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S J Graafsma

Publications and source records attributed to S J Graafsma.

14 recordsLinked to original sources
PubMed1992

Does treatment with beta-adrenergic blocking agents cause a decrease in beta 2-adrenoceptor affinity?

The effect of beta-adrenoceptor antagonists (BAAs) differing in lipophilicity and partial agonist activity (PAA), and a full agonist, on the dissociation constant for [125I]-(-)- iodocyanopindolol binding to beta 2-adrenoceptors (KD) has been investigated. Twelve healthy, normotensive male volunteers (mean age 22.3 y) were treated with different BAAs according to a cross-over design. The drugs used were propranolol (highly lipophilic BAA, no PAA), pindolol (moderately lipophilic BAA, strong PAA), dilevalol (highly lipophilic BAA, weak PAA) and salbutamol (full agonist). Before and after a single dose and an 8 day course of one of the drugs, blood pressure and the beta 2-adrenoceptor characteristics of mononuclear leukocytes (MNL) were determined. Between the treatment periods, there was a washout interval of 14 days. All BAAs decreased the blood pressure, but only propranolol lowered heart rate. Treatment with salbutamol decreased the diastolic and increased the systolic blood pressure and heart rate. Three hours after the single dose of any of the BAAs, a more than 2-fold increase in KD was observed, and the increase became larger after 8 days of administration (up to 3.7-fold increase). In contrast, no effect on KD was observed after treatment with salbutamol. BAAs with PAA and salbutamol induced a 30% decrease in beta 2-adrenoceptor density. It is concluded that treatment with BAAs, irrespective their lipophilicity or PAA, induces a decrease in the affinity of MNL beta 2-adrenoceptors for antagonists. This phenomenon may help to explain the contradictory relationship between the kinetics and dynamics of BAAs.

Adrenergic beta-Antagonists↗
PubMed1991

Adrenoceptors on blood cells from patients with primary Raynaud's phenomenon.

1. alpha 2-Adrenoceptors on platelet membranes and beta 2-adrenoceptors on lymphocytes were studied in 24 patients with primary Raynaud's phenomenon and in 24 age- and sex-matched control subjects. In two subgroups, a standardized mental arithmetic test and a finger-cooling test were performed. 2. Baseline blood pressure, heart rate and forearm blood flow did not differ between the two groups. 3. Baseline skin microcirculation (laser Doppler flux) was decreased in primary Raynaud's phenomenon (19 +/- 15 arbitrary units) compared with control subjects (33 +/- 14 arbitrary units) (P less than 0.01). 4. Baseline plasma noradrenaline concentration (2.00 +/- 1.44 versus 1.16 +/- 0.36 nmol/l) and alpha 2-adrenoceptor density (301 +/- 119 versus 210 +/- 82 fmol/mg) were increased in patients with primary Raynaud's phenomenon in comparison with the control subjects. The alpha 2-adrenoceptor density/beta 2-adrenoceptor density ratio in patients with primary Raynaud's phenomenon was, with a value of 0.37 +/- 0.04, higher than in the control subjects, where a value of 0.25 +/- 0.02 was measured (P less than 0.001). Plasma adrenaline concentration, beta 2-adrenoceptor density and the antagonist affinity to both receptor subtypes did not differ between both groups under baseline conditions. 5. Whereas during the finger-cooling test no differences were seen in the responses of the parameters measured, the mental arithmetic test induced an increase in laser Doppler flux in patients with primary Raynaud's phenomenon and a decrease in the control group.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

Increased bronchial hyperresponsiveness after inhaling salbutamol during 1 year is not caused by subsensitization to salbutamol.

Recently, it was suggested that long-term administration of an inhaled beta 2-agonist might increase bronchial hyperresponsiveness (BHR) to histamine, possibly as a consequence of subsensitization to the inhaled beta 2-agonist. To test this hypothesis, we studied two groups of patients with asthma or with chronic obstructive pulmonary disease. An experimental group of 15 patients, inhaling 400 micrograms of salbutamol four times daily during 1 year and subsequently 40 micrograms of ipratropium bromide four times daily for 6 months, and a control group, consisting of 22 patients with the opposite treatment regimen. The BHR, the response in FEV1 to cumulative doses of salbutamol, and the number of beta 2-adrenoceptors and antagonist affinity of these receptors on circulating lymphocytes were assessed at the start of the study and at 6-month intervals for 1 1/2 years. The BHR increased significantly (p = 0.001) during the year salbutamol was inhaled and returned to about the value at the start of the study after inhaling ipratropium bromide for 6 months. No change occurred in the bronchodilating responses to cumulative doses of salbutamol, nor was any change observed in the number and the affinity of beta 2-adrenoceptors on lymphocytes. It was concluded that long-term use of salbutamol caused a small but significant increase in BHR. The increase in BHR was not caused by subsensitization of beta 2-adrenoceptors to salbutamol.

Administration, Inhalation↗
PubMed1990

Beta 2-adrenoceptor up-regulation in relation to cAMP production in human lymphocytes after physical exercise.

The effect of isotonic bicycle exercise on beta 2-adrenoceptors and cAMP production in lymphocytes was studied. The origin of the newly exposed receptors was studied by measuring radioligand binding in the presence of hydrophylic or lipophylic 'cold' ligands. During exercise beta 2-adrenoceptor density increased from 1207 +/- 144 to 1776 +/- 152 sites/cell (56 +/- 14%). Isoprenaline induced an increase in cAMP synthesis, which was 68 +/- 15% higher than those values measured before the test. Forskolin did not induce a higher increase in cAMP production after exercise. The increase in receptor density seems not to be due to a transfer of internalized receptors to the membrane surface. We conclude that physical exercise induces an up-regulation of beta 2-adrenoceptors on lymphocytes and that these adrenoceptors are functional.

Adult↗
PubMed1990

The relationship between adrenaline and beta 2-adrenoceptors on human lymphocytes.

To study the relation between plasma adrenaline (AD) and noradrenaline (NA) and the beta 2-adrenoceptor number (Bmax) on lymphocytes these variables were measured in the following three groups: a) In 67 normotensive volunteers after a rest period of at least 15 min. b) In 10 essential hypertensive (HT) and 10 age and sex matched normotensive (NT) subjects before and after a standardized bicycle exercise test (BE). c) In 10 bilaterally adrenalectomized females (AF) and 10 healthy age matched females (NF) before and after a mental arithmetic test (MA). Significant correlations were found between AD and Bmax in NT (r = 0.30, P = 0.015) and between the proportional increase in AD and the proportional increase in Bmax after BE (r = 0.60, P less than 0.005). The MA induced elevation of Bmax was blunted after adrenalectomy. All these findings point to a relation between AD and beta 2-adrenoceptor regulation.

Adrenalectomy↗
PubMed1989

Adrenoceptors on blood cells in patients with essential hypertension before and after mental stress.

The effect of mental arithmetic (MA) on alpha 2- and beta 2-adrenoceptors on platelets and lymphocytes, respectively, and on plasma catecholamines was studied in normotensive (NT) and essential hypertensive (HT) subjects. There were no significant differences in responses of blood pressure, forearm blood flow (FBF) and heart rate to MA between the two groups. Baseline values and changes in adrenaline and noradrenaline levels during MA were similar in NT and HT. Alpha 2-adrenoceptor density and antagonist affinity did not differ between NT and HT and was not influenced by MA. Baseline values of beta 2-adrenoceptor density also did not differ between NT and HT and increased similarly after MA in both groups. Antagonist affinity to the beta 2-adrenoceptors under baseline conditions was lower in HT and did not change during MA in either group. Our results indicate that there are no differences between NT and HT in alpha 2- and beta 2-adrenoceptor density, either under baseline conditions or after mental stress.

Adult↗
PubMed1989

Effects of isometric exercise on blood cell adrenoceptors in essential hypertension.

The effect of handgrip (HG) isometric exercise on plasma catecholamines, alpha 2-adrenoceptors on platelets and beta 2-adrenoceptors on lymphocytes was studied in normotensive subjects (NT) and essential hypertensive subjects (HT). Whereas systolic blood pressure (SBP) increases were similar in NT and HT subjects, diastolic blood pressure (DBP) and heart rate (HR) increased more in the former group. Baseline values and changes in plasma epinephrine (E) and norepinephrine (NE) did not differ between both groups. No differences were apparent in alpha 2-adrenoceptor density and affinity between NT and HT subjects before or after the test. HG isometric exercise induced a similar increase in beta 2-adrenoceptors on lymphocytes of 22 +/- 7 and 13 +/- 5% in NT and HT subjects, respectively. Affinity to the beta 2-adrenoceptors under baseline conditions was somewhat lower in HT (8.1 +/- 0.4 pM) than in NT subjects (6.5 +/- 0.5 pM), and this difference persisted during the test. Our results indicate that there are no differences in alpha 2- and beta 2-adrenoceptor densities either at baseline conditions or after HG isometric exercise between NT and HT subjects. Small differences noted in affinity to the beta 2-adrenoceptors require further investigation.

Adult↗
PubMed1988

Role of adrenaline in the short-term upregulation of beta-adrenoceptors in essential hypertensive and adrenalectomized females.

The effect of mental arithmetic on beta 2-adrenoceptors on lymphocytes, as measured by (-)125I-iodocyanopindolol binding, was studied in normotensive and essential hypertensive females. To determine the role of adrenaline, mental arithmetic was also carried out in bilaterally adrenalectomized females. There were no significant differences in the blood pressure and heart rate responses to mental arithmetic among the three groups. Baseline values or changes in adrenaline levels during mental arithmetic were similar in normotensives and hypertensives, whereas levels of adrenaline remained undetectable throughout the test in adrenalectomized females. Baseline values of beta 2-adrenoceptors did not differ among the three groups. In normotensive and hypertensive females the increase in beta 2-adrenoceptor density was, respectively, 27 and 20%. Baseline values of beta 2-adrenoceptors were not related to the percentage changes in the receptor densities. In adrenalectomized females, in contrast to normotensives and hypertensives, there was no change in receptor density. These findings suggest that adrenaline plays a role in the short-term upregulation of beta 2-adrenoceptors after mental arithmetic.

Adrenalectomy↗
PubMed1988

Kinetics of (-)125iodocyanopindolol binding to intact human mononuclear cells.

In association experiments of (-)125Iodocyanopindolol (125ICYP) with human mononuclear cells (MNC) at 70 pM and a temperature of 37 degrees C equilibrium was reached within 30 min. However, when the same experiments were performed at a concentration of 4 pM 125ICYP, equilibrium was only reached after 3 hours. The consequences of incomplete equilibrium for the interpretation of binding experiments under the incorrect assumption that equilibrium has been reached, was investigated at equilibration times of one, two and three hours. The dissociation constant, Kd, decreased from 7.4 +/- 0.2 pM after one hour to 2.5 +/- 0.4 pM after three hours of incubation while the receptor density, RO, decreased from 970 +/- 170 to 713 +/- 58 sites/cell. Analysis of computer simulated binding curves confirmed the decrease in Kd and RO at prolonged incubations. We conclude that in 125ICYP binding in intact MNC one hour of incubation is not sufficient to obtain equilibrium at the lower concentrations. This leads to an overestimation of Kd- and to a lesser extent of RO-values. Extending the incubation time to three hours on the other hand may lead to a loss of cells and therefore to an underestimation of RO.

Humans↗
PubMed1987

Complications of (-)125I-iodocyanopindolol binding to human mononuclear cells.

(-)125I-Iodocyanopindolol (125ICYP) binding to intact and ultrasonically treated human mononuclear cells (MNC) was studied. Specific binding of 125ICYP defined as the difference in binding in the presence and absence of 2 microM (+/-)-propranolol displayed in intact cells a dissociation constant (Kd) of 11.8 +/- 2.7 pM and a beta-adrenoceptor number (Rt) of 2371 +/- 154 sites/cell. This specific binding, however, still had a complex character. In broken cells a homogeneous class of binding sites with a Kd-value of 6.7 +/- 1.0 pM and a Rt-value of 883 +/- 89 sites/cell was found. When in intact cells nonspecific binding was determined with CGP-12177, a hydrophilic beta-adrenoceptor antagonist, a homogeneous class of binding sites was found with a Kd of 7.0 +/- 0.3 pM and a Rt of 1645 +/- 95 sites/cell. Inhibition curves with (+)-, (-)-, (+/-)-propranolol, timolol and CGP-12177, obtained with ultrasonically treated cells were monophasic. In intact cells propranolol and timolol not only displaced 125ICYP from its specific sites, but in an almost monophasic way also from nonspecific binding sites. CGP-12177, however, showed a clear plateau. It is concluded that in broken MNC a loss of binding sites may occur, whereas in intact cells additional binding interferes with the correct determination of specific 125ICYP binding. The latter can be reduced to a minimum by using hydrophylic ligands such as CGP-12177 to measure nonspecific binding.

Binding, Competitive↗
PubMedDate not supplied

Modulation of proliferation of a human head and neck squamous carcinoma cell line (HN-1) by catecholamines and histamine.

The effects of catecholamines and histamine on the HN-1 human head and neck squamous carcinoma cell line were determined by analyzing binding of (-)125 I-iodocyanopindolol (delta-adrenergic antagonist), clonogenicity in soft agar, and cell cycle effects by dual-parameter flow cytometry. Binding studies revealed the presence of delta-adrenergic receptors with an affinity between 11-13 pM and a capacity between 5.8.-8.5 fmol/10(5) cells. A clonogenic assay demonstrated that both isoproterenol and histamine gave a minor inhibition of clonogenicity which could be reversed with propranolol and cimetidine respectively. Pretreatment with propranolol followed by isoproterenol treatment abolished the inhibitory effect of isoproterenol on clonogenicity. Catecholamines and histamine modulated the proliferation of HN-1 cells which was generated through receptor binding.

Carcinoma, Squamous Cell↗