Lymphocyte Beta 2-adrenoceptor Density Research Articles

Regulation of equine lymphocyte beta-adrenoceptors under the influence of clenbuterol and dexamethasone.

In 12 healthy horses, the effects of the beta2-agonist clenbuterol and the glucocorticoid dexamethasone on the lymphocyte beta2-adrenoceptor density and affinity (determined by (-)-[125I]-iodocyanopindolol binding) as well as its responsiveness (assessed by lymphocyte cyclic AMP [cAMP] responses to 10 micromol/l (-)-isoprenaline) were studied. Clenbuterol treatment, 2 x 0.8 microg/kg/day i.v. for 12 days, decreased significantly ICYP binding sites by approximately 30-40%; concomitantly, lymphocyte cAMP response to (-)-isoprenaline was reduced. After withdrawal of clenbuterol, beta2-adrenoceptor density and responsiveness gradually increased, reaching predrug levels after 4 days. The effects of dexamethasone on clenbuterol-induced desensitisation were further investigated. Administration of dexamethasone (1 x 0.1 mg/kg/day, i.v. for 5 days) immediately after clenbuterol withdrawal accelerated beta2-adrenoceptor recovery: only 24 h after administration dexamethasone restored the number of binding sites and cAMP response to (-)-isoprenaline to levels statistically indistinguishable from values before clenbuterol treatment. Three days after dexamethasone administration, lymphocyte beta2-adrenoceptors were further increased about 2-fold the pretreatment values, and this increase declined gradually after dexamethasone withdrawal, reaching baseline values after 4 days. Furthermore, in groups exposed simultaneously to both drugs, dexamethasone completely prevented clenbuterol-induced decrease in lymphocyte beta2-adrenergic receptor density and responsiveness. No significant change was observed in the dissociation constant for ICYP in any of the situations. We conclude that dexamethasone (glucocorticoids) can reverse and prevent Clenbuterol-induced desensitisation (down-regulation) of the lymphocyte beta2-adrenoceptors and therefore, a combined therapy with clenbuterol and dexamethasone may be potentially beneficial in horses suffering from chronic obstructive pulmonary disease (COPD).

A Bolus of Inhaled Budesonide Rapidly Reverses Airway Subsensitivity and β2-Adrenoceptor Down-regulation After Regular Inhaled Formoterol

Subsensitivity of airway beta2-adrenoceptors develops readily in asthmatics receiving regular long-acting beta2-agonists. This subsensitivity may be rapidly reversed by using systemic corticosteroids. The purpose of the present study was to investigate whether the same acute facilitatory effects occur when using a bolus dose of inhaled corticosteroid. Ten subjects with stable mild-to-moderate asthma, with a mean age of 27 years, mean (+/- SD) FEV1 of 2.95 L (0.94 L), 81% (15%) of predicted, all receiving inhaled corticosteroids, reactive to adenosine monophosphate (AMP) with a provocative concentration producing a 20% fall in FEV1 (PC20) < 200 mg/mL, were recruited into a randomized double-blind crossover study. The subjects received two separate 1-week treatment periods with formoterol dry powder, 24 microg bid, with an initial 1-week run-in and a 1-week washout period between the treatments. A single dose of placebo or budesonide turbuhaler, 1,600 microg, was taken in conjunction with the last dose of both treatment periods. AMP challenge was performed 2 h after the first and last dose of formoterol. Blood for lymphocyte beta2-adrenoceptor density (Bmax) was also measured before and after treatment with formoterol. There was no significant difference in the geometric mean PC20 after the first dose of formoterol comparing the two treatment periods: 362 mg/mL vs 391 mg/mL. The PC20 after the last dose of formoterol was significantly higher (p < 0.05) in conjunction with budesonide than with placebo: 427 mg/mL vs 99 mg/mL, amounting to a 4.3-fold difference (95% confidence interval [CI], 1.1 to 16.6). For comparison within each treatment period, there was significant subsensitivity (p < 0.05) between the first and last dose of formoterol when the latter was given with placebo: 391 mg/mL vs 99 mg/mL, a 3.9-fold fall (95% CI, 1.0 to 15.2), but not when the latter was given with budesonide: 362 mg/mL vs 427 mg/mL, a 1.2-fold rise (95% CI, 0.5 to 2.8). Lymphocyte 02-adrenoceptor density (geometric mean Bmax: fmol/10(6) cells) also showed significant down-regulation (p < 0.05) by formoterol given with placebo: preformoterol 2.53 vs postformoterol 1.91, but not by formoterol given with budesonide: preformoterol 2.43 vs postformoterol 2.67. The Bmax was significantly higher (p < 0.05) with formoterol + budesonide as compared to formoterol + placebo, amounting to a 1.40-fold difference (95% CI, 1.09 to 1.80). We have shown that a bolus dose of inhaled budesonide rapidly reverses subsensitivity to AMP bronchoprotection and associated beta2-adrenoceptor down-regulation in asthmatics taking regular formoterol. Further studies are indicated to assess whether high-dose inhaled corticosteroids should be administered as soon as possible along with beta2-agonists during an acute episode of bronchoconstriction.

Autonomic nervous system and adrenergic receptors in chronic hypotensive haemodialysis patients.

The pathophysiology of chronic hypotension (CH) in uraemia is not elucidated. The possible role of autonomic nervous system dysfunction and adrenoceptor alterations in the pathophysiology of CH in uraemia was evaluated in this study. Seventeen hypotensive haemodialysis (HD) patients, 17 normotensive HD patients, and 17 control subjects were studied. We evaluated the integrity of the baroreflex arc (Valsalva manoeuvre), the parasympathetic efferent pathway ('deep-breathing test') and the sympathetic efferent pathway ('hand-grip test'). We also evaluated platelet alpha 2-adrenoceptor and lymphocyte beta 2-adrenoceptor densities (radioligand binding assay), and beta 2-adrenoceptor response (intracellular cAMP generation after isoproterenol stimulation in lymphocytes). Responses to the Valsalva manoeuvre and the deep-breathing test were altered in all HD patients (P < 0.05). Valvalva ratio was lower in hypotensive patients than in normotensive patients (P < 0.01), whereas the pressor response to the hand-grip test was reduced only in hypotensive HD patients (P < 0.01). In haemodialysed patients, basal mean blood pressure (MBP) correlated with MBP increases during the hand-grip exercise (r = 0.59, P < 0.01). Plasma catecholamine levels were elevated in both groups of patients (P < 0.025). Plasma adrenaline levels were higher in hypotensive HD patients than in normotensive patients (P < 0.05). alpha 2- and beta 2-adrenoceptor densities and beta 2-adrenoceptor response were reduced in hypotensive patients (P < 0.05 vs normotensive patients). MBP correlated with alpha 2-adrenoceptor (r = 0.46, P < 0.01) and beta 2-adrenoceptor (r = 0.43, P < 0.025) densities in HD patients. Normotensive haemodialysed patients have increased plasma catecholamine levels with preserved alpha 2- and beta 2-adrenoceptor numbers, as well as beta 2-adrenoceptor responses. In hypotensive patients, plasma adrenaline levels were even higher; the increased plasma catecholamine levels induced an alpha 2- and beta 2-adrenoceptor downregulation. This downregulation may play a role in the reduced cardiovascular responses to adrenergic stimuli reported in hypotensive HD patients.

Circulating noradrenaline and beta-adrenergic receptors in children with congestive heart failure.

This study was designed to investigate changes in plasma catecholamine concentrations and the number of beta-adrenoceptors (beta-AR) of circulating lymphocyte in 94 noncyanotic congenital heart patients. In 43 patients with congestive heart failure, beta-AR density was significantly lower (p < 0.001) and plasma noradrenergic levels were significantly higher (p < 0.001) compared with corresponding values in 51 patients without heart failure. A significant negative correlation between lymphocyte beta-AR density and plasma noradrenergic levels was observed (r = -0.61, p < 0.001). The degree of left-to-right shunt and pulmonary pressure was correlated directly with noradrenaline level and inversely with lymphocyte beta-AR density. Both plasma noradrenaline level and lymphocyte beta-AR density return to normal in children with heart failure after surgical repair. Our results support the idea that changes in noradrenaline level and lymphocyte beta-adrenoceptor density occur concurrently with the presence and severity of heart failure in children.

Bronchodilator subsensitivity to salbutamol after twice daily salmeterol in asthmatic patients

In view of current concerns about use of regular beta-2 agonists, and the place of the newer long-acting drugs, we decided to evaluate whether continuous exposure to twice daily salmeterol results in a blunting of the acute bronchodilator response to repeated doses of salbutamol, as might be administered in the management of an acute asthma attack. After a 2 week run-in without beta-2 agonists, 17 asthmatic patients (mean [SE] age 34 [3] years, mean forced expiratory volume in 1 s [FEV 1] 64 [2·7]% of predicted) were randomised to receive salmeterol 50 μg twice daily or placebo for 4 weeks in a double-blind crossover fashion. A histamine challenge test was done 12 h after the last dose of each treatment period, and dose-response curves to inhaled salbutamol (200-3200 μg) were constructed 36 h after the last dose. Patients treated with salmeterol had reduced bronchodilator responses to salbutamol in terms of FEV 1 and peak expiratory flow rate (PEFR) than those treated with placebo. The reduction in response equated with a 2·5-fold and a fourfold greater dose of salbutamol being required to produce a given FEV 1 and PEFR, respectively. There was a significant reduction in lymphocyte beta-2 adrenoceptor density after salmeterol compared with placebo and run-in. Salmeterol remained effective in terms of disease control, with a significant improvement in morning PEFR compared with placebo that was maintained over the 4 week treatment period. Continuous exposure to salmeterol 50 μg twice daily results in subsensitivity to the acute bronchodilator response to repeated doses of inhaled salbutamol. Thus patients receiving regular treatment with salmeterol might require higher doses of salbutamol when used for relief of acute bronchoconstriction.

Plasma Catecholamines, Thrombocyte Alpha 2- and Lymphocyte Beta 2-Adrenoceptor Densities in Hypertensive Patients with Low or Normal Plasma Renin Concentrations

The sympathetic nervous system is unique in the regulation of plasma renin, for it can stimulate or suppress renin release by activation of either renal beta- or alpha 2-adrenoceptors. The authors studied plasma renin concentration (PRC), noradrenalin and adrenalin levels in plasma, and the densities of lymphocyte beta 2-adrenoceptors and thrombocyte alpha 2-adrenoceptors in 25 hypertensive patients with either normal (11-40 mU/L; n = 9) or low PRC (0-10 mU/L; n = 14). There were no differences in plasma catecholamine levels and adrenoceptor densities between the two patient groups. A positive correlation (r = 0.66; P < 0.005) between beta 2-adrenoceptor density and PRC in the patient group with low PRC, and a negative correlation (r = -0.72; P < 0.01) between alpha 2-adrenoceptor density and plasma renin in patients with normal PRC were found. They conclude that adrenoceptor densities on blood elements and plasma catecholamines do not differ in low and normal renin hypertension. The significant correlations between adrenoceptor densities and PRCs may indicate that adrenoceptors on blood elements mirror adrenoceptor densities in the kidney and that tonic suppression of renin release through alpha 2-adrenoceptors is preserved in hypertensive patients with normal plasma renin levels.

Influence of sex‐steroid hormones on the regulation of lymphocyte beta 2‐adrenoceptors during the menstrual cycle.

1. Up to 40% of female asthmatic subjects suffer a premenstrual deterioration in their condition which may be ameliorated by progesterone supplementation, although the mechanism responsible for this phenomenon is not understood. In vitro studies have shown that female sex-steroid hormones potentiate the bronchorelaxant effect of isoprenaline, whilst in vivo it has been shown that females exhibit greater sensitivity of systemic beta 2-adrenoceptor responses. 2. The aim of the present study was to determine whether cyclical alterations in beta 2-adrenoceptor expression, occurring under the influence of ovarian sex-steroid hormones, may offer an explanation for these findings. In vitro parameters of lymphocyte beta 2-adrenoceptor function were investigated in nine normal female subjects (aged 24 +/- 2 years) during the follicular (day 2-4) and luteal (day 21-23) phases of their menstrual cycle, and results were compared with those of nine age-matched healthy male controls studied at the same time intervals. 3. In female subjects there were significant increases in serum concentrations of oestradiol (3.3-fold) and progesterone (10.6-fold) between the follicular and luteal phases of the menstrual cycle, whereas no changes occurred in males. 4. In females during the luteal phase, the increase in sex-steroid hormones was mirrored by an increase in lymphocyte beta 2-adrenoceptor density (Bmax) and in maximal cyclic AMP response to isoprenaline (Emax), which were significantly higher than in male subjects. Mean differences (95% CI) between male and female subjects on visit 2 were 1.09 (0.49 to 1.69) fmol/10(6) cells (P = 0.001) for Bmax, and 3.42 (0.80 to 6.04) pmol/10(6) cells (P = 0.02) for Emax.(ABSTRACT TRUNCATED AT 250 WORDS)

Lymphocyte beta adrenoceptor upregulation and improved cardiac response to adrenergic stimulation following converting enzyme inhibition in congestive heart failure.

To determine the effect of ACE inhibitor therapy on lymphocyte beta-adrenoceptor function and density, as well as the in vivo myocardial response to beta-agonist stimulation, we studied 12 patients with chronic severe heart failure before and after 16 weeks' treatment with quinapril. Lymphocyte beta-adrenoceptor function (intracellular cAMP production in response to isoprenaline) was studied as a surrogate tissue for myocardium, and increased significantly after quinapril at concentrations of isoprenaline between 10(-3) and 50 mmol.l-1. Lymphocyte beta-adrenoceptor density (six patients) measured by [125I] iodocyanopindolol binding, increased from 242 +/- 72 (mean +/- SEM) to 884 +/- 17 receptors/cell (P < 0.05). Changes in functional myocardial beta-adrenoceptor status were determined by measuring changes in haemodynamic responses to exercise and to incremental dobutamine infusion. Following quinapril there were significant improvements in cardiac index, stroke volume and cardiac power output during sub-maximal exercise testing and dobutamine infusion; stroke work index in response to dobutamine (but not exercise) improved significantly. ACE inhibitors cause lymphocyte beta-adrenoceptor upregulation in heart failure, which is associated with an improved cardiac pumping capacity in response to beta-agonist stimulation.

Regulation of the lymphocyte adenylate cyclase system by prostaglandin E2 infusions in resistant hypertensive subjects.

The effects of prostaglandin E2 (PGE2) infusions on the beta 2-adrenoceptor-dependent adenylate cyclase (beta 2ARAC) system of lymphocytes were studied in 26 patients with resistant hypertension (RH). The density of beta 2-adrenoceptors and their affinity for l-isoproterenol were measured with 125ICYP, and adenylate cyclase activity was determined with alpha 32P-ATP in mononuclear lymphocytes of RH patients before and at 1, 7, and 14 days after the last PGE2 infusion. Plasma epinephrine and norepinephrine concentrations were analyzed using high-performance liquid chromatography. The patients were divided into two groups: 19 receiving clonidine (group I) and seven receiving four-drug antihypertensive therapy (group II) before and after PGE2 infusions. Resistance to antihypertensive drugs in patients of both groups was overcome by PGE2 infusions, and was correlated with a decrease in lymphocyte beta 2-adrenoceptor density, an increase in beta 2-receptor affinity for l-isoproterenol, and an increase in adenylate cyclase activation. The absence of a PGE2 effect was associated with an acute increase in plasma epinephrine content and a decrease in the sensitivity of the lymphocyte beta 2ARAC system.

Alteration of beta-adrenoceptor function in hypertensive patients with different degrees of left ventricular hypertrophy.

Previous assessment of beta-adrenoceptor function has shown alterations in essential hypertension (EH). In the present study, we compared lymphocyte beta-adrenoceptor density (Bmax) and adenylate cyclase (AC) activity stimulated by l-isoproterenol, Gpp(NH)p, Gpp(NH)p + l-isoproterenol, and forskolin in 46 patients with EH and in 17 normotensive subjects. The patients with EH were divided into two subgroups, one with left ventricular myocardial mass (LVMM) less than 200 g and the second with LVMM greater than 200 g (according to Teichholz' formula). There were no significant differences in Bmax or in AC activity [basal and stimulated by Gpp(NH)p and forskolin] between the patients and the normotensive subjects. Adenylate cyclase activity stimulated by l-isoproterenol was reduced (% from basal AC) in the patients (P less than .05), and Bmax was increased only in the patients with left ventricular hypertrophy (P less than .05). There were no differences in AC activity between the two patient subgroups, and Bmax and AC activity did not correlate with blood pressure in either the patients or the normotensive subjects. Correlations were found between Bmax and LVMM (r = 0.38, P less than .02) and between Bmax and interventricular septum thickness (r = 0.412, P less than .02) among the patients. Thus, beta-adrenergic-mediated AC sensitivity to catecholamines is reduced in patients with EH and may represent a generalized defect in beta-receptor function in EH. Increased Bmax is likely to characterize more pronounced involvement of the target organs in the pathologic process associated with EH than is a higher blood pressure level.

Terbutaline-Induced Downregulation of (β2-Adrenoceptors Without Gi-Protein Alterations in Human Lymphocytes

Recent evidence suggests that agonist-induced desensitization of Gs protein-coupled beta-adrenoceptors is accompanied by sensitization of Gi protein-coupled receptors and/or an increase in Gi protein. To find out whether such "cross-regulation" between Gs protein- and Gi protein-coupled receptors can be also demonstrated in vivo in humans, we studied the effects of a 2 week treatment of eight male volunteers with the beta 2-adrenoceptor agonist terbutaline (3 x 5 mg/day) on beta 2-adrenoceptor density and Gi-protein content in lymphocytes and on alpha 2-adrenoceptor density (Gi-coupled receptors) in platelets. Terbutaline decreased the lymphocyte beta 2-adrenoceptor density by about 30%, but had no significant influence on lymphocyte Gi-protein levels (assessed by pertussis toxin-catalyzed [32P]ADP ribosylation) or on platelet alpha 2-adrenoceptor density. We conclude that circulating blood cells are not suitable to demonstrate in humans in vivo a "cross-regulation" between Gs- and Gi-coupled beta- and alpha-adrenoceptors.

Effects of Insulin-Induced Hypoglycemia onβ2-Adrenoceptor Density and Proliferative Responses of Human Lymphocytes*

We studied the effects of insulin (0.1 IU/kg BW, iv)-induced hypoglycemia on lymphocyte beta 2-adrenoceptor function, lymphocyte subset distribution, and proliferative response to mitogen stimulation in 10 healthy volunteers. Thirty minutes after insulin injection plasma glucose levels were markedly decreased; concomitantly, plasma epinephrine levels had increased about 10-fold; plasma norepinephrine levels, however, increased only moderately. Lymphocyte beta 2-adrenoceptor density and the cAMP response to 10 mumol/L isoproterenol stimulation were elevated; lymphocyte Ts/c-cells had increased, whereas Th-cells had decreased, resulting in a decrease in the Th-/Ts/c-cell ratio from 1.7 to 1.0. These changes were accompanied by a significantly reduced lymphocyte proliferative response (measured as [3H]thymidine uptake) to mitogen stimulation. Two hours after insulin injection plasma catecholamines, lymphocyte beta 2-adrenoceptor function, lymphocyte subset distribution, and proliferative responses had returned to nearly preinsulin levels. We conclude that acute vigorous increases in endogenous epinephrine evoked by insulin-induced hypoglycemia are associated with increases in lymphocyte beta 2-adrenoceptor function, redistribution of lymphocyte subsets, and an (at least transiently) attenuated in vitro immune responsiveness.

Agonist-induced desensitization of beta-adrenoceptor function in humans. Subtype-selective reduction in beta 1- or beta 2-adrenoceptor-mediated physiological effects by xamoterol or procaterol.

We investigated the effects of beta 2- (procaterol 2 x 50 micrograms/day for 9 days) and beta 1- (xamoterol 2 x 200 mg/day for 14 days) adrenoceptor agonists on lymphocyte beta 2-adrenoceptor density and beta 1- and beta 2-adrenoceptor in vivo function (assessed as isoprenaline-infusion-evoked hemodynamic effects and exercise-induced tachycardia) in healthy volunteers. Procaterol decreased lymphocyte beta 2-adrenoceptor density and all beta 2-adrenoceptor-mediated in vivo effects but did not affect beta 1-adrenoceptor-mediated in vivo effects. In contrast, xamoterol neither affected lymphocyte beta 2-adrenoceptors nor beta 2-adrenoceptor-mediated in vivo effects but decreased beta 1-adrenoceptor-mediated in vivo effects. It is concluded that in humans, generally long-term application of beta 1- or beta 2-adrenoceptor agonists causes desensitization of beta-adrenoceptor function but in a beta-adrenoceptor subtype-selective fashion.

Defective venous beta-adrenergic response in borderline hypertensive subjects is corrected by a low sodium diet.

Hypertensive patients have reduced lymphocyte beta-adrenergic responsiveness which is corrected by a low sodium (Na) diet. To determine if this represents a more generalized abnormality in beta adrenoceptor response, we studied beta adrenergic-mediated vasodilation in hand veins of borderline hypertensive subjects and controls. Subjects received a 5-d diet containing high Na/low potassium (K), high Na/high K, or low Na/high K. Venous distension, as evaluated by a linear variable differential transformer, was measured in relation to infusion of phenylephrine followed by isoproterenol and nitroglycerin. On both the high Na/high K and high Na/low K diets, hypertensive subjects had significantly decreased isoproterenol-mediated vasodilation (47% decrease, P less than 0.01 and 36% decrease, P less than 0.01, respectively). On the low Na/high K diet, isoproterenol-mediated vasodilation in hypertensive subjects increased 41% (P less than 0.01) to a level not different from controls. Nitroglycerin-mediated vasodilation was not different in normotensive and hypertensive subjects, nor was it altered with Na intake. Phenylephrine-mediated vasoconstriction did not differ between normotensive and hypertensive groups. Venous beta-adrenergic response correlated with lymphocyte beta adrenoceptor density in normotensive (r = 0.53, P less than 0.005) but not hypertensive subjects. This study demonstrates that beta-adrenergic responsiveness is selectively reduced in peripheral veins of borderline hypertensive subjects, and this is corrected by a low Na diet. In view of our previous findings of reduced lymphocyte beta-adrenergic responsiveness in borderline hypertension, these studies suggest a generalized defect of beta adrenoceptor responsiveness in human hypertension. Further, dietary Na may play an important role in regulating this abnormality.

Decreased Numbers Of Lymphocyte β2‐Adrenoceptors In Pregnant Women Receiving β2‐Adrenergic Agonist Therapy

Intravenous infusion of buphenine hydrochloride was administered on 4 successive days to 8 pregnant women with imminent preterm labor. Serial blood samples taken before and throughout the study were assayed for lymphocyte beta 2-adrenoceptor density and cyclic adenosine-3',5'-monophosphate (cAMP). The lymphocyte beta 2-adrenoceptor density declined significantly (p less than 0.01) during the treatment. The plasma cAMP concentration was highest 4 h after commencement of infusion and decreased thereafter. Despite the decrease in lymphocyte beta 2-adrenoceptor density, the clinical response remained good and the parturients did not go into labor until several days after infusion was started.

Lymphocyte Beta-2-Adrenoceptors and Plasma Catecholamines in Fetal Hypoxia

Conclusive evidence has been furnished that the beta 2-adrenoceptor density in circulating lymphocytes is related to that of beta 2-adrenoceptors in tissues from the same subjects. This study was designed to evaluate the effect of fetal hypoxia on lymphocyte beta 2-adrenoceptor density. The material consisted of 8 hypoxic newborns, 4 delivered by vacuum extraction and 4 by Caesarean section, after approximately 10 h parturition. The control group consisted of 8 vaginally delivered newborns without hypoxia. Umbilical plasma adrenaline and noradrenaline were significantly elevated in the hypoxic newborns. Their lymphocyte beta 2-adrenoceptor density was lower (p less than 0.01) than that in the controls. A plausible explanation for this finding might be downregulation of beta 2-adrenoceptors because of elevated plasma catecholamine level.

Hemodynamic and beta-adrenergic receptor adaptations during long-term beta-adrenoceptor blockade. Studies with acebutolol, atenolol, pindolol, and propranolol in hypertensive patients.

In an attempt to further clarify the mechanism of the maintenance of the antihypertensive effect of beta-adrenoceptor antagonists, the effects of four antagonists with different ancillary properties (acebutolol, atenolol, pindolol, and propranolol) on systemic and renal hemodynamics, body fluid volumes, hormones, and lymphocyte beta-adrenoceptor density were studied in four groups of 10 hypertensive patients. The patients were observed for 3 weeks during active treatment and for 2 weeks after withdrawal of treatment. At the end of the 3-week treatment period, the four drugs had an equal antihypertensive effect (fall in mean arterial pressure, 10-13%). Although renin activity was suppressed (60-70%) by all four drugs, changes in renin or pretreatment values of renin levels were not correlated with the fall in blood pressure. The drugs had no effect on plasma catecholamine concentrations or body fluid volumes. Despite similar antihypertensive effects among the four drugs, the changes in flow and resistance underlying the fall in blood pressure differed considerably. With pindolol, the fall in blood pressure was associated with a fall in vascular resistance (26 +/- 6%), whereas with propranolol, it was predominantly associated with a fall in cardiac output (11 +/- 7%). No significant changes in vascular resistance or cardiac output occurred with atenolol or acebutolol. The changes in renal blood flow and renal vascular resistance occurred in parallel with the changes in cardiac output and systemic vascular resistance. Plasma epinephrine concentration and pretreatment cardiac chronotropic responsiveness to isoproterenol appeared to be inversely correlated with lymphocyte beta-adrenoceptor density (Bmax) (r = -0.41 and -0.43, respectively). With pindolol, Bmax decreased maximally by 39 +/- 6%, and with propranolol, it increased by 51 +/- 17%. With both drugs, significant changes in Bmax were already present 24 hours after treatment. Furthermore, 1 week after withdrawal of treatment with pindolol, Bmax was still down-regulated, and cardiac chronotropic responsiveness was still decreased, whereas 1 week after withdrawal of propranolol, Bmax was still up-regulated, and cardiac chronotropic responsiveness was still increased. No changes in Bmax occurred with the beta 1-selective antagonists acebutolol and atenolol. Thus, despite an equal antihypertensive effect, the four beta-adrenoceptor antagonists appear to have dissimilar effects on cardiac output, renal blood flow, and lymphocyte beta-adrenoceptors. Changes in cardiac output, the circulating blood volume, or angiotensin-mediated vasoconstriction are factors unlikely to be crucial for the antihypertensive effect of beta-adrenoceptor antagonists. Therefore, interference with vasoconstrictor nerve activity through blockade of either central or peripheral prejunctional beta-adrenoceptors could be an alternative explanation of their blood pressure-lowering potential.

Density of adrenoceptors in rat heart and lymphocytes 48 hours and 7 days after acute myocardial infarction

Down regulation of the beta adrenoceptor is thought to play an important role in the diminished response to catecholamines in heart failure. beta Adrenoceptor densities were measured on membrane homogenates of rat right ventricle and lymphocytes 48 h or 7 d after experimental myocardial infarction, and in rats exposed to a continuous infusion of isoprenaline (400 micrograms.kg-1.h1). The performance of the rat hearts was also evaluated 48 h post infarction in an isolated retrograde perfused heart preparation. In contrast to a 60% down regulation in right ventricle and a 20% down regulation in lymphocyte membranes after isoprenaline infusion, there was no change in right ventricle and lymphocyte beta adrenoceptor densities after myocardial infarction. Left ventricular contractile performance was significantly depressed 48 h after myocardial infarction. Mean basal left ventricular pressure decreased from 108(SEM 3) to 63(4) mm Hg while the maximal response to dobutamine was decreased from 204(4) to 105(12) mm Hg (n = 8). No correlation was found between the receptor densities of right ventricular and lymphocyte membranes. We conclude that diminished response to beta sympathomimetics after myocardial infarction cannot be attributed to a loss of surface beta adrenoceptors, and that the lymphocyte beta adrenoceptor does not provide an adequate system to monitor small receptor changes on the myocardium.

α- and β-Adrenoceptors in Hypertension. II. Platelet α2- and Lymphocyte β2-Adrenoceptors in Children of Parents with Essential Hypertension. A Model for the Pathogenesis of the Genetically Determined Hypertension

To study whether changes in alpha- and beta-adrenoceptors in human essential hypertension (EHT) might be genetically determined, we assessed platelet alpha 2- and lymphocyte beta 2-adrenoceptor density in 48 normotensive children of normotensive parents (NT) and in 41 normotensive children with one EHT-parent. Both groups did not differ in age, body weight and height, blood pressure, heart rate, plasma catecholamine levels, plasma renin activity (PRA), and lymphocyte beta 2-adrenoceptor density. Platelet alpha 2-adrenoceptor density, however, was in EHT-children significantly higher than in NT-children. In NT-children, platelet alpha 2-adrenoceptors were significantly, inversely correlated with PRA, indicating that they might mirror renal alpha 2-adrenoceptors which inhibitorily regulate renin release. In contrast, in EHT-children PRA was not at all related to platelet alpha 2-adrenoceptors, suggesting an early (even in the normotensive stage) disturbance of the alpha 2-adrenoceptor-mediated regulation in renin release. From these results and those obtained in the experimental rat models of acquired hypertension, a model for the pathogenesis of the genetically determined hypertension is proposed in which a very early step in the development of hypertension is a genetically determined increase in renal alpha-adrenoceptors that causes enhanced sodium retention. This initiates a chain of events that finally results in increased peripheral vascular resistance and, hence, blood pressure. On the other hand, beta-adrenoceptor changes seem to be secondary phenomena due to the elevation in blood pressure.

Mode of Delivery and Lymphocyte &amp;beta;&lt;sub&gt;2&lt;/sub&gt;-Adrenoceptor Density in Parturients and Newborns

Twenty-six women with uncomplicated pregnancy at term were selected for the study. Nine had spontaneous vaginal delivery without medication, 8 elective caesarean section under epidural and 9 under general anaesthesia. The results clearly demonstrate that newborns have lower lymphocyte beta 2-adrenoceptor density than their mothers. In vaginally delivered newborns the lymphocyte beta 2-adrenoceptor density was 38%, in the caesarean section group with general anaesthesia 27%, and with epidural anaesthesia 22% lower than in the corresponding mother group. Vaginally delivered newborns have lower lymphocyte beta 2-adrenoceptor density than those delivered by caesarean section. A plausible explanation is the down-regulation of the beta 2-adrenoceptors during labour and delivery.