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Biomedical subjects

O E Brodde

Publications and source records attributed to O E Brodde.

At least 163 records · Page 9Linked to original sources
PubMed1986

Differential changes in lymphocyte beta 2-adrenoceptor density by beta-blocker administration: role of intrinsic sympathomimetic activity.

To study the role of intrinsic sympathomimetic activity (ISA) in beta-blocker-induced changes of beta-adrenoceptors, the effects of administration of several beta-blockers for 9 days on lymphocyte beta 2-adrenoceptor density--assessed by 125iodocyanopindolol binding--were investigated in 47 normotensive volunteers. Propranolol (unselective; no ISA; 4 X 40 mg/day) increased beta 2-adrenoceptor density by 25-40%; after withdrawal beta 2-adrenoceptor density declined slowly, being still elevated for 3 days. In contrast, the unselective beta-blockers pindolol (ISA (isoprenaline = 1.0) = 0.39; 2 X 5 mg/day) and mepindolol (ISA = 0.27; 2 X 5 mg/day) decreased beta 2-adrenoceptor density by 50% and 35%, respectively, while alprenolol with weak ISA (=0.066; 4 X 100 mg/day) had no effect. Among the beta 1-selective blockers studied, celiprolol with ISA (=0.32; 1 X 200 mg/day) decreased beta 2-adrenoceptor density by 30% whereas bisoprolol without ISA (1 X 10 mg/day) had no effect. It is concluded that the ISA determines the direction and amount of beta-adrenoceptor alterations induced by beta-blockers. Furthermore, changes in human lymphocyte beta-adrenoceptors reflect subtype-selective changes in beta 2-adrenoceptors, since the beta 1-selective blocker bisoprolol without ISA--in contrast to propranolol--did not affect lymphocyte beta 2-adrenoceptors. Accordingly, the fact that the beta 1-selective blocker celiprolol with ISA decreased lymphocyte beta 2-adrenoceptors, is consistent with the hypothesis that celiprolol possesses in addition to its beta 1-antagonistic activity a beta 2-agonistic activity.

Adrenergic beta-Antagonists↗
PubMed1986

Lymphocyte beta 2-adrenoceptors mirror precisely beta 2-adrenoceptor, but poorly beta 1-adrenoceptor changes in the human heart.

To study the relationship of changes in human lymphocyte beta-adrenoceptors to changes potentially occurring in solid tissues we studied 16 patients undergoing elective coronary artery bypass grafting and determined the density of lymphocyte beta 2-adrenoceptors [by (-)125I-iodocyanopindolol (ICYP) binding] in comparison to beta-adrenoceptor density and responsiveness (contractile responses to isoprenaline) in the corresponding right atria. Lymphocyte beta 2-adrenoceptor density (with a range of 278-2442 ICYP binding sites/cell) was significantly correlated with beta-adrenoceptor density in the corresponding atria (54.8-171.6 fmol ICYP bound/mg protein, r = 0.784, P less than 0.001). In these atria the levels of beta 1- and beta 2-adrenoceptors (assessed by non-linear regression analysis of competition curves of the selective beta 2-adrenoceptor antagonist ICI 188,551 with ICYP binding) were approximately .70 and 30%, respectively. Lymphocyte beta 2-adrenoceptor density, however, correlated significantly better with atrial beta 2-adrenoceptor (r = 0.8441; P less than 0.001) than beta 1-adrenoceptor (r = 0.6226, P less than 0.05) density. On 12 of the 16 atria (electrically driven with 1 Hz at 37 degrees C) isoprenaline (10(-9) to 3 X 10(-6) mol/l) caused positive inotropic effects. The maximum increase in contractile force evoked by saturating concentrations of isoprenaline (mean: 3.52 +/- 0.62 mN), however, correlated equally well with beta 1- and beta 2-adrenoceptor density in the corresponding atria (r = 0.6834 and 0.6567, respectively). These results indicate that changes in lymphocyte beta 2-adrenoceptors can be taken as a precise index of changes of beta 2-adrenoceptors in other (solid) tissues; beta 1-adrenoceptor alterations, however, are only poorly reflected in the lymphocytes.

Adrenergic beta-Antagonists↗
PubMed1986

Differential haemodynamic effects induced by beta 1-(bisoprolol) or beta 2-(ICI 118,551) adrenoceptor blockade in man.

To characterize beta 1- and beta 2-adrenoceptor mediated effects in man the influence of the selective beta 1-adrenoceptor antagonist bisoprolol and the selective beta 2-adrenoceptor antagonist ICI 118,551 on changes in blood pressure, heart rate and lymphocyte beta 2-adrenoceptor density evoked by dynamic exercise or isoprenaline infusion was studied in 12 male normotensive volunteers. Bisoprolol administration (1 X 10 mg/day) did not affect lymphocyte beta 2-adrenoceptor density, while ICI 118,551 (3 X 25 mg/day) increased it by about 40%. Exercise as well as isoprenaline infusion caused 100% increases in lymphocyte beta 2-adrenoceptor density; these increases were completely abolished by ICI 118,551, but not affected by bisoprolol. ICI 118,551 markedly attenuated isoprenaline-induced decrease in diastolic blood pressure, but did not affect increase in systolic blood pressure; on the contrary, bisoprolol inhibited the isoprenaline-evoked increase in systolic blood pressure, but did not affect the decrease in diastolic blood pressure. ICI 118,551 antagonized the isoprenaline-induced tachycardia much more potently than bisoprolol, while bisoprolol, but not ICI 118,551, suppressed exercise-induced tachycardia. It is concluded that exercise-induced tachycardia is mediated by cardiac beta 1-adrenoceptor stimulation, whereas isoprenaline-induced tachycardia is mediated by both beta 1- and beta 2-adrenoceptor stimulation.

Adrenergic beta-Antagonists↗
PubMed1985

Selective labelling of beta 1-adrenoceptors in rabbit lung membranes by (-)[3H]bisoprolol.

The binding properties of a newly developed, highly selective beta 1-adrenoceptor antagonist radioligand, (-)[3H]bisoprolol (EMD 33512) were investigated in rabbit lung membranes containing a mixture of 80% beta 1-and 20% beta 2-adrenoceptors. The binding of (-)[3H]bisoprolol at 25 degrees C was saturable, of high affinity (KD = 4.7 +/- 0.6 nM, N = 4), rapid and readily reversible. The maximal number of (-)[3H]bisoprolol binding sites (244 +/- 31 fmol bound/mg protein, N = 4), however, was only 80% of the number of sites labelled by the non-selective beta-adrenoceptor radioligand (-)[125I]iodocyanopindolol (299 +/- 36 fmol bound/mg protein, N = 4). beta-Adrenoceptor antagonists (non-selective: propranolol, alprenolol; beta 1-selective: metoprolol, practolol, bisoprolol; beta 2-selective: ICI 118,551) inhibited (-)[3H]bisoprolol binding with monophasic displacement curves and pseudo-Hill coefficients of 1.0 indicating that in rabbit lung membranes (-)[3H]bisoprolol labels a homogeneous class of beta-adrenoceptors. Agonists inhibited binding with an order of potency: (-)-isoprenaline greater than (-)-noradrenaline = (-)-adrenaline, which is a typical one for beta 1-adrenoceptors. It is concluded that in rabbit lung membranes (-)[3H]bisoprolol selectively labels beta 1-adrenoceptors. (-)[3H]Bisoprolol therefore seems to be a suitable ligand for direct determination of the properties of beta 1-adrenoceptors in those tissues where both beta-adrenoceptor subtypes coexist.

Adrenergic beta-Antagonists↗
PubMed1985

Effects of beta-adrenoceptor antagonist administration on beta 2-adrenoceptor density in human lymphocytes. The role of the "intrinsic sympathomimetic activity".

Abrupt withdrawal of beta-adrenoceptor antagonists may lead to "rebound-effects". To study the mechanism underlying this phenomenon, the effects of the nonselective beta-adrenoceptor antagonists propranolol [no intrinsic sympathomimetic activity (ISA)], alprenolol (weak ISA) and mepindolol (strong ISA) on lymphocyte beta 2-adrenoceptor density--assessed by (+/-)-[125I]-iodocyanopindolol (ICYP) binding--and plasma renin activity (PRA) were investigated in male healthy volunteers aged 23-35 years. Propranolol treatment (4 X 40 mg/day) increased the density of beta 2-adrenoceptors by 25% after 2 days; concomitantly PRA and heart rate were reduced. During treatment beta 2-adrenoceptor density remained elevated. After withdrawal of propranolol PRA reached pre-drug levels rapidly, while heart rate was significantly enhanced. Beta 2-Adrenoceptor density, however, declined slowly being still significantly increased after 3 days, although propranolol was not detectable in plasma after 24 h. The affinity of ICYP to beta 2-adrenoceptors was not changed during or after treatment. Mepindolol treatment (2 X 5 mg/day) caused a 30% decrease of beta 2-adrenoceptor density and PRA after 2 days; both parameters remained reduced during treatment. After withdrawal, PRA reached rapidly pre-drug levels, whereas beta 2-adrenoceptor density was still after 4 days significantly diminished. The KD-values for ICYP, however, were not changed. During and after treatment heart rate was not affected. Alprenolol treatment (4 X 100 mg/day) led to a rapid fall in PRA, but did not significantly affect beta 2-adrenoceptor density. It is concluded, that the ISA may play an important role in modulating beta 2-adrenoceptor density and hence tissue responsiveness to beta-adrenoceptor stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗
PubMed1985

Properties of alpha- and beta-adrenoceptors in circulating blood cells of patients with essential hypertension.

The properties of platelet alpha 2-adrenoceptors and of lymphocyte beta 2-adrenoceptors were determined in 40 male patients with established essential hypertension and compared with those in 40 male normotensives. The densities of platelet alpha 2-adrenoceptors (assessed by 3H-yohimbine binding) and of lymphocyte beta 2-adrenoceptors [determined by (+/-)-125iodocyanopindolol binding] were in patients with essential hypertension significantly higher than in controls; there were significant positive correlations between the mean arterial blood pressure of the subjects and alpha 2- and beta 2-adrenoceptor density, respectively. Concomitantly with receptor densities, functional responses to adrenergic stimulation were exaggerated in essential hypertension: in platelets, the aggregatory response to (-)-adrenaline (via alpha 2-adrenoceptor stimulation) was enhanced; in lymphocytes, the cyclic AMP response to (-)-isoprenaline (via beta 2-adrenoceptor stimulation) was elevated. It is concluded that the increased adrenoceptor density and responsiveness in circulating blood cells of patients with essential hypertension may reflect increased sympathetic activity, which might contribute to the elevation of blood pressure.

Adult↗
PubMed1985

Terbutaline-induced desensitization of human lymphocyte beta 2-adrenoceptors. Accelerated restoration of beta-adrenoceptor responsiveness by prednisone and ketotifen.

We investigated, in 36 healthy volunteers, the effects of prednisone and ketotifen on recovery of lymphocyte beta 2-adrenoceptor density (determined by (-)-125iodocyanopindolol binding) and responsiveness (assessed by lymphocyte cyclic AMP [cAMP] responses to 10 microM (-)-isoprenaline) after desensitization by the beta 2-agonist terbutaline. Terbutaline (3 X 5 mg/d) decreased lymphocyte beta 2-adrenoceptor density by approximately 40-50%; concomitantly, lymphocyte cAMP responses to 10 microM (-)-isoprenaline were significantly reduced. After withdrawal of terbutaline beta 2-adrenoceptor, density and responsiveness gradually increased, reaching predrug levels after 4 d. Prednisone (1 X 100 mg orally) accelerated beta 2-adrenoceptor recovery; only 8-10 h after administration of the steroid beta 2-adrenoceptor density and cAMP responses to (-)-isoprenaline had reached values not significantly different from pretreatment levels. Similar effects were obtained with ketotifen (2 mg; thereafter 2 X 1 mg/d for 4 d): 24 h after application of the drug beta 2-adrenoceptor density and cAMP responses to (-)-isoprenaline had reached pretreatment levels. Furthermore, ketotifen simultaneously applied with terbutaline completely prevented terbutaline-induced decrease in lymphocyte beta 2-adrenoceptor density and responsiveness. Prednisone (1 X 100 mg orally) or ketotifen (2 mg; thereafter 2 X 1 mg/d for 2 d) had no significant influence on lymphocyte beta 2-adrenoceptor density in healthy volunteers not pretreated with terbutaline, but shifted the ratio high-to-low affinity state of the lymphocyte beta 2-adrenoceptor toward high affinity state. We conclude that glucocorticoids as well as ketotifen can accelerate recovery of density and responsiveness of lymphocyte beta 2-adrenoceptors desensitized by long-term treatment with beta 2-agonists. Such an effect may have clinical implications for preventing tachyphylaxis of asthmatic patients against therapy with beta 2-agonists.

Adult↗
PubMed1985

Alpha- and beta-adrenoceptors in circulating blood cells of essential hypertensive patients: increased receptor density and responsiveness.

In 40 male patients with established essential hypertension (P diast greater than 95 mmHg) platelet alpha 2-adrenoceptor density (by 3H-yohimbine binding) and -responsiveness (by adrenaline-induced aggregation) as well as lymphocyte beta 2-adrenoceptor density (by (+/-)-125 iodocyanopindolol binding) and -responsiveness (by cyclic AMP responses to isoprenaline) were determined and compared with those in 40 male age-matched normotensives (P diast less than 90 mmHg). In essential hypertensive patients mean platelet alpha 2- and lymphocyte beta 2-adrenoceptor densities were significantly increased. When data from all 80 subjects were combined, significant positive correlations between mean arterial blood pressure and alpha 2- and beta 2-adrenoceptor densities, respectively, were found. The increases in alpha 2- and beta 2-adrenoceptor densities were accompanied by enhanced responsiveness to adrenergic stimulation: in platelets adrenaline-induced aggregation--via alpha 2-adrenoceptor stimulation--was exaggerated, and in lymphocytes isoprenaline produced significantly greater increases in the intracellular level of cyclic AMP. It is concluded that the increased density and responsiveness of alpha 2-and beta 2-adrenoceptors in circulating blood cells of essential hypertensive patients may reflect increased sympathetic activity, which might contribute to the elevation of blood pressure.

Adenylyl Cyclases↗
PubMed1985

Acute regulation of lymphocyte beta 2-adrenoceptors is altered in patients with essential hypertension.

The effects of acute stimulation of the sympathetic activity by dynamic exercise on lymphocyte beta 2-adrenoceptor density [assessed by (-)-125iodocyanopindolol (ICYP) binding] and responsiveness [10 mumol/l isoprenaline-induced cyclic adenosine monophosphate (cAMP) increases] were studied in 10 normotensive (Pdiast < 90 mmHg) volunteers and in 10 patients with established essential hypertension (Pdiast > 95 mmHg). In normotensives, dynamic exercise on a bicycle (80% of maximum heart rate) for 15 min led to an increase in lymphocyte beta 2-adrenoceptor density from 1080 +/- 77 to 2033 +/- 152 ICYP binding sites/cell; concomitantly isoprenaline-induced increase in lymphocyte cAMP was enhanced. This effect appears to be mediated by beta 2-adrenoceptor stimulation, since the exercise-induced increase in beta 2-adrenoceptor density was markedly attenuated by pretreatment of the volunteers with propranolol (5 mg intravenously 45 min before exercise), but not by pretreatment with the beta 1-selective antagonist bisoprolol (2.5 mg intravenously 30 min before exercise). In patients with essential hypertension, lymphocyte beta 2-adrenoceptor density (1512 +/- 101 ICYP binding sites/cell) was significantly higher than in controls (P < 0.05); the same held true for isoprenaline-induced cAMP increases. In these patients, however, dynamic exercise caused only a slight increase in lymphocyte beta 2-adrenoceptor density (to 1859 +/- 154 ICYP binding sites/cell) and in isoprenaline-induced cAMP increases. From these results it is concluded that in essential hypertension acute regulation of the beta-adrenoceptor/adenylate cyclase system is impaired.

Adult↗
PubMed1985

Identification of a homogeneous class of beta 2-adrenoceptors in human platelets by (-)-125I-iodopindolol binding.

The highly specific beta-adrenoceptor radioligand (-)-125I-iodopindolol (IPIN) was used to label in membranes from human platelets beta-adrenoceptors. Binding of IPIN was at 25 degrees C saturable (Bmax = 7.4 +/- 2.5 fmoles bound/mg protein, N = 10) of high affinity (KD-value = 34.8 +/- 3.3 pM, N = 10), rapid and reversible. beta-Adrenoceptor antagonists inhibited binding of IPIN with monophasic displacement curves and pseudo Hill coefficients (nH) not significantly different from 1.0. The beta 2-selective antagonist ICI 118,551 was much more potent in inhibiting IPIN binding than the beta 1-selective antagonist bisoprolol. IPIN binding was stereospecific as indicated by the 100-times greater potencies of (-)-alprenolol and (-)-isoprenaline in inhibiting binding than their (+)-isomers. beta-Adrenoceptor agonists inhibited binding with slightly shallow displacement curves and nH-values of 0.85-0.88; the order of potency was: isoprenaline greater than adrenaline greater than noradrenaline. These results demonstrate that IPIN labels (in human platelet membranes with high affinity) a homogeneous population of beta 2-adrenoceptors with low capacity.

Adenylyl Cyclases↗
PubMed1985

Impaired regulation of beta-adrenoceptors in patients on maintenance haemodialysis.

In patients on maintenance haemodialysis the number of lymphocyte beta 2-adrenoceptors (determined by (+/-)-125 iodocyanopindolol binding) was not different from that in healthy controls; lymphocyte cyclic AMP responses to (-)-isoprenaline (10(-8)-10(-4) M) or NaF (10 and 50 mM), however, were significantly reduced. Dynamic exercise on a bicycle (80% of maximum heart rate) for 15 minutes caused in 10 healthy volunteers a fourfold increase in plasma catecholamines; concomitantly lymphocyte beta 2-adrenoceptor number increased by about 55 per cent. In contrast, in patients on maintenance haemodialysis exercise induced only a twofold increase in plasma catecholamines and did not affect beta 2-adrenoceptor number. It is concluded that in chronic uraemia regulation and responsiveness of beta-adrenoceptors is impaired.

Adult↗
PubMed1984

Beta-adrenoceptor changes in human lymphocytes, induced by dynamic exercise.

In 10 healthy volunteers the effects of acute increases in concentrations of catecholamines in plasma induced by dynamic exercise (on a bicycle for 15 min at 80% of maximum heart rate) on lymphocyte beta 2-adrenoceptor density (determined by (+/-)-125iodocyanopindolol binding) and -responsiveness (determined by cyclic AMP responses to 10 mumol/l isoprenaline) were investigated. Immediately after exercise plasma catecholamines were increased about 4-fold; concomitantly receptor density and cyclic AMP production increased 55% and 65%, respectively. One hour after exercise beta-adrenoceptor density and plasma catecholamines had reached values, which were not significantly different from pre-exercise values, while cyclic AMP production was significantly diminished. It is concluded, that acute increases in concentrations of catecholamines in plasma may increase beta-adrenoceptor density and - responsiveness in human lymphocytes.

Adult↗
PubMed1984

Changes in platelet alpha 2-adrenoceptors in human phaeochromocytoma.

In a 44 year-old male with a surgically proven phaeochromocytoma platelet alpha 2-adrenoceptor density, determined by 3H-yohimbine binding, was only 50% of that in an age-matched control group, and plasma catecholamines were elevated. Two weeks after removal of the tumour, platelet alpha 2-adrenoceptor density and plasma catecholamines had become normal and were not significantly different from the controls. It is concluded that endogenous catecholamines may play an important role in regulation of alpha 2-adrenoceptor density and hence tissue sensitivity to alpha-adrenergic stimulation in the human being.

Adrenal Gland Neoplasms↗
PubMed1984

Identical binding properties of (+/-)- and (-)-125Iodocyanopindolol to beta 2-adrenoceptors in intact human lymphocytes.

In intact human lymphocytes the properties of (+/-)- and (-)-125iodocyanopindolol (ICYP) binding to beta 2-adrenoceptors were investigated. Binding of both ligands was in concentrations ranging from 10-200 pM saturable resulting in identical Bmax-values (about 550-650 specific ICYP binding sites/cell); the KD-value of (-)-ICYP (14.8 +/- 0.1 pM, N = 3), however, was about two times lower than that of (+/-)-ICYP (26.5 +/- 2.5 pM, N = 3). Irrespective of the ligand used alprenolol, betaxolol, ICI 118,551 and isoprenaline inhibited binding with identical KI-values. Binding was stereospecific, since the (+)-isomers of alprenolol and isoprenaline were about 50 times less potent in inhibiting binding than their respective (-)-isomers. In concentrations greater than 250 pM both ligands labeled a second class of binding sites in a non-saturable manner. These low affinity sites showed no stereospecificity; they may be related to unspecific uptake of the ligands into the cell. In kinetic experiments biphasic dissociation reactions were obtained for (+/-)- as well as (-)-ICYP; for both ligands the ratio fast/slow dissociating component was 40/60. It is concluded, that at low receptor concentrations (2.5-5 pmoles/l in the present study) the contribution of the (+)-isomer of ICYP to binding of the racemic ligand can be neglected. Thus, at low receptor concentrations both (+/-) and (-)-ICYP exhibit identical binding properties to beta 2-adrenoceptors in intact human lymphocytes.

Alprenolol↗
PubMed1984

Increased density and responsiveness of alpha 2 and beta-adrenoceptors in circulating blood cells of essential hypertensive patients.

In 40 male patients with established essential hypertension (P diastolic greater than mmHg) the density and responsiveness of platelet alpha 2-adrenoceptors and lymphocyte beta 2-adrenoceptors were measured and compared with those in 40 male age-matched normotensive subjects (P diastolic less than 90 mmHg). The mean densities of platelet alpha 2-adrenoceptors (assessed by 3H-yohimbine binding) and of lymphocyte beta 2-adrenoceptors (assessed by (+/-) 125 iodocyanopindolol binding) were significantly increased in essential hypertensive patients (P less than 0.01). If data from all 80 subjects were combined there were significant positive correlations between mean arterial blood pressure of the subjects and alpha 2-adrenoceptor density (r = 0.591, P less than 0.001) and beta 2-adrenoceptor density (r = 0.648, P less than 0.001), respectively. The increases in and beta-adrenoceptor densities in essential hypertension were accompanied by enhanced responsiveness alpha- of platelets to 10 microM adrenaline to adrenergic stimulation: the aggregatory response via alpha 2-adrenoceptor stimulation) was increased, and in lymphocytes isoprenaline (0.01 - 100 microM) produced (via adrenoceptor stimulation) greater increases in cyclic AMP at each concentration than in control. Furthermore, activation of platelet adenylate cyclase by prostaglandin E1 was exaggerated in essential hypertensive patients. It is concluded that the increased density and responsiveness of alpha- and beta-adrenoceptors in essential hypertension may reflect enhanced sympathetic activity, and may contribute to the elevation of blood pressure.

Adolescent↗
PubMed1984

[Maternal and fetal hemodynamics under simultaneous beta stimulation and beta1 blockade in a tocolysis model. Considerations on status of the neonatal beta receptor and transplacental passage of metoprolol].

This report summarizes the clinical experiences in the treatment of preterm labor using the combination of hexoprenaline and the beta 1-antagonist metoprolol. We found a dose dependency in the antagonism of positive inotropic effects primarily induced by the beta-stimulator hexoprenaline. To verify the pharmacological properties of metoprolol in transplacental passage we evaluated the plasma concentration of metoprolol in umbilical cord blood. There is quite a low concentration of the beta-blocker nearly 24 h after the last course of administration. The beta 2-receptor density--determined by (+/-)-125-iodocyanopindolol (ICYP) binding--and beta 2-receptor responsiveness--assessed by cyclic AMP response to isoprenaline stimulation--in lymphocytes derived from neonatal blood were also investigated. These results were compared with identical investigations in adult lymphocytes. The results indicate that in neonates beta 2-receptor density and responsiveness is significantly diminished in comparison to the adult controls. The present investigations induce a new concept for the estimation of concomitant fetal cardiovascular reactions under maternal beta-blockade.

Adrenergic beta-Agonists↗