Phaeochromocytoma with associated somatostatin production.
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Adrenal Gland Neoplasms↗
Biomedical subjects
A H Morice
Publications and source records attributed to A H Morice.
Atrial natriuretic peptide, altitude and acute mountain sickness.
1. To investigate the mechanisms of acute mountain sickness, 22 subjects travelled to 3100 m by road and the following day walked to 4300 m on Mount Kenya. Control measurements were made over 2 days at 1300 m before ascent and for 2 days after arrival at 4300 m. These included body weight, 24 h urine volume, 24 h sodium and potassium excretion, blood haemoglobin, packed cell volume, and symptom score for acute mountain sickness. In 15 subjects blood samples were taken for assay of plasma aldosterone and atrial natriuretic peptide. 2. Altitude and the exercise in ascent resulted in a marked decrease in 24 h urine volume and sodium excretion. Aldosterone levels were elevated on the first day and atrial natriuretic peptide levels were higher on both altitude days compared with control. 3. Acute mountain sickness symptom scores showed a significant negative correlation with 24 h urinary sodium excretion on the first altitude day. Aldosterone levels tended to be lowest in subjects with low symptom scores and higher sodium excretion. No correlation was found between changes in haemoglobin concentration, packed cell volume, 24 h urine volume or body weight and acute mountain sickness symptom score. 4. Atrial natriuretic peptide levels at low altitude showed a significant inverse correlation with acute mountain sickness symptom scores on ascent.
Acute Disease↗
Cough associated with angiotensin converting enzyme inhibition.
The therapeutic inhibition of angiotensin converting enzyme (ACE) is associated with the production of a dry cough, which occurs more commonly in women than men and appears to be unrelated to concurrent illness. At present the exact incidence of ACE inhibitor cough and the substrate of ACE responsible for this effect is unknown. Cough challenge by inhalation of aerosols of tussive agents such as citric acid and capsaicin may be used to study the effect of drug administration on the cough reflex. In normal subjects, an oral dose of captopril (25 mg) causes a significant shift in the dose-response curve to capsaicin inhalation, but not that to distilled water or citric acid. The exacerbation of artificially induced cough by ACE inhibition may be the result of a local increase in perineuronal substance P or bradykinin concentrations within the lung.
Angiotensin-Converting Enzyme Inhibitors↗
Angiotensin-converting enzyme and the cough reflex.
The effect of inhibition of angiotensin-converting enzyme (ACE) on standard cough challenge was investigated in a double-blind, randomised study in sixteen normal volunteers. Captopril (25 mg) or matched placebo was given by mouth 2 h before inhalation of nebulised distilled water, citric acid, and incremental doses of capsaicin (0.5-20 mumol/l). Distilled water and citric acid challenge were not significantly changed by captopril pretreatment. However, captopril significantly shifted the dose-response curve to capsaicin inhalation. The geometric mean dose of capsaicin causing 20 coughs/min was 1.3 mumol/l for captopril and 2.8 mumol/l for placebo pretreatment (p = 0.04). Cough is a recognised side-effect of ACE inhibitors; the observation that cough challenge is changed by these drugs in normal subjects implies a role for ACE in the cough reflex, possibly by metabolism of substrates other than angiotensin I.
Adult↗
A comparison of the vasodilator responses to atrial peptides in the pulmonary and renal arteries of the pig in vitro.
Noradrenaline preconstricted pulmonary and renal artery segments from 20 large White pigs were examined in vitro for their responses to alpha-human atrial natriuretic peptide (alpha-hANP), rat-atriopeptin I (AP I) or rat-atriopeptin III (AP III) added in a cumulative manner. The role of the vascular endothelium in atrial peptide-induced relaxation was examined in the presence of indomethacin and propranolol by removal of the endothelium in one of a pair of arterial segments. Pulmonary artery was significantly (P less than 0.001) more sensitive than renal artery to alpha-hANP with a potency ratio of approximately 10. alpha-hANP appeared to be a more potent relaxant than AP III and AP I in pulmonary artery. Potency ratios were approximately 2 (AP III vs alpha-hANP; P less than 0.05) and 30 (API vs alpha-ANP; P less than 0.001). Removal of the endothelium increased the sensitivity of renal artery to a alpha-hANP, but made no difference to the pulmonary arterial relaxations. In man the highest circulating concentrations of ANP are found in the pulmonary artery. The demonstration of its potent relaxant effects at this site in the pig indicates a possible role in the modulation of pulmonary arterial tone.
Animals↗
Clinical pharmacology of vasodilator peptides.
Several neuropeptides cause mild flushing when infused intravenously in humans. However, only calcitonin gene-related peptide (CGRP), vasointestinal peptide, and substance P (SP) cause reproducible falls in blood pressure when infused into normal subjects. Of these, CGRP is of the most interest because it is the most potent and because it is present in vascular nerve endings. This paper summarises the evidence to date suggesting that CGRP release from vascular nerve endings may be of physiological importance in the regulation of blood pressure.
Animals↗
Autoradiographic localisation of VIP receptors in human lung.
Localisation and pharmacological properties of the VIP receptor in human lung sections are described. The receptor density determined by saturation analysis using 125I-VIP is approx. 100 fmol/mg protein, with a Kd of approx. 600 pM. Inhibition of 125I-VIP binding with VIP and related peptides gives a rank order of potency: VIP greater than peptide histidine methionine greater than secretin. Light microscope autoradiography reveals specific VIP binding sites, with a high density over the pulmonary artery smooth muscle and the alveolar walls and with a lower density over the bronchial epithelium.
Autoradiography↗
Vasoactive intestinal peptide as a bronchodilator in severe asthma.
In two studies vasoactive intestinal peptide (VIP) was administered intravenously to two groups of eight in-patient volunteers recovering from severe acute asthma. VIP (6 pmol/kg/min) infusion caused significant (p less than 0.01) increase in peak expiratory flow rate (PEFR) of 26 +/- 9 (SEM) l/min after 30 minutes infusion compared with a bronchodilation of 39 +/- 19 l/min seen with salbutamol (5 mcg/min). Following pretreatment with nebulized ipratropium bromide, VIP infusion caused a significant (p less than 0.02) bronchodilation of 25 l/min. VIP is a bronchodilator in severe asthma, although its effects are less than conventional medication. Reflex mechanisms are unlikely to explain the bronchodilatory effect of intravenous VIP.
Adult↗
A comparison of the ventilatory, cardiovascular and metabolic effects of salbutamol, aminophylline and vasoactive intestinal peptide in normal subjects.
Intravenous infusion of placebo for 30 min followed by either salbutamol 10 micrograms min-1, aminophylline 0.2 mg kg-1 min-1 or vasoactive intestinal peptide (VIP) 6 pmol kg-1 min-1 for 30 min was performed in a single blind fashion in six normal volunteers. Both salbutamol and aminophylline increased minute ventilation, (P less than 0.05) the mean increase being 26% and 19% respectively. Aminophylline also increased the ventilatory response to carbon dioxide by 47% (P less than 0.05) when measured by hyperoxic rebreathing, whereas salbutamol and VIP were without significant effect. All three drugs caused a tachycardia, mean increase in the pulse being 16, 8 and 2 beats min-1 for salbutamol, aminophylline and VIP respectively, and aminophylline also increased both systolic and diastolic blood pressure, mean arterial pressure increasing by 14 mmHg. VIP caused haemoconcentration and salbutamol the expected changes in plasma biochemistry. Plasma catecholamines increased slightly during drug infusion, although this effect is unlikely to be important.
Adult↗
Chyluria associated with bronchial carcinoma.
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Bronchial Neoplasms↗
Neutral endopeptidase inhibition increases the potency of ANP in isolated rat pulmonary resistance vessels and isolated blood perfused lungs.
We have investigated the effects of the neutral endopeptidase inhibitor, SCH 42354, on the vasoreactivity of atrial natriuretic peptide (ANP) in rat isolated pulmonary resistance vessels (PRV) and isolated perfused lungs (IPL). PRV (n = 37) were mounted onto the jaws of a myograph and precontracted with PGF2alpha (100 mu M). Concentration-responses to ANP (0.17 to 340 nM) were determined before and after the addition of SCH 42354 (10, 30 and 100 nM). Each concentration of SCH 42354 caused a significant increase in potency (- log EC50) of ANP in isolated PRV. Lungs from normoxic rats (n = 13) were isolated and perfused with whole blood. An increase in pulmonary artery pressure was achieved by ventilating with an hypoxic gas mixture and concentration-responses obtained by incremental additions of ANP (40 nM to 12 mu M), before and after the addition of SCH 42354 (100 nM). SCH 42354 significantly increased the potency (- log EC50) of ANP in the rat IPL. ANP is partly metabolized by NEP. That an inhibitor of NEP increased the potency of ANP in isolated pulmonary vessels, and in isolated perfused whole lungs, suggested that SCH 42354 may be having a local action within the pulmonary vasculature.
Animals↗
Inhalation cough challenge in the investigation of the cough reflex and antitussives.
Inhalation cough challenge is a useful tool in the physiological and pharmacological investigation of the cough reflex. There are three types of challenge used, capsaicin and the vanilloids, organic acids, and distilled water challenge. In addition, challenge may be administered in a single dose or cumulative dose fashion. The correct combination of inhalation technology and tussive stimulus produces a sensitive and specific method for estimating the cough reflex.
Antitussive Agents↗
The effect of the ETA receptor antagonist (CI-1020) in rats with established hypoxic pulmonary hypertension.
ETA receptor antagonists have previously been shown to prevent the development of pulmonary hypertension induced by chronic hypoxia in the rat. Clinically, however, patients present with already established pulmonary hypertension. We have investigated the effects of the ETA receptor antagonist CI-1020 in rats previously adapted to chronic hypoxia. Two protocols were followed. Rats (n=32) were divided into two batches of four groups: normoxic controls in air for 10 days (NC10), chronic hypoxic controls in hypoxia for 10 days (CHC10), chronic hypoxic vehicle treated in hypoxia for 20 days (CHV20) and chronic hypoxic drug treated in hypoxia for 20 days (CHT20). Ten days after the onset of hypoxia, oral treatment with drug (40 mg/kg per day) or vehicle was started. Animal weight, ratio of right ventricular weight to left ventricular weight including septum (RV/LV+S) and percentage of double elastic lamina (DEL) were determined. In the second study, 12 rats were divided into three groups; normoxic controls in air for 20 days (NC20), (CHV20) and (CHT20). After 10 days hypoxia, oral treatment with drug (40 mg/kg per day) or vehicle was started. Isolated perfused lung preparations were then used to determine pulmonary artery pressure and pulmonary vascular resistance. Treatment with CI-1020 reduced the increase in RV/LV+S and the percentage DEL induced by chronic hypoxia and significantly lowered the increase in pulmonary resistance in isolated perfused lungs from chronically hypoxic animals. These results suggest that CI-1020 could have an important role in the treatment and reversal of established pulmonary vascular remodelling.
Administration, Oral↗
The ETA antagonist CI-1020 inhibits hypoxic pulmonary vasoconstriction in small isolated rat pulmonary arteries.
Hypoxic pulmonary vasoconstriction (HPV) of rat pulmonary arteries in vitro occurs in four phases. Initial vasodilation (phase 1), is followed by transient contraction (phase 2), further vasodilation (phase 3) and finally a second sustained contraction (phase 4). We have investigated the role of ET-1 in HPV using the ETA receptor antagonist CI-1020. Small rat pulmonary arteries (SPA, n=32, diameter=454+/-22 microM) were mounted in a wire myograph. Two contractions to 80 microM KCl ensured response reproducibility and relaxation to 10 microM acetyl choline following constriction with 100 microM prostaglandin F2alpha (PGF2alpha) to indicate endothelial integrity. A control hypoxic response was produced following priming with 5 microM PGF2alpha. Vessels (n=8) were then exposed to either vehicle or CI-1020 (1, 10 or 100 microM) for 30 min in the dark before re-exposure to PGF2alpha and hypoxia. Responses were standardized as a percentage of contraction to 80 mM KCl. Vehicle caused an increase in phase 2 of HPV of +2.51+/-4.20% (expressed as difference between pre- and post-drug values). CI-1020 (1, 10 and 100 microM) caused a significant reduction in phase 2 of HPV of -9. 76+/-1.40%, -9.23+/-2.30% and -7.96+/-1.70%, respectively (P<0.05). These results suggest that phase 2 of HPV in rat SPA is attributed, in part, to the action of ET-1 at the ETA receptor.
Animals↗
Vasoactive intestinal peptide as a bronchodilator in asthmatic subjects.
Vasoactive intestinal peptide (V.I.P.) caused bronchodilatation in 7 asthmatic volunteers when given intravenously at the rate of 6 pmol kg-1 min-1 for 15 minutes during a double blind study. Mean baseline FEV1 was 2.8 (+/- 0.3 S.E.) which was 81% of predicted and increased by 0.21 (range 0.1-0.45) l after 15 minutes infusion (p greater than 0.02). Tachycardia and cutaneous flushing were also observed during the infusion. Subsequent induced bronchoconstriction with a predetermined dose of histamine was ameliorated at 180 seconds following challenge when compared with placebo. Mean fall in FEV1 0.26 compared with 0.741 when pre-infusion FEV1 was taken on baseline. Mean fall in FEV1 0.49 l compared with 0.75 l when the FEV1 immediately preceding challenge was used on baseline (p greater than 0.02). The demonstration that V.I.P. is a bronchodilator in asthmatics and ameliorates histamine induced bronchoconstriction has important implications for the pharmacology of asthma.
Adult↗
Human vascular reactivity and polymorphisms of the angiotensin-converting enzyme and the angiotensin type 1 receptor genes.
The D allele of the insertion (I)/deletion (D) polymorphism in the angiotensin-converting enzyme (ACE) gene and the C allele of the A1166-C polymorphism in the angiotensin II type 1 receptor (AGT1R) gene have been associated with altered vascular structure and with an increased risk of myocardial infarction. The aim of this study was to determine whether differences in vascular function could be demonstrated to link the previously described changes in structure and the disease outcome. 70 subjects were recruited at random from patients undergoing colonic resection, resistance arteries were excised and were mounted in a small vessel wire myograph. Vasomotor responses to potassium chloride, noradrenaline, prostaglandin F(2alpha), angiotensin I, angiotensin II, acetylcholine and substance P were performed in 30 subjects. Genotype was established in a blinded fashion after completion of myography. To exclude the possibility of masking of genetic influence by non-ACE conversion of angiotensin I, vasomotor responses were then performed to proline(10)-angiotensin I in a further 30 subjects and to angiotensin I in the presence of chymostatin in a further 10 subjects. No significant effect of the I/D polymorphism of the ACE gene was seen on vasomotor function. The C allele of the AGT1R gene was associated with an increase in sensitivity to prostaglandin F(2alpha) but not with alteration to the other vasoactive agents studied. The I/D ACE and A1166-C AGT1 receptor polymorphism do not appear to result in differences in vasomotor function in isolated human mesenteric resistance arterioles in subjects without evidence of underlying hypertensive or cardiovascular disease.
Aged↗
An in vitro study of the pharmacological responses of rat middle cerebral artery: effects of overnight storage.
This study was designed to establish the in vitro pharmacological responses of rat middle cerebral arteries (MCA), and also their susceptibility to overnight cold storage at 4 degrees C. MCAs were harvested from rats and pharmacological responses were studied using a Mulvany myograph. Responses to prostaglandin F2 alpha (PGF2 alpha), uridine triphosphate (UTP), noradrenaline (NA) and histamine were determined to investigate receptor-dependent responses, sodium nitroprusside and papaverine to investigate receptor-independent relaxation and L-arginine and N omega-Nitro-L-arginine methyl ester (L-NAME) to examine nitric oxide synthase-dependent responses. Responses in fresh arteries were established and compared with responses in arteries which had been mounted on a myograph and stored overnight at 4 degrees C before study the next day. The MCAs had an effective lumen diameter of 263 microns (SD 25) and sustained concentration-dependent contractions were produced by 124 mM K+, PGF2 alpha, UTP and L-NAME. Sodium nitroprusside, NA, histamine, papaverine and L-arginine produced concentration-dependent relaxations in precontracted arteries. Overnight cold storage did not alter the pharmacological responses to any of the agonists tested.
Animals↗