Substance P induces histamine release from human pulmonary mast cells.

Substance P elicits histamine release from human skin and rodent mast cells. Since neuropeptide-mediated reflexes may be important in asthma, we examined the ability of substance P to stimulate human mast cells obtained at bronchoalveolar lavage (BAL). BAL samples were obtained at routine bronchoscopy from 35 non-preselected patients. Histamine release experiments were performed in a standard manner using substance P and the calcium ionophore A23187. Both substance P (50 microM) and A23187 caused histamine release (median 26.7% range 6.2-62.8% and 32.1%, 7.7-56.8% respectively) which was significantly greater (P < 0.0001) than the spontaneous release (median 15.6%, range 4.1-33.4%), i.e. that in the absence of any stimulus. Substance P induced histamine release was via an energy dependent process and was blocked by preincubation with antimycin A. A significant correlation was observed between substance P induced release and spontaneous release but was not observed with A23187 induced release. Mast cell counts correlated significantly with substance P induced release but not with spontaneous or A23187 induced release. The substance P induced histamine secretion was elicited at similar concentrations to those used with rodent and human skin mast cells. Asthma is associated with increased numbers of mast cells which have both increased spontaneous and stimulated secretory responses. Thus, in vivo, the bronchoconstrictor action of substance P may in part result from activation of mast cells in the bronchial lumen.

Effect of exercise on the nasal transmucosal potential difference in patients with cystic fibrosis and normal subjects.

BACKGROUND: Normal subjects have a negative nasal transmucosal potential difference (TPD) at rest which becomes more negative with exercise. Patients with cystic fibrosis have a more negative resting nasal TPD than controls. The present study was designed to determine the effects of exercise on the TPD of patients with cystic fibrosis. METHODS: Seven subjects with cystic fibrosis and seven control subjects had their usual TPD measured at rest, and during and after a 12 minute period on an exercise bicycle designed to produce a pulse rate of 80% of their maximum predicted value. RESULTS: The normal subjects developed a more negative nasal TPD during exercise which returned towards normal at the completion of the rest period. The patients with cystic fibrosis had higher resting values which became less negative during exercise. At the end of the exercise period there was no difference between the two groups. At the end of the recovery period the results for the patients with cystic fibrosis had returned to their resting values. CONCLUSIONS: Exercise reduces the abnormally high resting values for nasal TPD in patients with cystic fibrosis. Elucidation of the mechanism for this change may help to produce functional improvement for patients with this disease.

Electronic cell counting to measure total cell numbers in bronchoalveolar lavage fluid.

Cell counting of bronchoalveolar lavage (BAL) fluid is performed manually in routine practice. This has both methodological and inherent errors; however, the accuracy and suitability of automated counting devices have been questioned. In this study, a Coulter Counter D Industrial model was calibrated and then used to measure the total cell count in unprocessed bronchoalveolar lavage fluid, and compared to a standard manual method. Bronchoalveolar lavage was performed on 34 patients undergoing routine bronchoscopy. An aliquot of unprocessed bronchoalveolar lavage fluid was taken for all counting procedures. Manual counts were performed blind by two experienced independent observers using improved Neubauer chambers. Electronic counting measured 1 ml aliquots suspended in 10 and 20 ml Isoton counting 0.5 and 1 ml duplicates. The correlation coefficients between electronic and manual counts were good. The coefficients of repeatability of electronic counts, for repeat counts, both on the same dilution (Intra-Coulter: 0.1 x 10(5) cells.ml-1) and different dilutions (Interdilution-Coulter: 0.48 x 10(5) cells.ml-1), were superior compared to those for repeat manual counts by the same observer (1.03 x 10(5) cells.ml-1), and counts between observers (1.82 x 10(5) cells.ml-1). This method offers a quick, precise and simple method for counting cells in unprocessed bronchoalveolar lavage fluid, which is both less labour intensive and subjective than manual counting.

Ventilatory and heart rate responses after exercise in chronic cardiac failure.

1. To determine if the recovery period after exercise is abnormal in chronic cardiac failure, we studied 15 patients with stable chronic cardiac failure, and 14 normal subjects during and after symptom-limited maximal treadmill exercise. 2. In patients, O2 consumption fell exponentially from 16.8 (13.7-20.0) ml min-1 kg-1 at peak exercise to 6.0 (5.2-6.7) ml min-1 kg-1 at 3 min of recovery and in control subjects it fell from 30.2 (27.0-33.5) ml min-1 kg-1 to 6.7 (5.9-7.4) ml min-1 kg-1 (mean and 95% confidence intervals). The associated decay constants were slower in patients [0.70 (0.58-0.83) min-1 versus 0.93 (0.81-1.05) min-1 in control subjects (P < 0.01, t-test)]. 3. CO2 consumption kinetics displayed similar abnormalities [(k: 0.55 (0.41-0.69) min-1 versus 0.71 (0.59-0.83) min-1, P < 0.05)] and heart rate kinetics showed a similar trend [(k: 0.53 (0.33-0.74) min-1 versus 0.76 (0.62-0.89) min-1, P = 0.08]. 4. We conclude that patients with cardiac failure recover more slowly from exercise than normal subjects, and that this may further impair their ability to perform exercise, with consequent effect on quality of life.

Gas exchange responses to constant work rate exercise in chronic cardiac failure.

OBJECTIVE: To examine the time course of changes in minute oxygen consumption and other gas exchange variables and heart rate during constant work rate exercise in patients with chronic cardiac failure. DESIGN: Treadmill exercise with on line measurement of gas exchange and a target duration of 10 minutes. SUBJECTS: Seven men in New York Heart Association class II, six in class III, and seven controls. MAIN OUTCOME MEASURES: Gas exchange variables and heart rate were averaged for the final two minutes of exercise. Time constants were calculated for the increase in all variables. RESULTS: Consumption of oxygen at the end of exercise (VO2) was similar in class II patients (mean (95% confidence interval (95% CI) 14.9 (13.6 to 16.1) ml kg-1 min-1), class III patients (13.2 (11.2 to 15.1) ml kg-1 min-1), and controls (13.3 (12.5 to 14.2) ml kg-1 min-1). The patients reached this VO2 more slowly with longer exponential time constants of 0.82 (0.59 to 1.04) min in class II and 1.19 (0.86 to 1.51) min in class III, than the 0.49 (0.35 to 0.64) min in the controls. Time constants of other gas exchange variables and heart rate were also longer in patients. By analysis of covariance, peak VO2 accounted for the between group difference in the time constant for VO2, suggesting that circulatory factors may be an important cause of the delayed kinetics. CONCLUSIONS: A delayed rise in VO2 in response to exercise may be responsible for subnormal values of VO2 early in exercise in patients with chronic cardiac failure.

Differential reactivity of human bronchoalveolar lavage mast cells to substance P.

Substance P (SP) stimulates human skin and rodent mast cells. Since neuropeptide-mediated reflexes may be important in asthma, the ability of SP to stimulate human mast cells obtained at bronchoalveolar lavage (BAL) was examined. Routine BAL (n = 22) samples were obtained and histamine release experiments performed in a standard manner. Spontaneous histamine release was bimodally distributed (Group A, high spontaneous release/Group B, normal spontaneous release). Further, Group A had significantly elevated corrected SP-induced histamine release compared to Group B but the corrected calcium ionophore A23187-induced responses were similar. No differences were found in clinical history, age, lavage return or total cell numbers between groups. However, differential cell counts revealed significantly elevated mast cell numbers in Group A providing further evidence for altered mast cell responsivity associated with mast cell hyperplasia. In asthma, BAL mast cells have increased spontaneous and stimulated secretory responses; thus, in asthma SP may also stimulate pulmonary mast cells.

Non-invasive measurement of cardiac output by a carbon dioxide rebreathing method at rest and during exercise.

Cardiac output was measured in 11 patients undergoing routine cardiac catheterization using a carbon dioxide rebreathing technique and compared with cardiac output measured by direct Fick and thermodilution. The carbon dioxide rebreathing technique gave consistently lower values for cardiac output than the other two methods (mean difference -0.73, 95% CI -0.95 to -0.51 l.min-1 with the direct Fick and -0.72, 95% CI -1.19 to -0.26 l.min-1 with thermodilution). The direct Fick and thermodilution methods gave similar results (mean difference -0.08, 95% CI -0.32 to 0.16 l.min-1). Cardiac output was also measured in 10 healthy subjects at rest and during two steady-state levels of exercise using the carbon dioxide rebreathing technique. Measurements were made in triplicate on 3 separate days. The technique gave reproducible results between replicates at rest (coefficient of variation 9.1%) and became more reproducible on exercise (coefficients of variation 5.6% and 5.4% respectively at each exercise level). There was a good correlation between cardiac output and oxygen consumption (r = 0.98). The carbon dioxide rebreathing technique is a feasible non-invasive way of measuring cardiac output. It tends to underestimate cardiac output at rest but is reproducible and becomes more so on exercise which is where it should be of most value.

Anaerobic threshold in patients with chronic cardiac failure due to ischaemic heart disease.

OBJECTIVES: Anaerobic threshold was measured to examine its relationship with venous lactate levels and the reproducibility of gas exchange methods. METHODS: Twenty patients with chronic cardiac failure due to ischaemic heart disease underwent two successive treadmill tests with measurements of respiratory gas exchange. RESULTS: An anaerobic threshold was demonstrated in 78 p. 100 of tests, by plotting either VE/VO2 or VCO2/VO2, and reproducibility between the two tests was satisfactory. Peripheral venous lactate levels did not increase from rest to the end of the exercise stage prior to the anaerobic threshold, but did increase significantly thereafter. Where an anaerobic threshold could be demonstrated, it was reproducible and correlated strongly with peak achieved VO2. CONCLUSION: However, as measurement of anaerobic threshold requires exercise to 90 p. 100 maximum VO2, it may be preferable to continue until limiting symptoms, and use peak achieved VO2 as the end point. Anaerobic threshold is a reproducible measure of anaerobic exercise capacity.

Cicatricial pemphigoid presenting as upper airways obstruction.

A 53-year-old woman presented with a history of increased shortness of breath, stridor and dryness of the eyes. Flow volume loops demonstrated evidence of upper airways obstruction. Conjunctival and laryngeal biopsies suggested a diagnosis of cicatricial pemphigoid. Immunosuppressive therapy improved symptoms and the flow volume loops returned to normal.

Stress responses after treatment of hypercholesterolaemia with simvastatin.

In order to determine whether treatment of hyperlipidaemia with simvastatin impairs exercise stress responses and so may contribute to an excess of suicides and violent deaths, the effects of simvastatin 20 mg daily and placebo on exercise physiology were compared in 19 patients. After 6 weeks of treatment there was no evidence of reduced exercise capacity, or of reduced cortisol or catecholamine responses. It is concluded that treatment of hyperlipidaemia with an inhibitor of HMG-CoA reductase does not significantly modify stress responses, and so the explanation for a possible increase in non-cardiac mortality must be sought elsewhere.

Metabolic responses to graded exercise in chronic heart failure.

To determine if exercise intolerance and fatigue in chronic heart failure could be exacerbated by an abnormal metabolic response to exercise, we studied 12 patients with stable chronic heart failure and 12 normal volunteers during symptom-limited maximal treadmill exercise. Peak VO2 was 17.2 (15.1-19.2) ml.kg-1 x min-1 in patients and 29.9 (26.3-33.5) in controls (mean and 95% confidence intervals; P < 0.0001, t-test). Overall, levels in peripheral venous blood of glucose, glycerol and free fatty acids were greater in patients, although the differences became less marked with increasing exercise intensity. Noradrenaline was elevated in patients at rest, but the peak exercise response was similar to controls. Responses of adrenaline, insulin and glucagon were similar in both groups. We conclude that depletion of the levels of circulating substrates is not contributory to exercise intolerance and fatigue in chronic heart failure. Greater levels of glycerol and free fatty acids may be mediated by excess sympathetic nervous system activity, reflected in elevated noradrenaline levels.

Respiratory gas exchange and metabolic responses during exercise in McArdle's disease.

During normal progressive exercise, the gas exchange anaerobic threshold occurs when CO2 production (VCO2) and ventilation (VE) increase so as to depart from a linear relationship to O2 consumption (VO2). This is thought to represent a gas exchange response to metabolic acidosis due to lactate accumulation. Patients with McArdle's disease have previously been reported to exhibit a steepened ventilatory response relative to VCO2, despite an inability to produce lactate. However, the VCO2 response has not been studied. We therefore investigated the VCO2-VO2 and VE-VO2 relationships in seven McArdle's disease patients and seven control subjects during symptom-limited maximal treadmill exercise. Analysis of gas exchange showed that whereas all control subjects had an easily identifiable anaerobic threshold, four of the patients had none and the other three displayed an attenuated threshold. The occurrence of the threshold in one patient was associated with a small rise in lactate and in another patient with an abrupt rise in leg discomfort, suggesting a pain response. Ammonia and the purine metabolite hypoxanthine were elevated during exercise in all patients, suggesting that ammonia may be a product of adenosine monophosphate degradation. Free fatty acid levels were also elevated, and a shift toward utilization of lipid may contribute to abnormal gas exchange responses. It is concluded that lactic acidosis contributes to the gas exchange anaerobic threshold but that other factors, such as discomfort, may be involved in the excess Ve seen during heavy exercise.

The effect of methacholine on nasal transmucosal potential difference in normal human subjects.

This study was proposed to test the hypothesis that the parasympathetic system might attribute to the transmucosal potential difference. In a double-blind, placebo-controlled study six volunteers had nasal transmucosal potential difference (NTPD) recorded at 4-min intervals during 12-min periods of rest, before and after treatment, as well as during exercise and recovery. Application of placebo did not significantly alter NTPD at rest. There was a significant rise during exercise (p < 0.05). The application of methacholine significantly increased NTPD at rest (p < 0.01); there was a further rise during exercise (p < 0.02). We conclude that parasympathetic stimulation can increase the transmucosal potential difference.

The prevalence of preferential nasal breathing in adults.

The prevalence of preferential nasal breathing was studied in an awake adult population. One hundred and ninety-four people consented to gentle manual compression of the nostrils. They were advised to 'breathe in and out', but no further information regarding breathing was given to avoid influencing the patient. One hundred and eighty patients (92.8%) commenced immediate regular relaxed breathing. Fourteen patients (7.2%) had difficulty with oral breathing which ranged from irregular mouth breathing associated with distress to no spontaneous respiration. The prevalence of preferential nasal breathing was strongly associated with increasing age (chi 2 for trend, P = 0.007). In addition, a weakly significant association was demonstrated between a history of asthma and this phenomenon (P = 0.047). These findings suggest a tendency for the elderly person to revert to the infant pattern of obligate nasal breathing. Physicians should be aware of this possibility in the elderly patient, especially prior to any procedure which may induce nasal obstruction.

Effect of beta-adrenoceptor blockade on atrial natriuretic peptide levels during exercise in angina pectoris.

The effects of epanolol (200 mg once daily) and diltiazem (60 mg three times daily) on the response of atrial natriuretic peptide (ANP) to exercise were investigated in a double-blind placebo-controlled crossover study in 16 patients with angina pectoris. Exercise tolerance as assessed by peak oxygen consumption was similar with all treatments. Peak heart rate (mean and 95% confidence intervals) was lower (P < 0.05) with epanolol (121 (115-130) beats min-1) than with diltiazem (137 (126-148) beats min-1) or placebo (141 (130-152) beats min-1). ANP did not change from resting values with placebo or diltiazem, but rose significantly (P < 0.05) with epanolol from 19.7 (13.0-29.8) pg ml-1 (geometric mean and 95% confidence intervals) during supine rest to 49.6 (33.7-73.0) pg ml-1 at peak exercise. Since ANP release is stimulated by atrial distension, patients with untreated angina may stop exercise before atrial dilatation occurs. With beta-adrenoceptor blockade, a reduction in peak heart rate may necessitate increased chamber volumes to maintain cardiac output, accounting for the rise in ANP.

The use of an exponential protocol for bicycle and treadmill exercise testing in patients with chronic cardiac failure.

We have studied a standardized exercise protocol suitable for use with a treadmill or bicycle (STEEP protocol) and compared it with a modified Bruce treadmill protocol in a group of patients with chronic cardiac failure. The STEEP protocol has been previously validated in normal subjects. Exercise time (6.79 +/- 2.42 vs 5.34 +/- 1.95 min, P < 0.05) and peak VO2 (16.66 +/- 4.09 vs 15.01 +/- 3.72 ml.min-1.kg-1, P < 0.05) were greater with the STEEP treadmill compared with the bicycle protocol, but VO2 was very similar at equal exercise stages in both modalities. Heart rate and respiratory exchange ratio tended to be greater during bicycle exercise at equal stages. Exercise time was greater with the modified Bruce protocol (9.00 +/- 3.02 min, P < 0.05) than with either STEEP protocol, but peak VO2 (17.13 +/- 4.52 ml.min-1.kg-1) was similar to that obtained with the STEEP treadmill test. We conclude that the STEEP protocol may be used to test patients with chronic cardiac failure, and that exercise times relate well in both treadmill and bicycle. The protocol should prove useful in studies involving a wide range of exercise capacities or both bicycle and treadmill exercise.

Regulatory peptides in the plasma of patients with chronic cardiac failure at rest and during exercise.

The levels of several regulatory peptides were measured in peripheral plasma samples from individuals with chronic cardiac failure (CCF) and matched controls in both the resting state and during a short period of maximal exercise. Basal levels of noradrenaline (NA; 705 +/- 114 vs 195 +/- 54 ng.l-1; mean +/- SEM; P < 0.05), plasma renin activity (PRA; 12.9 +/- 2.9 vs 2.1 +/- 0.3 ng AI ml-1.h-1; P < 0.05) and aldosterone (ALDO; 325 +/- 49 vs 87 +/- 8 ng.l-1; P < 0.05) were all raised in the patients with CCF, and increased further with exercise. Basal circulating levels of atrial natriuretic peptide (ANP) were also significantly higher in the CCF group compared to controls (136 +/- 35 vs 27 +/- 5 ng.l-1; P < 0.01), but the response to exercise was attenuated, so that at peak exercise, no significant difference was observed. Basal circulating levels of gastrin-releasing peptide (GRP) (29 +/- 4 vs 40 +/- 4 ng.l-1; P < 0.05) and secretin (13 +/- 1 vs 32 +/- 4 ng.l-1; P < 0.05) were significantly lower in the CCF group when compared to controls and there was no significant change in the levels of either peptide with exercise. Levels of neurokinin A (NKA), neuropeptide Y (NPY) and neurotensin (NT) were somewhat higher in patients, but the differences were not significant, and there were no changes during exercise. There were also no significant differences in the levels of vasoactive intestinal peptide (VIP), glucose-dependent insulinotropic polypeptide (GIP), insulin or glucagon in either experimental group both before and during exercise. We have therefore identified different circulating levels of certain regulatory peptides in patients with CCF, but the significance of these remains unclear.

Lung function testing in adults with preferential nasal breathing.

Three adult patients with asthma with preferential nasal breathing were found to have a typical pattern of lung function test results with substantial between test variation. This condition can be identified as a cause of unsatisfactory performance in respiratory tests by observing the patient's reaction after the nostrils have been occluded.

Comparative effects of epanolol and diltiazem on exercise performance and respiratory gas exchange in angina pectoris.

The effects of epanolol (a new selective beta-adrenoceptor antagonist), diltiazem and placebo were compared in a group of 16 patients with chronic stable angina pectoris. Each patient received each treatment in random order. Diltiazem reduced weekly angina attack rate from 7.2 (95% CI 3.9-10.5) to 3.9 (1.9-5.9) (P less than 0.01), whereas a lesser reduction was observed after epanolol. Both drugs produced a small but significant (P less than 0.05) increase in treadmill exercise time (placebo 474 s (374-574), epanolol 527 s (431-623) and diltiazem 554 s (462-646). However, aerobic work capacity, assessed by peak achieved oxygen consumption, was not different from the placebo value of 21.2 (18.0-24.4) ml.min-1.kg-1, and clearly subnormal when compared to age- and sex-matched controls (33.0 (30.1-35.9) ml.min-1.kg-1). Ventilatory abnormalities and increased lactate levels on active treatment were observed at peak exercise only. We conclude that the cardiodepressant effects of both active drugs limit blood supply to working skeletal muscle, and that chest pain may be replaced by dyspnoea or fatigue as the limiting factors to exercise.