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Biomedical subjects

D B Barnett

Publications and source records attributed to D B Barnett.

At least 73 records · Page 4Linked to original sources
PubMed1986

Heterogeneous properties of alpha 2 adrenoceptors in particulate and soluble preparations of human platelet and rat and rabbit kidney.

Alpha 2 adrenoceptors of the human platelet and rat and rabbit renal cortex were compared in binding studies using the selective antagonist ligand [3H]rauwolscine. Significant differences in the pharmacological characteristics of the alpha 2 adrenoceptor were observed between the tissues with reference to both absolute drug affinities as well as rank order of drug potency. Two subsets of the alpha 2 adrenoceptor sites could be described: one exhibiting equal affinity for the alpha 2 selective diastereoisomers, yohimbine and rauwolscine, and low affinity for the alpha 1 antagonist prazosin (human platelet); the other displaying significantly higher affinity for rauwolscine than yohimbine but also relatively high affinity for prazosin (rat and rabbit kidney). Digitonin solubilised alpha 2 adrenoceptors from these tissues identified by [3H]rauwolscine generally displayed reduced drug affinities. This was most apparent for agonists (10-50-fold lower) indicating separation of the soluble receptors from the guanine nucleotide binding proteins. However, the solubilised alpha 2 adrenoceptors retained the overall pharmacological properties of their respective membrane receptors, including rank order of drug potency, reflecting similar inter-tissue differences. These results suggest that the pharmacological differences in alpha 2 adrenoceptors observed are not species specific and are not related to variation in receptor effector coupling mechanisms or problems of ligand access due to membrane constraints. This may reflect true intrinsic differences in the molecular structure of these receptors.

Adrenergic alpha-Antagonists↗
PubMed1986

Intravenous infusion of magnesium sulphate after acute myocardial infarction: effects on arrhythmias and mortality.

Two hundred patients with acute myocardial infarction were entered into a randomised double-blind trial where they received either intravenous magnesium sulphate or saline for 24 hours after admission to hospital. The incidence of ventricular arrhythmias necessitating treatment was reduced by more than half in the group receiving magnesium sulphate. There were two deaths in the group receiving magnesium sulphate and seven receiving saline placebo. Total cardiac events were significantly reduced in the magnesium treated group. These reductions cannot be attributed to differences in risk factors or therapy between the two groups, either before or during the period of study. These results suggest that magnesium administration reduces the incidence of serious tachyarrhythmias and death after acute myocardial infarction and that this simple regime warrants further study.

Arrhythmias, Cardiac↗
PubMed1985

Differential labeling of platelet alpha 2 adrenoceptors by 3H dihydroergocryptine and 3H yohimbine in patients with myeloproliferative disorders.

Platelet alpha adrenoceptor status was examined using the radioligands 3H-yohimbine (3H-YOH) and 3H-dihydroergocryptine (3H-DHE) in 14 patients with myeloproliferative disorder (MPD) and 10 normal controls. Platelets from normal controls and MPD patients sensitive to adrenaline induced aggregation exhibited approximately 50% more binding sites identified by 3H-DHE than 3H-YOH, whereas MPD platelets insensitive to adrenaline showed selective loss of these 'extra' 3H-DHE sites. In functional studies after 30 minutes preincubation with the unlabelled antagonists, DHE was more potent than YOH at inhibiting adrenaline induced aggregation in normal platelets. In addition, the affinity constant for DHE was virtually identical in binding and functional experiments, whereas for YOH the affinity constant for binding was approximately 10 fold more potent than that for aggregation. These results suggest that the alpha adrenoceptor binding site on human platelets labelled by 3H-DHE may be of more functional relevance than that labelled by 3H-YOH alone.

Blood Platelets↗
PubMed1985

Alpha 2-adrenoceptor coupling to adenylate cyclase in adrenaline insensitive human platelets.

Coupling of the alpha 2-adrenoceptor to adenylate cyclase was assessed in platelets from 3 groups of subjects: normal controls and patients with myeloproliferative disorders whose platelets were either sensitive or specifically insensitive to the aggregatory effects of adrenaline. The ability of adrenaline to induce the formation of a complex between the alpha 2-adrenoceptor and the inhibitory guanine nucleotide binding protein was examined in all three groups by assessment of the effect of mono and divalent cations and Gpp(NH)p on the displacement of [3H]yohimbine binding to platelet membranes by adrenaline. Coupling to adenylate cyclase was also assessed in separate studies of the inhibition by adrenaline of PGE1 stimulated cyclic AMP accumulation in whole platelets. Both the formation of the ternary complex and the inhibition by adrenaline of cyclic AMP accumulation was not significantly different in platelets sensitive or insensitive to adrenaline. These results suggest that inhibition of cyclic AMP alone does not explain the mechanisms of adrenaline induced platelet aggregation.

Adenylyl Cyclases↗
PubMed1985

(-)-[125I]pindolol binding to the human platelet beta-adrenoceptor: characterisation and agonist interactions.

The binding of (-)-[125I]pindolol ((-)-[125I]PIN) to human platelet membranes has been examined and identifies a relatively low density of beta-adrenoceptor binding sites in this tissue. The relative order of potency of the catecholamines in displacement experiments, isoprenaline greater than adrenaline greater than noradrenaline and curve-fitting analysis of the competition binding isotherms using subtype selective beta-adrenergic antagonists, suggests the presence of an homogeneous population of beta 2-adrenoceptors. The effects of guanine nucleotides and mono- and divalent cations on the isoprenaline displacement of (-)-[125I]PIN binding to human platelet and rat lung membrane beta-adrenoceptors was compared in parallel experiments. In the presence of Mg2+ the agonist showed relatively lower overall affinity for the platelet receptor with a steep displacement curve, Hill slope approaching unity. Under these circumstances Gpp(NH)p characteristically produced a shift to the right and a steepening of the agonist displacement curve in rat lung but had no effect in platelet membranes. NaCl caused a parallel shift to the right of the curves in both systems in the presence or absence of Gpp(NH)p. The significance of these results in relationship to the efficiency of coupling of the human platelet beta-adrenoceptor to adenylate cyclase is discussed.

Adrenergic beta-Agonists↗
PubMed1985

Reversible abnormalities of myocardial relaxation in hypothyroidism.

Fifteen selected hypothyroid patients without symptoms or signs of cardiovascular disease and an equal number of matched control subjects underwent simultaneous recording of electrocardiogram and phono-, apex-, and echocardiography to assess dynamic systolic and diastolic left ventricular function. Both the systolic preejection period and the isovolumic relaxation period were significantly increased in the hypothyroid group. However, whereas the rate of myocardial contraction, assessed from the echocardiograph of the left ventricular posterior wall, was identical in patients and control subjects, the diastolic thinning rate of the muscle was markedly slowed in the hypothyroid individuals. The abnormalities demonstrated were in the main completely reversed after 3 months of T4 therapy. These results demonstrate a relatively selective and readily reversible disturbance of the rate of myocardial relaxation in hypothyroidism, suggesting an intrinsic abnormality of cardiac muscle. This allows an intriguing parallel to be drawn with the delayed relaxation phase of voluntary muscle contraction, long recognized as a direct measure of tissue thyroid function in hypothyroidism. The abnormality of diastolic function we have described is of similar character to that found in patients with other cardiomyopathies and which has been shown to be a major cause of disturbance of global cardiac action.

Adult↗
PubMed1984

Effects of adrenaline and alpha adrenergic antagonists on platelet aggregation in whole blood: evaluation of electrical impedance aggregometry.

The effects of adrenaline and alpha adrenergic antagonists on platelet aggregation in whole blood were assessed by electrical impedance. These effects were then compared to those found in platelet rich plasma assessed by both optical and impedance methods. Our data demonstrate a number of difficulties in attempting to measure platelet responsiveness by electrical impedance and re-emphasise the need for caution in interpretation of in vitro platelet aggregation studies in terms of their clinical relevance.

Adrenergic alpha-Antagonists↗
PubMed1984

Human platelet alpha 2-adrenoceptors: relationship between radioligand binding studies and adrenaline-induced aggregation in normal individuals.

Using the alpha 2-adrenoceptor selective radioligand [3H]yohimbine maximum binding capacities (Bmax), dissociation constants (KD), and the affinity (KI) of adrenaline for the binding sites were measured in platelets obtained from a group of 42 normal individuals. These results were compared with the efficacy of adrenaline induced aggregation in platelet rich plasma in the same subjects. Wide interindividual variation was found in Bmax values as measured in whole platelets (sites/platelet) or platelet lysates (fmol/mg protein) and in KI values for adrenaline displacement of [3H]yohimbine binding. Adrenaline's ability to induce platelet aggregation measured as the concentration required to achieve half maximal aggregation assessed from dose-response curves showed similar interindividual variation. No correlation was found, however, between alpha 2-adrenoceptor status as assessed by radioligand binding studies and the functional studies. These results suggest that the present understanding of the relationship between alpha 2-adrenoceptor occupation and platelet aggregation may be incorrect.

Adult↗
PubMed1984

Interactions of endogenous and exogenous norepinephrine with alpha 2 adrenoceptor binding sites in rat cerebral cortex.

The specific binding of (3H)yohimbine to alpha 2 adrenoceptors in rat cerebral cortex varied significantly with methods of membrane preparation. Membranes prepared in a sucrose containing buffer showed markedly lower Bmax values than those prepared in hypotonic buffer without any change in affinity (Kd) for (3H)yohimbine. Higher concentrations of residual endogenous norepinephrine were found in sucrose prepared membranes. In the presence of exogenous norepinephrine (10(-8), 10(-7) M), membranes prepared in hypotonic buffer showed apparent reduced receptor densities similar to those observed in sucrose prepared cerebral membranes. The presence of exogenous norepinephrine did not produce any apparent change in the overall Kd for (3H)yohimbine. The depression of (3H)yohimbine binding capacities could, in all cases, be reversed by performing incubations in the presence of 200 mM NaCl and 10 microM Gpp(NH)p which synergistically dramatically reduce the affinity of norepinephrine for cerebral alpha 2 adrenoceptors. It is concluded, therefore, that the lower (3H)yohimbine binding capacities in sucrose prepared membranes appears to be due to the occupancy of receptor sites by residual norepinephrine in a pseudo non competitive manner. The reduced affinity of retained endogenous norepinephrine for the alpha 2 adrenoceptor, in the presence of Na+ and guanine nucleotides, would seem to be the cause of the apparent increase in (3H)yohimbine binding sites produced by these modulators in sucrose prepared membranes.

Animals↗
PubMed1984

Comparison of the beta 1 selective affinity of prenalterol and corwin demonstrated by radioligand binding.

The ability of the beta 1 partial agonists prenalterol and corwin , to displace the binding of [3H]dihydroalprenolol to the heterogeneous populations of beta-adrenoceptors on rat and rabbit lung membranes was compared. Both drugs exhibited higher affinity for the binding sites in rabbit lung (predominant beta 1) as compared to rat lung (predominant beta 2). Curve fitting analysis of the displacement curves into high affinity (beta 1) and low affinity (beta 2) components indicates that both drugs exhibit beta 1 selective affinity. Further competition experiments performed in the presence of carefully calculated concentrations of highly selective beta 1 (atenolol) or beta 2 (ICI 118,551) antagonists to produce homogeneous receptor subtype populations in rat and rabbit lung membranes respectively, confirmed this beta 1 selective affinity. These results suggest an approximate selective affinity ratio (beta 1 to beta 2) of ten and forty fold for prenalterol and corwin respectively.

Adrenergic beta-Agonists↗
PubMed1984

Functional significance of the platelet alpha2-adrenoceptor: studies in patients with myeloproliferative disorders.

Platelet alpha-adrenoceptor status was examined in 35 patients with myeloproliferative disorders (MPD) and 35 normal controls by means of radioligand binding studies with 3H-yohimbine (3H-YOH) and in vitro platelet function tests. A group of 'adrenaline insensitive' MPD patients identified in the functional studies were found to be identical to normal controls and other MPD patients with respect to their alpha 2-adrenoceptor status as assessed by the binding studies. Possible explanations for the dissociation between radioligand binding studies and functional responses in the platelet are discussed.

Adenine Nucleotides↗
PubMed1984

The role of serotonin (5-HT) in the control of TSH and prolactin release in euthyroid subjects as assessed by the administration of ketanserin (5-HT2 antagonist) and zimelidine (5-HT re-uptake inhibitor).

We have studied the effects of ketanserin, a specific 5-HT2 antagonist, and zimelidine, a selective inhibitor of 5-HT re-uptake into central nervous system presynaptic terminals, upon basal and TRH stimulated serum TSH and prolactin levels in euthyroid individuals. Ten normal volunteers were studied (five male and five female), each receiving oral ketanserin and oral zimelidine during respective seven day periods, separated by an interval of at least two weeks. A standard TRH test (200 micrograms i.v.) was carried out before and after each period of drug administration, serum samples being obtained for TSH and prolactin estimation. We were unable to demonstrate any modification of basal or TRH-stimulated TSH and prolactin levels by the oral administration of either ketanserin or zimelidine, suggesting that 5-HT has no significant role in the physiological release of either TSH or prolactin.

Female↗
PubMed1984

Circulating catecholamine, thyrotrophin, thyroid hormone and prolactin responses of normal subjects to acute cold exposure.

The responses of circulating catecholamines, TSH, thyroid hormones and prolactin to 30 min of acute cold exposure (4 degrees C) were measured in eight normal volunteers over a 2 h period. There was a rise in circulating noradrenaline, TSH, T4 and T3 levels and a fall in circulating prolactin in the subjects studied, but no change in circulating adrenaline levels nor any alteration in the T4/T3 ratio. The thyroid axis of normal individuals can respond rapidly to acute cold exposure. In addition, the increased plasma noradrenaline levels accompanied by unaltered adrenaline levels suggest that the stimulus exerted by cold does not evoke a generalised stress response, but rather that the sympathetic nervous system is selectively stimulated.

Adult↗
PubMed1984

The effects of dopaminergic blockade on serum TSH and prolactin levels in thyrotoxicosis.

In the first part of this study, we have demonstrated that, in 7 patients with untreated thyrotoxicosis, a 7 day regime of the long acting dopamine antagonist metoclopramide (10 mg orally 8 hourly) produces more adequate dopaminergic blockade at pituitary level than a single oral 10 mg dose of the compound as assessed by serum prolactin responses. Subsequently, we have employed this protracted oral metoclopramide regime to evaluate the contribution of dopaminergic tone to the abnormal TSH and prolactin responsiveness of thyrotoxicosis. Serum TSH and prolactin responses to iv TRH (200 micrograms) were measured in 10 untreated thyrotoxic patients before and after a 7 day period of metoclopramide 10 mg orally 8 hourly. Ten euthyroid individuals were studied in similar fashion, their serum samples being analysed for prolactin levels alone, thus providing a control group for prolactin responsiveness to TRH, before and after metoclopramide. In the thyrotoxic patients basal TSH levels did not change as a consequence of metoclopramide therapy and the TSH response to TRH remained flat. Basal prolactin levels were similar in thyrotoxic and euthyroid individuals and the increase in prolactin, seen in both groups after metoclopramide, was smaller in the thyrotoxic group than in the euthyroid group. Prolactin responsiveness to TRH was significantly impaired in the thyrotoxic subjects as compared to euthyroid subjects. After metoclopramide there was a significant decline in prolactin responsiveness in the euthyroid group, and a similar, though insignificant, trend in the thyrotoxic patients. We conclude that in thyrotoxicosis dopaminergic tone plays no major part in the suppression of TSH levels, nor in the impaired prolactin responsiveness to TRH.

Administration, Oral↗
PubMed1983

The characteristics of adrenoceptors in homogenates of human cerebral cortex labelled by (3H)-rauwolscine.

The alpha-2-adrenoceptor antagonist (3H)-rauwolscine has been used to label adrenoceptors in membranes from human cerebral cortex. The radioligand binds with high affinity (KD 2.08 nM) to a single population of sites with a density of 135 fmoles/mg protein. Adrenoceptor antagonists displaced binding in a simple monomolecular fashion with an order of affinity rauwolscine greater than yohimbine greater than phentolamine greater than corynanthine greater than prazosin indicating binding to alpha-2-adrenoceptors. Agonists displaced with an order of affinity clonidine greater than (-) adrenaline greater than (-) noradrenaline greater than dopamine greater than (-) isoprenaline but all displayed apparent Hill coefficients less than unity indicating heterogeneity of binding. The relatively high affinity of the alpha-1 antagonist prazosin for (3H)-rauwolscine binding sites in rat cerebral cortex was not observed in the human tissue which had pharmacological properties similar to those described previously in human platelet.

Adrenergic alpha-Agonists↗