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Biomedical subjects

M E Conolly

Publications and source records attributed to M E Conolly.

At least 19 recordsLinked to original sources
PubMed1990

Beta-adrenergic receptors on human lymphocytes: comparison of down-regulation in vivo and in vitro.

beta-Adrenergic receptors on isolated human lymphocytes were enumerated using 125I-cyanopindolol (125I-CYP), after a 90-min exposure to 50 mumols/l l-isoproterenol in vitro. No change in receptor density could be shown in assays performed at 37 degrees C, although a 40% reduction was apparent in binding studies carried out at 4 degrees C. In contrast, beta-adrenergic receptors on lymphocytes from mild asthmatics after a 3-week course of oral terbutaline showed a 40% reduction in receptor density regardless of the assay temperature, in addition to a 2.5-fold reduction in the receptor affinity for isoproterenol. The data are consistent with reports that a fraction of receptors are sequestered during short-term exposure to agonists. Sequestered receptors may or may not be detected by radioligand binding assays depending on the ligand of choice, temperature of the binding assay and duration of prior exposure to the agonist. After extended exposure to an agonist in vivo, the number of surface receptors was reduced, and sequestered receptors were not present, presumably as a result of degradation.

Adrenergic beta-Antagonists↗
PubMed1985

Orthostatic effect of imipramine and doxepin in depressed geriatric outpatients.

Blood pressure measurements were collected from 36 depressed geriatric outpatients (ages 55 to 81 years) enrolled in a double-blind, placebo-controlled study of the efficacy of doxepin and imipramine. Mean systolic postural changes were 25.9 mm Hg for imipramine, significantly higher than the 10.5 mm Hg for doxepin, and 12.4 mm Hg for placebo. The orthostatic drop in the imipramine group was only weakly related to dose and did not correlate with amount of pretreatment orthostatic hypotension or with duration of treatment. The increased orthostatic hypotension occurred early in treatment and at low doses of imipramine. Accordingly, caution is advised in the use of imipramine for the elderly.

Age Factors↗
PubMed1985

Rebound hyperresponsiveness to muscarinic stimulation after chronic therapy with an inhaled muscarinic antagonist.

In 9 young subjects with mild asthma, we investigated the possibility that chronic daily administration of an inhaled muscarinic antagonist (ipratropium bromide) might increase the response of muscarinic receptors in airway smooth muscle to agonist stimulation caused by receptor upregulation. Subjects inhaled 60 micrograms of ipratropium 4 times daily for 3 wk. Methacholine bronchoprovocation (with or without acute pretreatment with ipratropium) was performed before (control period) and during 3 wk of daily ipratropium therapy (medication period). At the end of the medication period, subjects returned at 12, 24, 48, and 72 h after the last dose of ipratropium (withdrawal period) to determine the provocative concentration of methacholine producing a 20% decrease in FEV1 (PC20). During the medication period, there was no significant diminution of the acute bronchodilator response to ipratropium or of the protective effect of ipratropium against methacholine-induced bronchospasm when compared with the control period. During the withdrawal period, mean in PC20 was significantly less (increased airway responsiveness) at 24 h than during the control period (p less than 0.01) and returned to the control period value within 48 to 72 h. We conclude that daily administration of ipratropium to mildly asthmatic subjects for 3 wk does not produce tolerance to either the bronchodilator effect of ipratropium or to its inhibition of methacholine-induced bronchospasm but does induce transient supersensitivity of airway cholinergic receptors to muscarinic stimulation.

Adult↗
PubMed1985

The effects of some beta lactam antibiotics on (3H)-methyl-yohimbine binding to intact human platelets.

Several antibiotics have been reported to cause a bleeding diathesis in man, characterized by reduced platelet aggregation. We investigated the effects of several of the penicillins and of moxalactam on the binding of (3H)-methyl-yohimbine to intact human platelets. The (3H)-methyl-yohimbine binding met the criteria for interaction at an alpha2 adrenergic binding site and showed low interindividual variability. Penicillin G, ticarcillin, carbenicillin, piperacillin and moxalactam all inhibited (3H)-methyl-yohimbine binding, but at concentrations far in excess of clinically achievable plasma levels. We conclude that these compounds exert their antiplatelet effects by a mechanism other than competitive inhibition of catecholamine binding.

Adrenergic alpha-Antagonists↗
PubMed1982

Selective subsensitization of beta-adrenergic receptors in central airways of asthmatics and normal subjects during long-term therapy with inhaled salbutamol.

In five subjects with mild asthma and in five normal subjects, we determined the effect of a 4 wk course of inhaled salbutamol (albuterol), 200 micrograms q.i.d., on (1) acute bronchodilator responsiveness, (2) bronchial sensitivity to inhaled histamine, (3) beta-adrenergic protection against histamine-induced bronchospasm, and (4) beta-receptor density of peripheral blood lymphocytes. We observed a diminution in central airway bronchodilator responsiveness (as measured by airway conductance responses) to acutely inhaled salbutamol and to subcutaneous terbutaline in both groups of subjects, although only the response to subcutaneous terbutaline was statistically significant (p less than 0.02). On the other hand, no impairment of small airway bronchodilator responsiveness was noted in either group of subjects when responses were measured as partial expiratory flow rates at 60% below total lung capacity. These findings suggest the development of selective subsensitization of beta-receptors in the larger central airways, where a proportionately greater amount of the inhaled beta-agonist aerosol would necessarily be deposited. A greater loss of protection against histamine-induced bronchospasm was seen in asthmatics than in normals (approximately twofold), although the difference was not significant. A modest but not significant reduction in peripheral blood lymphocyte beta-receptor density was observed by the end of the 4 wk treatment period. The possibility that the observed changes in bronchodilator responsiveness might influence the morbidity and mortality associated with bronchial asthma is discussed.

Administration, Intranasal↗
PubMed1982

A study of beta-adrenergic and prostaglandin receptors in patients with aspirin-induced bronchospasm.

Nine patients with aspirin-induced bronchospasm were compared with age-matched normal controls to test the hypothesis that a defect in the beta-adrenergic system could lead to excessive dependence on prostaglandins to maintain bronchodilator function. Lymphocyte beta-receptor density and affinity were measured by 3H-dihydroalprenolol binding. Beta-receptor function was measured in terms of cyclic AMP accumulation in response to isoproterenol. Prostaglandin (PG) responsiveness was measured in terms of cyclic AMP accumulation caused by PGE1 stimulation. No difference was found in either ther number of beta-adrenergic receptors (1234 +115 vs 1213 +82) or dissociation constant (1.40 +0.23 nM vs 1.19 +0.07nM) (mean +SEM) between the asthmatic and the control group, respectively. Furthermore, neither group showed any difference in maximally stimulated cyclic AMP in response to isoproterenol and PGE 1. Thus we find no evidence of an inherent defect of beta-adrenergic receptor and function to account for the susceptibility to aspirin-induced bronchospasm.

Adult↗
PubMed1982

Lymphocyte beta-adrenergic receptors are not altered in hyperthyroidism.

Binding of (-)3H]-dihydroalprenolol (3H-DHA) to lymphocytes from five thyrotoxic patients and five age- and sex-matched contents were examined to ascertain whether beta-adrenergic receptor number or binding affinity were altered in thyrotoxicosis. Whereas an increase in beta-adrenoceptor density has been reported in triiodothyronine-induced hyperthyroidism, we did not find changes in beta-adrenergic receptor density or binding affinity. In one patient studied sequentially, we did not find alteration in 3H-DHA bindings before or after the subject was rendered euthyroid. We conclude that lymphocyte beta-adrenergic receptor density and affinity are not altered in spontaneous hyperthyroidism.

Adult↗
PubMed1982

Reversal of human lymphocyte beta-adrenoceptor desensitization by glucocorticoids.

To investigate the effect of glucocorticoids on beta-agonist-induced desensitization, we studied the effect of a single intravenous dose of methylprednisolone (2 mg/kg) on beta-receptor density and affinity in lymphocytes from four normal and four mildly asthmatic subjects at the end of 3 to 5 wk of terbutaline therapy and from four normal subjects taking no other drug. Terbutaline decreased (-)[3H]-dihydroalprenolol binding sites by 53% in normal and by 42% in asthmatic subjects. Methylprednisolone restored the number of binding sites to levels statistically indistinguishable from the preterbutaline values in both groups of subjects. In subjects not exposed to terbutaline beforehand there was no significant alteration in receptor density after methylprednisolone, nor in normal lymphocytes incubated in vitro for 90 min with hydrocortisone (10(-5)M). No significant change in the dissociation constant was observed in any situation. A single intravenous dose of methylprednisolone reverses terbutaline-induced down-regulation of beta-adrenoceptors. This may provide a mechanism for the beneficial effect of steroids in restoring catecholamine responsiveness in asthmatic subjects.

Adult↗
PubMed1982

Subsensitization of beta-adrenoceptors in airways and lymphocytes of healthy and asthmatic subjects.

Subsensitization of beta-adrenoceptors in airways and lymphocytes developing during 4 to 5 wk of orally administered terbutaline (a long-acting beta 2 selective bronchodilator) was compared in 10 healthy subjects and 11 subjects with mild asthma. The following results were obtained. Normal subjects developed a significant reduction in acute bronchodilator responsiveness to inhaled isoproterenol but not to subcutaneously administered terbutaline. The subjects with asthma failed to develop any alteration in responsiveness to either inhaled isoproterenol or subcutaneously administered terbutaline. None of 5 normal or 4 asthmatic subjects studied demonstrated any significant change in sensitivity to histamine-induced bronchospasm or any significant decrease in the acute protective effect of subcutaneously administered terbutaline against histamine-induced bronchospasm. Marked and significant decreases occurred in the density of lymphocyte beta-receptor sites in both groups. Maximal isoproterenol-stimulated cyclic AMP responses in lymphocytes from normal subjects were reduced, but in asthmatics, in whom the baseline values were lower to begin with, a similar decrease was not observed. In most instances, the number of receptor sites returned to normal within 2 wk after cessation of terbutaline. A single dose of methylprednisolone caused a return to normal values within 16 h. We conclude that chronic therapy with an oral beta 2-adrenostimulant, although producing striking and significant down-regulation of beta-adrenergic receptors of peripheral lymphocytes, does not lead to physiologically detectable beta-adrenoceptor subsensitivity in the airways of asthmatics or to consistent subsensitivity in the airways of healthy persons.

Adolescent↗
PubMed1981

Studies of prostaglandins and sulphasalazine in ulcerative colitis.

Specific evidence is presented of the release of prostaglandins from the colon in active ulcerative colitis. An increase in the levels of bioassayed prostaglandin-like activity in the stools and colo-rectal venous plasma from patients with active ulcerative colitis is described. Radioimmunoassay confirms the presence of prostaglandin E and prostaglandin F in the stools in colitis. Increased urinary levels of prostaglandin F metabolite occur in patients with active colitis and return to normal as the disease becomes quiescent. Sulphasalazine and its faecal metabolite, 5-aminosalicylic acid, were shown by an indirect method (reduction of the tone of the isolated rat fundus strip) to inhibit prostaglandin biosynthesis in vitro. In contrast, sulphasalazine was without effect on the urinary excretion of prostaglandin F metabolite in 7 healthy subjects. In 2 patients with colitis withdrawal of sulphasalazine was associated with increasing levels of stool prostaglandin-like activity and urinary prostaglandin F metabolite excretion. Indomethacin, given to 3 patients with chronically active ulcerative colitis, unresponsive to standard medical treatment, was associated with a decreased urinary excretion of prostaglandin F metabolite but was without clinical benefit. The possible mode of action of sulphasalazine as a prostaglandin inhibitor in colitis is discussed along with the potential use of other prostaglandin inhibitors.

Adolescent↗
PubMed1980

Tachyphylaxis to beta-adrenoceptor agonists in human bronchial smooth muscle: studies in vitro.

In studies on human isolated peripheral airway smooth muscle; 1 A concentration dependent beta-adrenoceptor tachyphylaxis was observed to isoprenaline. 2 Cross desensitization to other beta-adrenoceptor agonists was demonstrated. 3 The desensitization was reversible with time. Hydrocortisone appeared to accelerate the recovery from the desensitized state. Low concentration isoprenaline (10(-9) mol l-1) prevented recovery whereas cyclohexamide 1.8 x 10(-4) mol l-1 had no noticeable effect on recovery. Continued occupancy of the receptor appears to prevent recovery. The recovery from the desensitized state does not apparently require synthesis of new proteins. 4 Bronchial wall cyclic AMP response to isoprenaline was attenuated after isoprenaline induced desensitization whereas total phosphodiesterase activity of bronchial wall was not altered by desensitization. Thus by exclusion the adenylate cyclase receptor complex may be altered in human peripheral airway smooth muscle beta-adrenoceptor tachyphylaxis.

Adrenergic beta-Agonists↗