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Biomedical subjects

A H Morice

Publications and source records attributed to A H Morice.

At least 91 records · Page 5Linked to original sources
PubMed1996

Acute pulmonary vasodilatory properties of amlodipine in humans with pulmonary hypertension.

OBJECTIVE: Calcium antagonists are the only oral vasodilators shown to influence mortality in primary pulmonary hypertension, but the high doses required are often poorly tolerated. Amlodipine is a novel, relatively well tolerated, calcium antagonist. It has not been previously tested in humans with pulmonary hypertension. DESIGN: Calcium antagonists are claimed to be of benefit in the 20-30% of patients who respond--that is, whose mean pulmonary artery pressure and pulmonary vascular resistance decreased by 20% after acute administration. Increasing oral doses of amlodipine (up to 40 mg) were given and haemodynamic measurements were obtained by the use of indwelling pulmonary artery catheters 12 h after each dose. SETTING: Large teaching hospital, primary referral centre. PATIENTS: Six patients (four women; age range 37-78 years) with pulmonary hypertension (one with primary pulmonary hypertension, five with thromboembolic disease. MAIN OUTCOME MEASURES: Mean pulmonary artery pressure and pulmonary vascular resistance decreased by greater than 20% in two patients, mean pulmonary artery pressure decreased by greater than 20% in one patient with a pulmonary vascular resistance reduction of 19%. Thus, two of six patients responded to amlodipine and one partially responded. RESULTS: The whole group mean (SEM) pulmonary artery pressure decreased from 47.7 (4.2) to 41.7 (4.4) mm Hg and mean pulmonary vascular resistance from 8.6 (2.1) to 7.1 (1.8) Wood units. Cardiac output rose by a mean (range) of 4% (-20.8 to+20.8), heart rate by 8.8% (-10 to +33), and systemic systolic blood pressure decreased by 12% (-29.2 to -5.8) and diastolic blood pressure by 6.8% (-28.2 to+20.0). There were no symptoms of systemic hypotension. CONCLUSION: These results show that oral amlodipine can produce acute pulmonary vasodilatation in patients with pulmonary hypertension. Further studies are required, but amlodipine may prove to be of value in the treatment of primary pulmonary hypertension.

Adult↗
PubMed1996

In vitro contractility studies of the rat middle cerebral artery after stereotactic Gamma Knife radiosurgery.

The middle cerebral artery (MCA) was irradiated in 94 rats using the Gamma Knife. The vessels receiving 20, 50, 80 and 200 Gy were removed 24 h later and mounted on a myograph. Contractility responses to potassium and prostaglandin (PG) F2 alpha were tested. After precontraction with PGF2 alpha, the relaxant effects of histamine, papaverine, L-arginine and sodium nitroprusside were examined. Other vessels were preincubated with ouabain or N omega-nitro-L-arginine methyl ester before testing with the relaxant agents. After irradiation, the contractile response to maximal potassium and PGF concentrations was diminished, suggesting dose-dependent radiation damage to the contractile mechanism. The normal MCA shows an initial relaxation in the presence of a low K+ concentration, which is Na+, K(+)-ATPase dependent. According to this study, the endothelium-derived relaxation function was suppressed by radiation, suggesting that there is an early change in irradiated vessels, demonstrable by functional studies, which affects both the smooth muscle and endothelial layers.

Animals↗
PubMed1996

A comparison of pathophysiological changes during hypobaric and normobaric hypoxia in rats.

Littermate male Wistar specific pathogen-free rats were divided into three groups at 28 days of age. The pathophysiological effects seen in rats exposed to normobaric hypoxia (NB) at 10% O2 were compared with those seen in animals exposed to hypobaric hypoxia (HB) at 500 mbar, equivalent to an inspired O2 concentration of 10%, and controls after periods of 5, 10 and 14 days. 5 days' exposure to a low oxygen environment resulted in less weight gain, the development of right ventricular hypertrophy and double elastic laminae in the pulmonary arterioles and an increase in haematocrit and plasma levels of atrial natriuretic peptide (ANP) in both the HB and NB animals compared to controls. There was no significant difference in these values between the two hypoxic groups. After 10 days' exposure to a low oxygen environment, body weight, ventricular ratio, plasma ANP levels and double elastic laminae were higher than the levels seen after 5 days in both NB and HB groups of rats. At day 14 only body weight and haematocrit were greater when compared to day 10 values in NB and HB groups. In conclusion the stress of this hypobaric environment caused no additional changes in the pathophysiological variables studied, compared with the changes seen in NB.

Animals↗
PubMed1996

Plasma levels of atrial natriuretic peptide and brain natriuretic peptide following intravenous saline infusion in oedematous chronic obstructive pulmonary disease and non-oedematous chronic obstructive pulmonary disease.

Some patients with chronic obstructive pulmonary disease (COPD) develop oedematous COPD (oCOPD) with peripheral oedema and have a poor prognosis. The cause of the fluid retention is poorly understood but could be due to defective release of a natriuretic factor. We investigated this hypothesis by measuring levels of brain natriuretic peptide (BNP) and atrial natriuretic peptide (ANP) before and after a 0.1 ml/kg/min 2.7% saline infusion in 6 patients with hypoxemic COPD but no history of oedema and 7 COPD patients with oCOPD. Vasopressin, aldosterone, plasma and urinary urea and electrolytes and osmolality were measured. Arterial blood gases and spirometry were also recorded. The two groups were similar in terms of age, weight, PaO2, PaCO2 and FVC. FEV1 was significantly lower in the oCOPD group. The oCOPD group excreted less urine (202 +/- 23 vs. 364 +/- 48 ml; p < 0.05) and less sodium (32 +/- 3 vs. 68 +/- 9 mmol/l; p < 0.01) as a percentage of the saline load given (18 +/- 2 vs. 30 +/- 4%; p < 0.05). Pre-infusion BNP and ANP levels were similar in both groups. BNP and ANP had an exaggerated increase in the oCOPD group on saline loading. In the oCOPD group, ANP levels were significantly greater 1 h after the saline load compared to the pre-infusion values (30 +/- 7 vs. 11 +/- 2; p < 0.05). BNP did not reach significantly greater levels than baseline values until 3 h after the infusion had ended (45 +/- 6 vs. 27 +/- 2; p < 0.05). At 1 h after the saline load, BNP and ANP levels were significantly greater in the oCOPD group (BNP 32 +/- 2 vs. 24 +/- 1; p < 0.01 and ANP 30 +/- 7 vs. 7 +/- 2; p < 0.05) when compared to COPD controls. BNP levels remained significantly different from the COPD control group 3 h after the infusion ended (45 +/- 6 vs. 26 +/- 2; p < 0.05). Although aldosterone levels were greater in the oCOPD group before the saline infusion, the hormone level was suppressed appropriately by the infusion. In conclusion, the cause of oedema in oCOPD and the inability to excrete a saline load is not due to a failure of release of BNP or ANP.

Aged↗
PubMed1995

Effect of the calcium antagonist amlodipine on the two phases of hypoxic pulmonary vasoconstriction in rat large and small isolated pulmonary arteries.

Calcium antagonists inhibit hypoxic pulmonary vasoconstriction (HPV), which was recently shown to be biphasic in isolated vessels, but the sensitivity of the two phases to calcium antagonism is unknown. We studied HPV in rat isolated large pulmonary arteries (PA) and resistance pulmonary arteries (PRV), using a small vessel myograph. Two phases of acute hypoxic pulmonary vasoconstriction were confirmed to occur in both sizes of vessel. The first phase was short-lived and was followed by a more persistent phase of gradual onset. The magnitude of the first phase of contraction was greater than the second (p < 0.01). The first phase was reproducible, but the second was variable. Tension generated per square millimeter of vessel during both phases of hypoxic contraction was significantly greater in PRV than in PA (p < 0.05). Amlodipine caused dose-dependent inhibition of the first phase of HPV (p = 0.01), with a greater effect in PRV (p < 0.01). The second phase was not significantly inhibited. These results confirm that HPV is biphasic in isolated large and small PA, with a greater sensitivity of the first phase to calcium antagonism. Therefore, the first phase may represent HPV as observed in vivo.

Amlodipine↗
PubMed1995

The effect of inhaled and oral dextromethorphan on citric acid induced cough in man.

1. Dextromethorphan is a widely used antitussive agent which is a non-narcotic codeine analogue. We have investigated whether inhaled administration of dextromethorphan provides antitussive activity in a citric acid induced cough model. 2. Twenty normal subjects underwent repeated cough challenge with 5% citric acid. Subjects were studied on six occasions. Study medication consisted of oral dextromethorphan 30 mg or oral matched placebo or 1, 3 and 30 mg inhaled dextromethorphan or matched inhaled placebo. Cough challenge was administered 10 min after study medication and hourly thereafter up to 250 min. 3. No significant differences were seen between baseline cough responses. Oral dextromethorphan (30 mg) produced a mean percentage reduction in cough of 38% (P < 0.002), which remained significant at 250 min. Inhaled dextromethorphan had no clinically significant effect although activity at later time points was not excluded. The antitussive effect of oral dextromethorphan is confirmed with prolonged inhibition of induced cough. It is possible that dextromethorphan or its active metabolites act centrally to inhibit the cough reflex.

Administration, Inhalation↗
PubMed1995

Functional desensitization of beta agonist responses in human lung mast cells.

The beta adrenergic agonist isoprenaline inhibited the IgE-triggered release of the preformed mediator histamine from human lung mast cells (HLMC) in a dose-dependent fashion. After prolonged (> or = 4 h) preexposure of HLMC to isoprenaline, there was a subsequent diminution in the effectiveness of a second exposure of isoprenaline to inhibit the release of histamine from activated HLMC. This induced hyporesponsiveness to isoprenaline was both concentration and time dependent. Although maximal levels of desensitization were obtained after an initial prolonged (14-h) preincubation with a high (10(-5) M) concentration of isoprenaline, exposure of HLMC for a shorter (4-h) time period with a lower (3 x 10(-7) M) concentration of isoprenaline was also effective at inducing a functional desensitization to isoprenaline. The inhibitory activity of the beta 2 agonist fenoterol was attenuated after a prolonged (14-h) pretreatment step with isoprenaline (10(-5)M), whereas the inhibitory properties of other adenylate cyclase activators, prostaglandin E2 and forskolin, were not affected appreciably. Prolonged (12-h) exposure of HLMC to the beta agonists fenoterol, salbutamol, and terbutaline also induced hyporesponsive states of beta agonists, qualitatively similar to that obtained with isoprenaline. The beta receptor antagonist propranolol, if coincubated with isoprenaline during the prolonged pretreatment step, protected against the subsequent refractoriness of the HLMC to isoprenaline. The glucocorticoid dexamethasone failed to prevent the isoprenaline-induced functional desensitization. In total, these results indicate that prolonged exposure of HLMC to beta agonists induces a state of selective hyporesponsiveness to agonists that act at beta adrenoreceptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Agonists↗
PubMed1995

Acute hypoxic vasoconstriction in isolated rat small and large pulmonary arteries.

Hypoxic vasoconstriction (HPV) has been shown to consist of a biphasic contraction change. The first phase of the hypoxic response peaks at approximately five minutes. The second phase is at about 30 minutes. The force of contraction of both phases of HPV were found to be significantly greater in pulmonary resistance vessels (PRV) than in pulmonary artery (PA) (P < 0.01). The endothelium modulates the hypoxic response, especially of the second phase of HPV (68% reduction in PRV) (P < 0.05). In Ca(2+)-free solution, the first peak and the second peak of HPV were reduced to 11 and 32% contraction in PRV and to 26 and 21% contraction in PA. A calcium channel antagonist (amlodipine) caused significant dose-dependent inhibition of the first phase of HPV (P = 0.001), with a significantly greater effect on PRV compared to PA (P < 0.01). Levcromakalim caused a dose-dependent inhibition of HPV in PRV (58% at 10 microM). In contrast, HPV in PA was not significantly inhibited by levcromakalim. In conclusion, this study has confirmed that hypoxia induces a biphasic contractile response in isolated pulmonary arteries requiring extracellular calcium. Both amlodipine and levcromakalim inhibit hypoxic pulmonary vasoconstriction and these agents may be of value in the treatment of pulmonary hypertension.

Acute Disease↗
PubMed1994

The antitussive effects of menthol, camphor and cineole in conscious guinea-pigs.

Menthol and other aromatic vapours have been widely used in the symptomatic treatment of upper respiratory tract infections, although there is little objective evidence as to their benefit. We have investigated the action of aromatic vapours on the cough reflex in conscious guinea-pigs. Animals (n = 13) were pretreated with air or test vapours for 5 min at a rate of 1 l/min. One minute later the animal was challenged with aerosolized citric acid for 2 min. Control responses to air pretreatment were not significantly different throughout the procedures. Three concentrations of each aromatic vapour were used (3, 10 and 30 micrograms/l menthol, 50, 133 and 500 micrograms/l camphor and 0.8, 2.7 and 8 mg/l cineole). Menthol proved the most effective antitussive--10 and 30 micrograms/l produced a significant 28 and 56% reduction in cough frequency--500 micrograms/l camphor gave a significant 33% reduction, while cineole, at the concentrations used, had no significant effect. An increase in cough latency coincided with a reduction in cough frequency. These results demonstrate the efficacy of aromatic vapours as antitussives in chemically induced cough.

Administration, Inhalation↗
PubMed1994

Detection of changes in intrathoracic fluid in man using electrical impedance tomography.

1. The Sheffield electrical impedance tomography system produces information on changes in the distribution of resistivity within tissue. We report on the assessment of electrical impedance tomography in monitoring changes in lung resistivity during a fluid challenge in normal man. 2. Eight normal subjects were studied. Electrical impedance tomography recordings were made at three different lung volumes before, during and after the intravenous infusion of 1 litre of 0.9% NaCl (saline). 3. The mean fall in lung resistivity during the infusion was -22% at total lung capacity (range -10% to -28%), -24% at tidal breathing (-15% to -37%) and -11% at residual volume (-5% to -19%) (P < 0.05 mean pre-infusion resistivity compared with the nadir value after infusion, Wilcoxon). 4. These changes in lung resistivity were probably due to a combination of a fall in haematocrit and an expansion of pulmonary blood volume.

Adult↗
PubMed1994

Effects of the neutral endopeptidase inhibitor, SCH 42495, on the cardiovascular remodelling secondary to chronic hypoxia in rats.

1. We have investigated the effects of inhibition of neutral endopeptidase on the cardiovascular remodelling secondary to chronic hypoxia in rats using a novel neutral endopeptidase inhibitor, SCH 42495. 2. Rats were divided into four groups, two of which were maintained in a normobaric, hypoxic chamber (10% O2) and two in room air. Animals received either neutral endopeptidase inhibitor, SCH 42495 (30 mg/kg), or aqueous methyl cellulose vehicle (0.4%) twice daily by oral gavage. 3. At 1, 3, 7, 10 and 14 days, animals (n = 4 per group for days 1, 3, 7 and 14, and n = 8 for day 10) were killed. Hearts were dissected and weighed for determination of ventricular ratios, lungs were perfused with formol saline for histological examination of the pulmonary vasculature, and blood was collected for measurement of plasma atrial natriuretic peptide level. 4. Treatment with SCH 42495 caused a significant reduction in the pulmonary vascular remodelling and ventricular hypertrophy in hypoxic rats after 10 days. Plasma atrial natriuretic peptide levels were significantly elevated in both SCH 42495-treated and control hypoxic animals (n = 8) after 10 days when compared with the normoxic groups. However, there was no difference in plasma ANP levels between SCH 42495-treated and control hypoxic groups at day 10. 5. Treatment with SCH 42495 leads to a decrease in cardiovascular remodelling secondary to chronic hypoxia in rats. A local action of atrial natriuretic peptide within the pulmonary vasculature may be responsible for this effect. Modulation of atrial natriuretic peptide may have therapeutic potential in the management of conditions characterized by pulmonary hypertension and pulmonary vascular remodelling.

Animals↗
PubMed1994

A comparison of ventilatory and cardiac related changes in EIT images of normal human lungs and of lungs with pulmonary emboli.

EIT images have been recorded from the upper thorax of 10 normal subjects and from two patients with pulmonary emboli. The Sheffield Mk2 system was used to obtain the EIT images during quiet tidal breathing and the images were then analysed to extract the cardiac and respiratory related components. In the 10 normal subjects the mean measured change in resistivity during tidal breathing was 9% (SD 3%) with no significant difference in four lung regions. The mean changes during the cardiac cycle were different in the four regions, ranging from -0.9% to -2.6%. The two patients showed very different cardiac related changes from those found in the normals in the posterior lung regions. The sign of the changes was positive, whereas it was negative in the normals. The changes in the anterior lung regions were within the range found in our normal group.

Adult↗
PubMed1994

Clinical applications of electrical impedance tomography in the monitoring of changes in intrathoracic fluid volumes.

We have previously shown that EIT can detect changes in intrathoracic fluid volumes in normal subjects undergoing a fluid challenge. We now report the preliminary results of two studies designed to investigate the ability of EIT to monitor changes in intrathoracic fluid in disease states. All recordings were made using the Sheffield Mark 1 system with the 16 electrode array placed around the lower thorax. Ten patients were studied during the sequential aspiration of unilateral pleural effusions. Following recording of a baseline dataset during tidal breathing (600 cycles) fluid was aspirated in 300 ml aliquots up to a maximum of 1000 ml, 600 cycles of data being collected after each aspiration. On the side of the effusion there was a progressive increase in intrathoracic resistivity in all patients as the fluid was aspirated. The mean increase in resistivity per 100 ml aspirated was 7%, range 3%-13%, p < 0.01 pre- versus post-aspiration resistivity. In the contralateral lung there was a smaller increase in all subjects (mean 1.8%, range 1%-3%) consistent with a reduction in mediastinal shift following aspiration. In these preliminary observations we have shown that EIT can be used in the clinical environment to detect small changes in intrathoracic fluid.

Adult↗
PubMed1994

Cardiac and respiratory related electrical impedance changes in the human thorax.

Electrical impedance measurements have been made from the human trunk over the frequency range 9.6 kHz to 614 kHz. Measurements have been made from 12 normal subjects and the amplitude of the impedance changes associated with the cardiac and respiratory cycles have been recorded. It was found that the real part of the impedance fell to 64.0% of its low frequency value over the measured range of frequencies and that the changes associated with respiration fell in a similar manner. However, the cardiac related changes fell more rapidly with increasing frequency to 28.2% of the low frequency value. The origin of the measured changes is discussed with a view to understanding why the cardiac related changes fall more rapidly. It is not possible to relate in any simple way the frequency dispersion of a single component to that of the whole trunk. However, the results are consistent with the lungs being the major origin of both the cardiac and respiratory related components. The origin of the cardiac related impedance changes could be the pulsatile volume changes in the pulmonary tree. These could be shunted by nonpulsatile lung tissue that has decreasing impedance at high frequency and thus decreases the relative magnitude of the cardiac related changes. This hypothesis needs to be tested using localized measurements from the thorax and 3-D modeling of the trunk.

Adult↗
PubMed1994

Neutral endopeptidase (NEP) inhibition in rats with established pulmonary hypertension secondary to chronic hypoxia.

1. Atrial natriuretic peptide (ANP) causes vasorelaxation in the pulmonary vasculature. ANP levels are elevated in conditions characterized by pulmonary hypertension and it has been hypothesized that ANP may be autoregulatory in the pulmonary circulation. 2. One route of ANP metabolism in vivo is by the action of the enzyme neutral endopeptidase (NEP). We have studied the effects of the NEP inhibitor, SCH 42495, in rats with established pulmonary hypertension secondary to chronic hypoxia. 3. Rats (n = 32) were divided into 4 groups. Normoxic controls were kept in air for 10 days (NC10) and all other animals were placed in a normobaric hypoxic chamber (F1 O2 10%). Chronic hypoxic controls were studied at 10 days (CHC10). After 10 days hypoxia the two remaining groups received oral treatment for a further 10 days, consisting of either SCH 42495 (30 mg kg-1, twice daily CHT20) or methyl cellulose vehicle (0.4%, twice daily, CHV20). 4. Animals were anaesthetized and blood collected for measurement of plasma ANP. Hearts were dissected and ventricles weighed and the histology of the pulmonary vasculature examined. 5. CHC10 rats had significant right ventricular hypertrophy (0.53 +/- 0.08) and pulmonary vascular remodelling (29.0 +/- 0.01%) and had gained significantly less body weight (33.2 +/- 5.5 g) than NC10 rats (0.31 +/- 0.04, 10.9 +/- 0.01%, and 59.2 +/- 11.9 g respectively). CHC10 rats had significantly elevated plasma ANP levels (58.4 +/- 9.9 pM) compared with NC10 rats (23.9 +/- 32 pM). Treatment with SCH 42495 caused a significant reduction in pulmonary vascular remodelling (25.0 +/- 0.01%) and right ventricular hypertrophy (0.52 +/- 0.09) in CHT20 rats compared with CHV20 controls (33.0 +/- 0.02% and 0.61 +/- 0.09 respectively). Pulmonary vascular remodelling was also significantly lower in CHT20 rats than CHC1O animals.6. Thus, short term inhibition of NEP causes regression of established pulmonary vascular remodelling and may be a useful therapeutic strategy in pulmonary hypertension.

Animals↗
PubMed1994

Effect of inhaled menthol on citric acid induced cough in normal subjects.

BACKGROUND: Menthol is a commonly used ingredient in many over the counter cough remedies, but there is little objective evidence as to its efficacy. METHODS: Twenty healthy subjects received a cough challenge consisting of five inhalations of 33 mumol citric acid from an air driven dosimeter. The challenge was repeated at hourly intervals for five hours. Five minutes before each challenge subjects inhaled, in a randomised design, either menthol 75% in eucalyptus oil or one of two placebos (pine oil or air). RESULTS: Menthol inhalation caused a reduction in evoked cough when compared with either placebo. CONCLUSIONS: Menthol is an effective antitussive agent in an evoked cough model.

Administration, Inhalation↗