.

1. The effects of a new long-acting inhaled beta 2-adrenoceptor agonist aerosol formoterol (12 micrograms), on FEV1, and on methacholine-induced bronchoconstriction, were compared with those of terbutaline (250 micrograms) and placebo in 12 midly asthmatic subjects. 2. PC20, the concentration of methacholine needed to cause a 20% fall in baseline FEV1, was determined 2 and 5 h after formoterol, terbutaline and placebo on separate days. Baseline PC20 was determined on a different day. 3. Compared with terbutaline and placebo, formoterol hastened recovery from methacholine-induced bronchoconstriction, and significantly increased mean PC20 (by 2.2- and 2.9-fold at 2 and 5 h respectively). 4. Thus, formoterol has a protective effect against methacholine-induced bronchoconstriction which lasts for at least 5 h.

Inhaled furosemide inhibits cough induced by low chloride content solutions but not by capsaicin.

Inhaled furosemide prevents bronchoconstriction induced by nebulized distilled water, exercise, and antigen challenge. We examined the effect of furosemide on cough induced by low chloride content solutions and by capsaicin in double-blind, placebo-controlled studies. A group of eight nonsmoking normal subjects was given furosemide (3.75 mg/ml inhaled for 8 min) and placebo (saline) immediately before consecutive 1-min inhalations of four isosmolar solutions with decreasing chloride content every 5 min from an ultrasonic nebulizer. Decreasing concentrations of chloride induced dose-related coughing, which was inhibited by furosemide. Thus, chloride-free solution induced 13.1 +/- 1.6 coughs after placebo and 8.4 +/- 1.9 coughs after furosemide (p less than 0.005). In a separate study, six of the same normal subjects were given inhaled furosemide or placebo before inhaling one breath of capsaicin solution given in three consecutive increasing concentrations. Capsaicin induced dose-related coughing, which was not inhibited by furosemide. Thus, after placebo the highest concentration of capsaicin induced 20.8 +/- 1.8 coughs and after furosemide, 21.5 +/- 2.7 coughs. We conclude that furosemide may act by inhibiting the cough reflex indirectly, perhaps by changing local chloride ions within the vicinity of epithelial cough receptors.

Effect of frusemide on the induction and potentiation of cough induced by prostaglandin F2 alpha.

We examined whether inhaled frusemide could reduce the potentiation of capsaicin-induced cough by prostaglandin (PG) F2 alpha. Eight non-smoking normal subjects, after a baseline capsaicin challenge were given inhaled frusemide or saline followed by capsaicin challenge, then PGF2 alpha and finally capsaicin challenge again. PGF2 alpha-induced coughs were reduced after frusemide to 3.6 +/- 1.0 compared with 5.7 +/- 1.2 after saline (P less than 0.05). PGF2 alpha increased capsaicin-induced coughs by 11.1 +/- 3.7 and 7.9 +/- 3.4 after placebo and frusemide, respectively (P less than 0.05). Frusemide had no effect on capsaicin-induced cough alone. Changes in local ionic concentrations by frusemide, particularly chloride ions within the vicinity of epithelial cough receptors, may determine the cough response to low chloride solutions and to PGF2 alpha, but not to capsaicin which acts directly on the cough receptors, and alter the sensitivity of the receptors to capsaicin.

Characterisation of bronchoconstrictor responses to sodium metabisulphite aerosol in atopic subjects with and without asthma.

Inhalation of sodium metabisulphite is thought to induce bronchoconstriction by release of sulphur dioxide. We sought to establish the reproducibility of the airway response to inhaled sodium metabisulphite given in increasing doubling concentrations (0.3 to 160 mg/ml) to 13 asthmatic and five atopic non-asthmatic subjects and the contribution of cholinergic mechanisms to this response. In 15 of the 18 subjects bronchoconstriction was sufficient to allow calculation of the dose of metabisulphite causing a 20% reduction in the forced expiratory volume in one second (FEV1) from baseline values (PD20 metabisulphite). The 95% confidence limit for the difference between this and a second PD20 metabisulphite determined 2-14 days later was 2.5 doubling doses. The difference between repeat PD20 metabisulphite measurements was unrelated to the number of days between challenges or change in baseline FEV1. Ten subjects returned for a third study 3-120 days after the second challenge; variability in PD20 metabisulphite did not differ from that seen between the first and second challenges. PD20 methacholine was determined between the two metabisulphite challenges and found to correlate with PD20 metabisulphite (r = 0.71). Inhaled ipratropium bromide 200 micrograms given in a randomised, placebo controlled, crossover study to 10 subjects increased PD20 methacholine 42 fold but had no significant effect on the response to metabisulphite. A single inhalation of the PD20 metabisulphite in five subjects induced maximal bronchoconstriction 2-3 minutes after inhalation, with a plateau in FEV1 lasting a further four minutes before recovery. A further single inhalation of the same PD20 dose 43 minutes later produced a 27% (SEM 4%) smaller fall in FEV1 than the first inhalation. These results show that metabisulphite PD20 values measured over days and weeks show similar reproducibility to those reported for histamine inhalation and that PD20 metabisulphite correlates with methacholine responsiveness. Most of the bronchoconstriction is not inhibited by antimuscarinic agents; the underlying mechanisms require further investigation.

A case of severe Strongyloides stercoralis infection with jejunal perforation in an Australian ex-prisoner-of-war.

After the resection of a localized lung carcinoma, a 65-year-old veteran developed jejunal perforation and pneumonia, both of which subsequently were shown to be caused by infection with Strongyloides stercoralis. The patient recovered after jejunal resection and treatment with thiabendazole. Several unusual aspects of the case are discussed.

Effect of neutral endopeptidase inhibitor on airway function and bronchial responsiveness in asthmatic subjects.

We determined the effect of an inhibitor of neutral endopeptidase, acetorphan, on the skin responses to substance P and on the bronchostrictor effects of sodium metabisulphite aerosol in asthmatic subjects. One hour following ingestion of acetorphan (200 mg) or placebo tablets, cutaneous responses to substance P were performed in four subjects. In seven subjects, bronchial challenge with increasing concentrations of sodium metabisulphite solutions was performed and the concentration required to cause a 20% fall in baseline FEV1 determined (PC20). On the acetorphan day, there was a significant increase in the wheal and flare responses to substance P and to the diluent (0.9% NaCl) alone. However, there was no significant effect of acetorphan on the PC20 metabisulphite. We conclude that metabisulphite airway challenge in vivo may not invoke the release of endogenous neuropeptides. However, the degree of inhibition of neuropeptide breakdown by the oral dose of acetorphan used may not have been optimal.

Effect of theophylline on airway responses to inhaled platelet-activating factor in man.

It has been suggested that theophylline may possess anti-inflammatory actions which underlie its antiasthma properties. We examined whether theophylline could inhibit the bronchoconstriction and the bronchial hyperresponsiveness induced by inhaled platelet-activating factor (PAF) in eight nonasthmatic subjects in a double-blind, cross-over study. After oral theophylline (6 mg.kg-1), plasma theophylline at 1 h was 10.4 +/- 1.8 mg.ml-1 (mean +/- SEM) compared to 0.39 +/- 0.19 mg.ml-1 on the placebo day (p less than 0.005). PAF, inhaled in five successive doses every 15 min, caused a 56 +/- 11% fall in Vp30 (flow at 30% of vital capacity from a partial expiratory manoeuvre) after the first dose at 5 min, and diminishing responses with successive doses. Theophylline had no significant effect on PAF-induced bronchoconstriction. PAF caused a significant decrease in PC40 (the concentration of methacholine needed to cause 40% fall in baseline Vp30) from a baseline of 12.8 mg.ml-1 (geometric standard error of mean (GSEM) 1.98) to 7.9 (1.79) mg.ml-1 on day 3 and 6.9 (1.74) on day 7 (p less than 0.02). There was no significant difference when mean PC40 values on corresponding days after PAF were compared between placebo and theophylline treatment periods. Our results suggest that theophylline has negligible influence on the airway effects of PAF.

Effects of prostacyclin on bronchoconstriction and neutropenia induced by inhaled platelet-activating factor in man.

We studied the effects of prostacyclin (PGI2) on the airway responses to platelet-activating factor (PAF) in a randomized and crossover study in eight normal subjects. PGI2 or diluent (glycine buffer) was continuously infused on 2 separate days. Two breaths of PAF (21 micrograms) were inhaled three times every 15 minutes and airflow at 30% of vital capacity from partial flow-volume curves (Vp30) was measured. PGI2 (4 ng/kg/min) had no effect on Vp30 or blood pressure, whereas heart rate increased from 70.3 +/- 3.9 to 73.7 +/- 4.0 beats/min (mean +/- SEM; p less than 0.01). Two subjects did not complete the study because of transient hypotension. PGI2 had no effect on PAF-induced bronchoconstriction with maximal decreases in Vp30 of 42.0 +/- 8.0% (p less than 0.01) during PGI2 and 49.8 +/- 14.2% (p less than 0.02) during diluent infusion. Ex vivo platelet aggregation to PAF (10(-9) to 10(-7) mol/L) was significantly inhibited by PGI2. Circulating neutrophils decreased from 4.7 +/- 0.9 x 10(9)/L to 1.5 +/- 0.3 x 10(9)/L (p less than 0.05) 5 minutes after the first PAF inhalation during diluent infusion, whereas there was no significant change with PGI2. Thus, PGI2 does not influence PAF-induced bronchoconstriction in man despite causing marked inhibition of ex vivo PAF-induced platelet aggregation and preventing the fall of neutrophils.

Effect of inhaled furosemide on metabisulfite- and methacholine-induced bronchoconstriction and nasal potential difference in asthmatic subjects.

To evaluate the hypothesis that furosemide inhibits indirect bronchoconstrictor challenges by altering airway epithelial ion transport, we studied its effects on indirect bronchoconstriction induced by inhaled metabisulfite (MBS) and nasal potential difference (PD) in seven subjects with mild asthma. Its effect on direct bronchoconstriction by the inhaled muscarinic agonist methacholine (MC) was studied in six of these subjects. Each subject inhaled furosemide, 30 mg, in a randomized, double-blind, placebo-controlled fashion immediately before challenge with MBS (0.3 to 160 mg/ml in increasing doubling concentrations) and, in another study, MC (0.125 to 32 mg/ml) aerosols from a nebulizer attached to a dosimeter. PC20MBS and PC20MC, the concentration of each agent needed to lower FEV1 by 20%, were calculated by linear interpolation of the log dose-response curves. Furosemide had no effect on resting lung function, but it caused a significant threefold reduction in sensitivity to MBS (PC20MBS: GM +/- GSEM, 15.1 +/- 1.6 mg/ml after placebo and 40.7 +/- 1.7 mg/ml after furosemide; p less than 0.001) with a protective index of 64.8 +/- 10.7%. Furosemide caused no change in sensitivity to MC (PC20 MC:GM +/- GSEM, 2.37 +/- 1.61 mg/ml after placebo and 2.19 +/- 1.751 mg/ml after furosemide; NS). In a third study, furosemide, 30 mg, and placebo were inhaled through the nose in a randomized double-blind fashion immediately prior to inhalation of a PC20 concentration of MBS through the nose. Nasal PD was measured before and after placebo or furosemide, and again after MBS inhalation.(ABSTRACT TRUNCATED AT 250 WORDS)