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Biomedical subjects

A H Morice

Publications and source records attributed to A H Morice.

At least 55 records · Page 3Linked to original sources
PubMed2000

The effect of the nitric oxide synthase inhibitor N-gamma-nitro-L-argine methyl ester on hypoxic pulmonary vasoconstriction.

We studied the role of nitric oxide in the regulation of pulmonary arterial tone and hypoxic pulmonary vasoconstriction. Rat pulmonary arteries (n=65, diameter=440+/-12 microm) were loaded to 17.5 mm Hg in a wire myograph and incubated with the nitric oxide synthase inhibitor N-gamma-nitro-L-argine methyl ester (L-NAME; 1, 10 or 100 microM) or distilled water (50 microl) prior to preconstriction with either 100 microM prostaglandin F(2 alpha) followed by acetylcholine (0.1-100 microM) or 5 microM prostaglandin F(2 alpha) followed by hypoxia. Concentrations of L-NAME (10 and 100 microM) which attenuated acetylcholine dilatation, elevated basal tone from 0. 2+/-0.5% to 9.4+/-2.1% (P<0.01) and 18.3+/-3.2% (P<0.001), respectively, potentiated contraction to 5 microM prostaglandin F(2 alpha) from 35.9+/-3.1% to 56.2+/-6.8% (P<0.05) and 66.4+/-5.8% (P<0.001), respectively, but had no significant effect on hypoxic pulmonary vasoconstriction. This suggests basal pulmonary nitric oxide release occurs, as well as in response to agonist-induced contraction, but not hypoxic pulmonary vasoconstriction.

Animals↗
PubMed2000

Hydrogen peroxide--an intracellular signal in the pulmonary circulation: involvement in hypoxic pulmonary vasoconstriction.

Hypoxic pulmonary vasoconstriction (HPV) is a regulatory feature of the pulmonary circulation that ensures consistent matching of perfusion to ventilation in the normal lung. However, under pathophysiological conditions, HPV contributes to the elevated pulmonary arterial pressure inherent to numerous disease states. Consequently, control of HPV is an avenue of potential therapy for such conditions. This review discusses the role of hydrogen peroxide (H(2)O(2)) as an intracellular signal in the pulmonary circulation, concentrating on the potential involvement of H(2)O(2) in HPV and in the control of pulmonary arterial tone. Sites of hypoxic pulmonary arterial H(2)O(2) production include the mitochondrial electron transport chain, a microsomal electron transport chain containing an NADH oxidoreductase and alternatively, a membrane-bound NADPH oxidase. Each of these sources of H(2)O(2) and the effect of hypoxia on the production of reactive oxygen species are considered. The review also discusses the variance in vascular reactivity of H(2)O(2), which is described to elicit both pulmonary arterial vasoconstriction and dilatation at varying concentrations. The redox capabilities of H(2)O(2) are also considered. The relevance of all of these actions of H(2)O(2) are also assessed as potential pharmacological targets for the future development of therapy for lung diseases that are characterised by some degree of HPV and in the pathogenesis of pulmonary diseases in which reactive oxygen species are implicated.

Humans↗
PubMed2000

Diuretic induced change in lung water assessed by electrical impedance tomography.

Monitoring patients with left ventricular failure can be difficult. Electrical impedance tomography (EIT) produces cross-sectional images of changes in the impedance of the thorax. We measured changes in the electrical impedance of the lung in nine volunteers following a diuretic challenge. The hypothesis was that lung impedance would increase with diuretic induced fluid loss. Heart rate, blood pressure and urine output were also recorded. After diuretic the mean urine output was 1220 ml compared with 187 ml after placebo. Following diuretic administration, mean thoracic impedance increased by 13.6% (p < 0.01) and lung impedance increased by 7.8% (p < 0.05). Taken as a group there was a correlation between overall impedance change and total urine output. However, for each individual, the time course of change in impedance and urine output did not correlate significantly. Our findings show that EIT may offer a better guide to the response of the lung to diuretic treatment than simply measuring urine output. The urine output is neither specific nor sensitive in the assessment of lung water. Mean lung impedance, however, is largely determined by lung water. The study showed that lung impedance can be recorded at supra-normal values. EIT may help in the management of patients with excess lung water.

Adolescent↗
PubMed2000

Comparison of the effect on bronchial hyperresponsiveness of beclomethasone dipropionate administered via a novel multidose dry-powder inhaler or a conventional pressurised metered dose inhaler.

BACKGROUND: Treatment with inhaled corticosteroids improves symptoms and reduces bronchial hyperresponsiveness (BHR) associated with asthma. Delivery of drugs into the lung is dependent on the inhaler device. Furthermore, environmental concerns regarding the use of chlorofluorocarbon propellants in pressurised inhalers and patient acceptability of inhaler devices both influence the extent of use of different delivery systems. OBJECTIVES: To compare the efficacy of beclomethasone dipropionate (BDP) administered via a novel multidose dry-powder inhaler (DPI) and a conventional pressurised metered-dose inhaler (pMDI) with spacer in patients with BHR. METHODS: A randomised, double-blind, crossover study was carried out in a group of 27 patients (aged 19-55 years) with a clinical diagnosis of reversible airway disease, who demonstrated BHR to methacholine (PD(20) < or =6.4 mg). Each patient received BDP (< or =2 mg/day) via the DPI or pMDI, for periods of 4 weeks. The randomised treatment periods were preceded by 3-week washout periods when no corticosteroid was used. Five clinic visits marked the start and end of each study phase. The primary efficacy endpoint was BHR as defined by the pharmacodynamic parameter, PD(20), which was determined at the start and end of each treatment period. Clinical endpoints including lung function, symptoms and adverse events were also evaluated. RESULTS: Both treatments caused a significant decrease in BHR (p<0.05 vs. pre-treatment values). Mean +/- SD changes in log PD(20) were: DPI 0.59+/-1.29; pMDI 0.59+/-0.94 mg. There was no statistically significant difference between treatments and no evidence of a carry-over effect between treatments on BHR. Clinical efficacy and safety parameters also demonstrated no statistically significant treatment differences, and patients found the DPI easier to use. CONCLUSION: Efficacy of BDP in reducing BHR is comparable via the DPI and pMDI plus spacer.

Administration, Inhalation↗
PubMed2000

Breath carbon monoxide as an indication of smoking habit.

STUDY OBJECTIVE: To assess whether the breath carbon monoxide (CO) concentration can be used to determine a patient's smoking habits in a respiratory outpatient clinic. DESIGN: To provide a normal range for smokers and nonsmokers, 41 outpatients and 24 healthy subjects were questioned on their smoking habits and asked to provide two breaths into a CO monitor (EC50 Smokerlyser; Bedfont Instruments; Kent, UK). In a subsequent single-blind study, 51 different outpatients were not told of the purpose of the study and were assessed by extensive questionnaire, spirometry, and Smokerlyser estimation. SETTING: The Chest Clinic and Pulmonary Medicine Department at the Northern General Hospital, Sheffield, UK. PARTICIPANTS: Phase 1 involved 41 outpatients attending the Chest Clinic and 24 nonoutpatient colleagues. In phase 2, an additional 51 different outpatients were studied. MEASUREMENTS AND RESULTS: The mean (SD) breath CO levels were 17.4 (11.6) parts per million (ppm) for smokers and 1.8 (1.3) ppm for nonsmokers (p < 0.001). A level of 6 ppm was taken as the cutoff, as this gave a selectivity of 96% and a sensitivity of 94% for outpatients. Of the 51 study patients, 5 admitted to smoking in the administered questionnaire. Eight denied smoking but had a mean breath CO > 6 ppm (7.5 to 42 ppm). Of these, three admitted to smoking after being explained the implication of the reading. CONCLUSIONS: Breath CO concentration provides an easy, noninvasive, and immediate way of assessing a patient's smoking status. A reading > 6 ppm strongly suggests that an outpatient is a smoker.

Adult↗
PubMed2000

Reproducibility of bronchodilator response for a reservoir dry powder inhaler following routine clinical use.

The performance of dry powder inhaler (DPI) devices, particularly reservoir DPIs, may be influenced by environmental conditions. This study compared the bronchodilator efficacy and in vitro aerosol characteristics of salbutamol, delivered via a novel reservoir DPI (Clickhaler) and a conventional pressurized metered-dose inhaler (MDI) before and after use of the DPI in clinical practice. Following a screening visit, patients received cumulative doses of salbutamol (100, 200, and 400 microg) via DPI or MDI on separate days in a double-blind, crossover design before and after a 4-week period, during which the DPI was used as the patients' first-line bronchodilator. Lung function responses (forced expiratory volume in 1 sec [FEV1], forced vital capacity [FVC], and peak expiratory flow [PEF]) to salbutamol delivered by DPI and MDI and in vitro aerosol characteristics were not significantly different before and after the period of DPI patient use. DPI performance, assessed in vivo and in vitro, is maintained following an extended period of patient use.

Adult↗
PubMed2000

Efficacy and safety of a novel beclomethasone dipropionate dry powder inhaler (Clickhaler) for the treatment of adult asthma. Amsterdam Clinical Study Group.

A randomized, double-blind, double-dummy protocol was used to compare the safety and efficacy of beclomethasone dipropionate (BDP) delivered by a novel dry powder inhaler (DPI, Clickhaler) or by a pressurized metered-dose inhaler (MDI) plus spacer. There was a four-week run-in period, completed by 240 adult patients, who received BDP via an MDI. Patients with stable asthma were then randomized into a 12-week treatment period and received BDP (< or =2 mg/day via DPI or MDI). There were no significant differences in morning peak expiratory flow (PEF) (primary endpoint), evening PEF, overall daytime or nighttime symptom scores, or lung function parameters (forced expiratory volume in 1 sec, forced vital capacity) between DPI and MDI. The safety profiles were similar and patient acceptability for Clickhaler was high. In conclusion, BDP administered via Clickhaler was found to be clinically equivalent to an optimally used MDI. Patients with stable asthma currently receiving BDP via MDI may be effectively switched to treatment via Clickhaler DPI.

Anti-Asthmatic Agents↗
PubMed2000

Aging reduces the responsiveness of coronary arteries from male Wistar rats to the vasodilatory action of testosterone.

This study was performed to examine whether aging affects the vasodilatory effects of testosterone in the coronary arteries of male rats. Isolated coronary arteries from young mature (3-4 months) and elderly (22-26 months) male Wistar rats were studied in a wire myograph. Contractile function and endothelial function were assessed by measuring vasomotor responses to 10-100 mmol/l KCl, 0.1 mmol/l prostaglandin F(2alpha) (PGF(2alpha)) and 10 micromol/l acetylcholine. Sensitivity to the vasodilatory effects of testosterone was assessed by constructing dose-response curves to concentrations between 1 micromol/l and 1 mmol/l testosterone dissolved in water in vessels maximally preconstricted with PGF(2alpha). The compliance characteristics of each vessel and serum testosterone levels from each animal were measured. Histological sections of myocardium were examined for differences in coronary artery morphology. Vessels from elderly animals were significantly more resistant to the vasodilatory effects of testosterone than vessels from young animals (P=0.001 by analysis of covariance). Vessels from elderly animals were also significantly less compliant (7.32+/-0.43 microm/mN, compared with 10.99+/-1.52 microm/mN in young animals; P=0.011), and the levels of circulating testosterone in elderly animals were lower, but not significantly so (2.04+/-0.63 nmol/l compared with 3.88+/-1.7 nmol/l; P=0.32). Vessels from elderly animals were less contractile in response to KCl than those from young animals (P=0.004 by analysis of covariance). There were no significant differences between the two groups in their responses to PGF(2alpha) or acetylcholine. Thus it is concluded that coronary arteries from elderly rats are significantly less sensitive to the vasodilatory effects of testosterone than those from young animals.

Acetylcholine↗
PubMed2000

The NADPH oxidase inhibitors iodonium diphenyl and cadmium sulphate inhibit hypoxic pulmonary vasoconstriction in isolated rat pulmonary arteries.

Interest surrounds the role of an NADPH oxidase-like enzyme in hypoxic pulmonary vasoconstriction (HPV). We have studied the effects of the NADPH oxidase inhibitors iodonium diphenyl (ID) and cadmium sulphate (CdSO4) upon HPV of isolated rat pulmonary arteries (n = 73, internal diameter 545 +/- 23 microm). Vessels were preconstricted with prostaglandin F2alpha (PGF2alpha, 0.5 or 5 microM) prior to a hypoxic challenge. ID (10 or 50 microM), CdSO4 (100 microM) or vehicle (50 microl) was added for 30 min before re-exposure to PGF2alpha and hypoxia. ID and CdSO4 significantly inhibited HPV. In vessels preconstricted with 5 microM PGF2alpha, ID (10 and 50 microM) reduced HPV from 37.4 +/- 5.6 % to 9.67 +/- 4.4 % of the contractile response elicited by 80 mM KCl (P<0.05) and from 30.1 +/- 5.0 % to 0.63 +/- 0.6% 80 mM KCl response (P<0.01), respectively. CdSO4 (100 microM) reduced HPV from 29.4 +/-4.0 % to 17.1 +/- 2.2% 80 mM KCl response (P<0.05). In vessels preconstricted with 0.5 microM PGF2alpha, ID (10 and 50 microM) reduced HPV from 16.0 +/- 3.15% to 3.36 +/- 1.44 % 80 mM KCl response (P<0.01) and from 15.0 +/- 1.67 % to 2.82 +/- 1.40 % 80 mM KCl response (P<0.001), respectively. Constriction to PGF2alpha was potentiated by ID. ID and CdSO4, at concentrations previously shown to inhibit neutrophil NADPH oxidase, attenuate HPV in isolated rat pulmonary arteries. This suggests that an NADPH oxidase-like enzyme is involved in HPV and could act as the pulmonary oxygen sensor.

Animals↗
PubMed1999

The effect of the endothelin ET(A) receptor antagonist CI-1020 on hypoxic pulmonary vasoconstriction.

The mechanism of Hypoxic Pulmonary Vasoconstriction is unknown. The role of endothelin-1 in hypoxic pulmonary vasoconstriction was studied in precontracted small and large pulmonary arteries using the endothelin ETA receptor antagonist sodium-2-benzol [1,3]dioxol-5-yl-4-(4-methoxyphenyl)-4-oxo-3-(3,4,5-trimethoxy-ben zyl)-but-2-enoate (CI-1020). Small rat pulmonary arteries exhibit a mixed endothelin ETA receptor and endothelin ETB2 receptor population whereas large rat pulmonary arteries contain only endothelin ETA receptors. CI-1020 inhibited endothelin-1 in small vessels via endothelin ETA receptor blockade (1 and 10 microM) and at high concentrations via endothelin ETA receptor and endothelin ETB2 receptor blockade (100 microM). CI-1020 (0.01, 0.1 and 1 microM) inhibited endothelin-1 in large vessels via endothelin ETA receptor blockade alone. CI-1020 (1, 10 and 100 microM) significantly reduced hypoxic pulmonary vasoconstriction in small vessels, by -9.8+/-1.4, -9.2+/-2.3 and -8.0+/-1.7% 80 mM K+, respectively, compared to +2.5+/-4.2% with vehicle (P < 0.05). CI-1020 (0.01, 0.1 and 1 microM) had no significant effect upon hypoxic pulmonary vasoconstriction in large vessels. In small, but not large, pulmonary arteries hypoxic pulmonary vasoconstriction is due in part to the action of endothelin-1 at the endothelin ETA receptor.

Animals↗
PubMed1999

Cough induced by low pH.

Citric acid has been used as a tussive agent in the investigation of the cough reflex. The mechanism of cough stimulation remains unclear. We conducted studies to compare the cough response of citric acid to an organic (acetic acid) and an inorganic acid (phosphoric acid). We also compared the cough response of citric acid to capsaicin, a non-acid tussive stimulus. In study 1, 26 subjects inhaled equimolar concentrations of citric and acetic acid. In study, 2, 22 subjects inhaled citric acid and phosphoric acid in concentrations of similar pH. Eighteen subjects from study 2 completed a capsaicin cough challenge test. The cough response was recorded and the concentration causing two coughs, the cough threshold, calculated (D2). The correlation of cough thresholds between both citric and acetic acid (r = 0.79, 95% CI 0.37-0.90, P < 0.0001) and citric acid and phosphoric acid (r = 0.68, 95% CI 0.37-0.86, P = 0.0005) were significant. There was no correlation between the citric acid and capsaicin cough thresholds. These results show that an individual's cough response to acetic and phosphoric acid are similar to that caused by citric acid. Thus these acids may cause cough by a common mechanism such as disturbance of the pH of the airway surface liquid. Capsaicin does not appear to share this common pathway.

Acetic Acid↗
PubMed1999

Monitoring patients with left ventricular failure by electrical impedance tomography.

Acute left ventricular failure (LVF) is a common medical emergency but detection and monitoring of pulmonary oedema remains problematic. Fluid is an important determinant of tissue impedance. Electrical impedance tomography (EIT) is a non-invasive technique allowing localisation of impedance changes within tissue. We have investigated the relationship between LVF and the electrical impedance of lung tissue. Twenty patients with a clinical diagnosis of acute left ventricular failure were compared with 30 normal subjects. Patients were monitored using serial chest radiographs and electrical impedance tomography measurements of lung impedance during hospital admission. Radiographs were graded according to the severity of pulmonary oedema by two independent radiologists. Lung impedance was significantly (P<0.0001) lower than normal in patients with left ventricular failure. Values returned towards the normal range as LVF resolved. There was a similar improvement in the score of the chest radiographs. The electrical impedance of the lung is low in left ventricular failure and increases following treatment.

Acute Disease↗
PubMed1999

The antitussive effect of dextromethorphan in relation to CYP2D6 activity.

AIMS: To test the hypothesis that inhibition of cytochrome P450 2D6 (CYP2D6) by quinidine increases the antitussive effect of dextromethorphan (DEX) in an induced cough model. METHODS: Twenty-two healthy extensive metaboliser phenotypes for CYP2D6 were studied according to a double-blind, randomised cross-over design after administration of: (1) Placebo antitussive preceded at 1 h by placebo inhibitor; (2) 30 mg oral DEX preceded at 1 h by placebo inhibitor (DEX30); (3) 60 mg oral DEX preceded at 1 h by placebo inhibitor (DEX60); (4) 30 mg oral DEX preceded at 1 h by 50 mg oral quinidine sulphate (QDEX30). Cough frequency following inhalation of 10% citric acid was measured at baseline and at intervals up to 12 h. Plasma concentrations of DEX and its metabolites were measured up to 96 h by h.p.l.c. RESULTS: Inhibition of CYP2D6 by quinidine caused a significant increase in the mean ratio of DEX to dextrorphan (DEX:DOR) plasma AUC(96) (0.04 vs 1.81, P<0.001). The mean (+/-s.d.) decrements in cough frequency below baseline over 12 h (AUEC) were: 8% (11), 17% (14.5), 25% (16.2) and 25% (16.9) for placebo, DEX30, DEX60 and QDEX30 treatments, respectively. Statistically significant differences in antitussive effect were detected for the contrasts between DEX60/placebo (P<0.001; 95% CI of difference +80, +327) and QDEX30/placebo (P<0.001, +88, +336), but not for DEX30/placebo, DEX30/DEX60 or DEX30/QDEX30 (P=0.071, -7, +241; P=0.254, -37, +211; P=0.187, -29, +219, respectively). CONCLUSIONS: A significant antitussive effect was demonstrated after 60 mg dextromethorphan and 30 mg dextromethorphan preceded by 50 mg quinidine using an induced cough model. However, although the study was powered to detect a 10% difference in cough response, the observed differences for other contrasts were less than 10%, such that it was possible only to imply a dose effect (30 vs 60 mg) in the antitussive activity of DEX and enhancement of this effect by CYP2D6 inhibition.

Adolescent↗
PubMed1999

Cough threshold in patients with chronic obstructive pulmonary disease.

BACKGROUND: Cough is an important symptom of patients with chronic obstructive pulmonary disease (COPD). The cough threshold to citric acid and capsaicin in patients with COPD and in normal volunteers was measured, as well as bronchial hyperresponsiveness to methacholine. METHODS: Nineteen patients with COPD and 22 controls were recruited. Subjects underwent a methacholine bronchoprovocation test and a cough challenge to citric acid and capsaicin. RESULTS: The log citric acid cough threshold D2 (concentration causing two coughs) was significantly lower in patients with COPD (mean 2.17 versus 2.56, mean difference (95% CI) 0.39 (0.04 to 0.74), p = 0.02) but not for capsaicin cough D2 (0.66 versus 0.8, p = 0.41). Sixteen patients with COPD had bronchial hyperresponsiveness which was correlated with baseline FEV1 (r = 0.6, p = 0.01, 95% CI 0.15 to 0.84). CONCLUSIONS: Patients with COPD have a lower cough threshold to citric acid, possibly due to a differential effect of cigarette smoke on citric acid sensitive cough receptors.

Adult↗
PubMed1998

Inhibition of hypoxic pulmonary vasoconstriction in isolated rat pulmonary arteries by diphenyleneiodonium (DPI).

The NADPH oxidase inhibitor, diphenyleneiodonium (DPI), is known to selectively inhibit hypoxic pulmonary vasoconstriction (HPV) in isolated rat and rabbit lungs. We have investigated whether DPI has similar effects in rat pulmonary arteries in vitro. Vessels (n=38, internal diameters 327+/-41 microM) were mounted in an automated myograph and preconstricted with prostaglandin F2alpha (PGF2alpha, 5 microM) before an acute hypoxic challenge. The effects of DPI (10 microM), or the vehicle DMSO, were studied on the first contractile phase of HPV. DPI (10 microM) was found to significantly inhibit HPV; 1.83+/-0.42 mN/mm (pre-DPI) compared to 0.11+/-0.22 mN/mm (post-DPI,P<0.01). However, the vehicle DMSO (0.2%) also resulted in a reduction of HPV, although this was significantly different from inhibition via DPI (P<0.05), implying a DPI-sensitive component. The effects of DPI (0.1-300 microM) were also studied on the second contractile phase of HPV. DPI (300 microM) caused a significant reversal of 45% (0.50-0.27 mN/mm) compared to 9% reversal (0.38-0.35 mN/mm) seen with DMSO (P<0.0001). The fact that an inhibitor of NADPH oxidase, the enzyme responsible for producing reactive oxygen species from oxygen, attenuated the pulmonary vascular response to hypoxia, may indicate that this, or a similar, enzyme is involved in oxygen sensing.

Animals↗
PubMed1998

Identification of the L-menthol binding site in guinea-pig lung membranes.

1. L-Menthol inhibits both neurokinin A and capsaicin-induced bronchoconstriction in the guinea-pig and relaxes pre-constricted guinea-pig isolated bronchi. Structure-activity relationships have been defined for the action of (-)-menthol and related compounds on cold receptors, suggesting an action of L-menthol at a pharmacological receptor. We have performed radioligand binding studies to characterize the binding sites for [3H]-L-menthol in whole cell membranes prepared from guinea-pig lung tissue. 2. In kinetic studies. [3H]-L-menthol was found to bind rapidly and reversibly. Binding of [3H]-L-menthol to lung membranes was found to be time-dependent becoming fully associated to its site within 40 min, and half-maximum association occurred within 8 min (t1/2=8 min). [3H]-L-menthol was fully dissociated from its binding site within 8 min, (t1/2=2 min). 3. Inhibition studies presented a pharmacological profile of the 'L-menthol site'. Capsaicin, capsazepine, D-menthol, eugenol, SCH23390 and camphor were all found to displace [3H]-L-menthol binding. In contrast WS3, noradrenaline, 5-hydroxytryptamine, spiperone, flunarazine, bepridil and nicardipine were without effect. 4. We have identified a L-menthol binding site in the guinea-pig, which may represent a site common to a variety of compounds.

Animals↗
PubMed1998

Respiratory symptoms among glass bottle workers--cough and airways irritancy syndrome?

Glass bottle workers have been shown to experience an excess of respiratory symptoms. This work describes in detail the symptoms reported by a cohort of 69 symptomatic glass bottle workers. Symptoms, employment history and clinical investigations including radiology, spirometry and serial peak expiratory flow rate records were retrospectively analyzed from clinical records. The results showed a consistent syndrome of work-related eye, nose and throat irritation followed after a variable period by shortness of breath. The latent interval between starting work and first developing symptoms was typically 4 years (median = 4 yrs; range = 0-28). The interval preceding the development of dysponea was longer and much more variable (median = 16 yrs; range = 3-40). Spirometry was not markedly abnormal in the group but 57% of workers had abnormal serial peak expiratory flow rate charts. Workers in this industry experience upper and lower respiratory tract symptoms consistent with irritant exposure. The long-term functional significance of these symptoms should be formally investigated.

Adult↗