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Biomedical subjects

M E Conolly

Publications and source records attributed to M E Conolly.

At least 37 records · Page 2Linked to original sources
PubMed1978

Use of exercise challenge to investigate possible tolerance to beta-adrenoceptor stimulation in asthma.

The effect of prolonged salbutamol administration on beta-adrenoceptor function in asthma has been examined. Six adult patients received salbutamol tablets (16 mg daily) for between 4 and 20 weeks and six adolescents received salbutamol aerosol (800 microgram daily) for 2--5 weeks. Before and after the treatment period the acute bronchodilator response to inhaled salbutamol and the ability of inhaled salbutamol to protect against exercise-induced asthma were examined. Lymphocyte beta-adrenoceptor function was also measured in the patients on tablet therapy. Inhaled salbutamol was less effective in protecting against exercise-induced asthma at the end of the treatment period in the patients who had received tablet therapy, but otherwise there was no significant change in beta-receptor function of either airways or lymphocytes. This apparent loss of efficacy of inhaled salbutamol in the prevention of exercise-induced asthma in some subjects, even when its acute bronchodilator effect is preserved, might reflect differences in the susceptibility of different beta-adrenoceptors to desensitization after prolonged stimulation: its clinical importance remains uncertain.

Adolescent↗
PubMed1978

The effect of indomethacin on the biosynthesis and metabolism of prostaglandin F2alpha in man.

Healthy volunteers received 60 microgram of [8,10,10(-2)H3] PGF2alpha by intravenous infusion both before and during a course of treatment with indomethacin (200 mg/day). Excretion of deuterated 5alpha, 7alpha-dihydroxy-11-ketotetranor-prostane-1, 16-dioic acid in urine was quantified by GC-MS using a reverse stable isotope dilution procedure. Indomethacin was found to have no detectable effect on the metabolism of the labelled PGF2alpha whereas output of the endogenous metabolite was markedly reduced by the effect of the drug on prostaglandin biosynthesis.

Adult↗
PubMed1978

Desensitization of the beta-adrenoceptor of lymphocytes from normal subjects and patients with phaeochromocytoma: studies in vivo.

1 Following the observation that lymphocyte beta-adrenoceptor responsiveness was not depressed in asthmatics treated only with non-adrenergic drugs we have explored the effects of prolonged exposure to beta-adrenoceptor agonists in normal subjects. 2 Treatment with oral salbutamol (12-16 mg/kg/day for 10 days), or with inhaled salbutamol (3000 microgram/day for 8-10 days) resulted in a significant reduction in lymphocyte beta-adrenoceptor responsiveness. 3 A 48 h infusion of isoxsuprine (10 mg/h) resulted in a marked depression of lymphocyte beta-adrenoceptor responsiveness (P less than 0.001). 4 Prolonged elevation of endogenous catecholamines caused by phaeochromocytoma was also associated with a marked depression of lymphocyte beta-adrenoceptor responsiveness (P less than 0.001). 5 There was no evidence that an increase in phosphodiesterase activity could explain the reduced cyclic AMP response. 6 It is concluded that diminished beta-adrenoceptor response occurs as a response to prolonged exposure to beta-adrenoceptor agonists. It is likely that the diminished response seen in asthmatic subjects can be explained on a similar basis and does not indicate an inherent cellular defect. 7 The possible clinical significance of such changes in asthmatics are discussed.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1978

Desensitization of the beta-adrenoceptor of lymphocytes from normal subjects and asthmatic patients in vitro.

1 A lymphocyte culture method has been developed for studying in vitro the effect of prolonged exposure (24 h) to isoprenaline (10(-8) to 10(-6) mol/l) and prostaglandin E1 (PGE1; 2.8 x 10(-6) mol/l). 2 The cyclic AMP response to isoprenaline is reduced by prolonged exposure to isoprenaline. The degree of desensitization is in proportion to the concentration of isoprenaline in the culture medium. 3 Culture with isoprenaline does not reduce the cyclic AMP response to PGE1. 4 Culture for 24 h with PGE1 (2.8 x 10(-6) mol/l) reduces the cyclic AMP response to PGE1. It also significantly reduces the response to isoprenaline. 5 Lymphocytes from asthmatic patients show a similar degree of desensitization to isoprenaline (after 24 h culture with isoprenaline) to that seen in lymphocytes from normal subjects. 6 A modified assay for phosphodiesterase (PDE) activity was developed. PDE activity increased 24.5% (P less than 0.02) after culture with PGE1 but was not significantly affected by culture with isoprenaline. 7 It is concluded that desensitization caused by prolonged exposure to various stimulators of adenylate cyclase is an event dependent on several components, not all of which are yet defined.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1977

The beta-adrenoceptor of the human lymphocyte and human lung parenchyma.

1 The response of the beta-adrenoceptors of human lymphocytes to selective agonists and antagonists has been studied quantitatively by measuring changes in cyclic adenosine-3',5'-monophosphate (cyclic AMP) levels. 2 The receptor was activated by isoprenaline and by salbutamol, and blocked by propranolol but not by practolol. A similar pattern of response was obtained with fragments of human lung tissue. 3 The mean value for pA2 for propranolol was 8.34 and for practolol was 3.95. 4 These findings indicate that the lymphocyte beta-adrenoceptor is a beta2-receptor and support the solidity of using lymphocytes to study beta-adrenoceptor function in bronchial asthma. It may also be of use in the evaluation of selective beta2-blocking drugs in man.

Albuterol↗
PubMed1977

Effect of the prostaglandin precursor, arachidonic acid, on histamine stimulated gastric secretion in the conscious dog, and observations on the effect of inhibiting endogenous prostaglandin synthesis.

The effects of intravenous infusions of prostaglandin E2 (PGE2) and arachidonic acid (AA) on histamine-stimulated gastric secretion have been studied in conscious dogs with either a simple gastric fistula or a denervated Heidenhain pouch. Both compounds produced a dose-related inhibition of acid secretion, though AA was 86-5 to 203-2 times less potent than PGE2. The maximal effect of AA was not achieved until 20 to 40 minutes after the infusion had ceased, suggesting that AA has to undergo some kinetic or metabolic process before it can act. Eicosatetraynoic acid (ETYN) 1-0 microgram.kg-1min-1, an inhibitor of PG biosynthesis, almost totally abolished the anti-secretory effect of AA up to 200 microgram.kg-1min-1. At 400 microgram AA.kg-1min-1, the antisecretory effect was reduced by about one half. The effect of PGE2 was not altered by ETYN. Furthermore, ETYN did not increase the response to histamine stimulation in control studies, which suggests that, in this model at least, prostaglandins are not involved in regulating gastric secretion.

5,8,11,14-Eicosatetraynoic Acid↗
PubMed1976

The lymphocyte beta-adrenoceptor in normal subjects and patients with bronchial asthma: the effect of different forms of treatment on receptor function.

beta-Adrenoceptor function has been compared in lymphocytes of normal subjects, asthmatic patients taking large doses of beta-adrenergic bronchodilators, and comparable asthmatics treated exclusively with nonadrenergic medication. The effect of prolonged administration of beta-adrenoceptor agonists on receptor function in normal subjects has also been examined. beta-receptor response in each situation was quantitated by changes in levels of cyclic AMP, measured by a protein-binding assay. Dose response curves to isoproterenol (10 nM-0.1 mM) have been constructed for each group. Maximal increase in cyclic AMP in lymphocytes from normal subjects (393.2+/-44.0%) and in asthmatics on nonadrenergic preparations (408.3+/-46.7%) was significantly greater (P less than 0.001) than in asthmatics taking large doses of beta-sympathomimetics (67.5+/-24.2%). Depression of the cyclic AMP response appeared to correlate with the degree of exposure to beta-adrenergic agonists but not with the prevailing severity of the patient's asthma. Withdrawal of beta-adrenergic drugs was followed by a reversion of the cyclic AMP response to normal values, which suggests that the depression was drug-induced rather than an inherent feature of the disease. This interpretation was confirmed by the finding that prolonged exposure of normal subjects to high doses of a beta-adrenergic agonist caused a marked and significant (p less than 0.001) reduction in the cyclic AMP response, very similar to that seen in asthmatics on large doses of adrenergic bronchodilators. A possible link between drug-induced changes in the cyclic AMP response and the rise in the United Kingdom asthma death rate in the 1960's is discussed.

Adolescent↗
PubMed1974

Metabolism of isoprenaline after aerosol and direct intrabronchial administration in man and dog.

1 Administration of isoprenaline by aerosol inhalation to man results in over 80% being metabolized to the sulphate conjugate.2 The majority of an inhaled dose is probably swallowed since the metabolic pattern resembles that after an oral dose.3 Isoprenaline, administered in aqueous solution directly into the bronchial tree in both man and dog, is rapidly O-methylated to 3-O-methyl isoprenaline, which is subsequently conjugated with sulphate.4 3-O-Methylation is the main metabolic pathway for the small part of an inhaled dose which does enter the bronchial tree.

Administration, Topical↗