Identification of Alprenolol Hydrochloride as an Anti-prion Compound Using Surface Plasmon Resonance Imaging.

Prion diseases are transmissible neurodegenerative disorders of humans and animals, which are characterized by the aggregation of abnormal prion protein (PrPSc) in the central nervous system. Although several small compounds that bind to normal PrP (PrPC) have been shown to inhibit structural conversion of the protein, an effective therapy for human prion disease remains to be established. In this study, we screened 1200 existing drugs approved by the US Food and Drug Administration (FDA) for anti-prion activity using surface plasmon resonance imaging (SPRi). Of these drugs, 31 showed strong binding activity to recombinant human PrP, and three of these reduced the accumulation of PrPSc in prion-infected cells. One of the active compounds, alprenolol hydrochloride, which is used clinically as a ß-adrenergic blocker for hypertension, also reduced the accumulation of PrPSc in the brains of prion-infected mice at the middle stage of the disease when the drug was administered orally with their daily water from the day after infection. Docking simulation analysis suggested that alprenolol hydrochloride fitted into the hotspot within mouse PrPC, which is known as the most fragile structure within the protein. These findings provide evidence that SPRi is useful in identifying effective drug candidates for neurodegenerative diseases caused by abnormal protein aggregation, such as prion diseases.

The interactivities with lipid membranes differentially characterize selective and nonselective beta1-blockers.

BACKGROUND AND OBJECTIVE: beta-Adrenoceptor-blocking agents have been used for perioperative management during anaesthesia, in which selective beta1-blockers are advantageous over nonselective beta-blockers. Apart from the different affinity for beta-adrenoceptors, beta1-blockers were differentially characterized in light of their different interaction with lipid membranes. METHODS: Selective (atenolol, metoprolol and esmolol) and nonselective (alprenolol, oxprenolol and propranolol) beta1-blockers were reacted at 0.2-1 mmol l with 1,2-dipalmitoylphosphatidylcholine liposomes and biomimetic membranes consisting of phospholipids, sphingolipid and cholesterol. Their membrane interactivities were comparatively determined using the potency to modify membrane fluidity by measuring fluorescence polarization. Their relative hydrophobicities were evaluated by reversed-phase liquid chromatography. RESULTS: The chromatographic evaluation divided the tested drugs into more hydrophobic ones containing nonselective beta-blockers and less hydrophobic ones containing selective beta1-blockers. Nonselective beta-blockers, but not selective beta1-blockers, fluidized liposomal membranes, with the potency being oxprenolol < alprenolol < propranolol. Membrane-active alprenolol preferentially acted on the hydrophobic deeper regions of phospholipid bilayers. The potency of nonselective beta-blockers to fluidize biomimetic membranes was greatest in propranolol, followed by alprenolol and oxprenolol, whereas all selective beta1-blockers were inactive. CONCLUSION: The membrane-fluidizing effects of beta-blockers are correlated with their relative hydrophobicities and their respective conformations to perturb the alignment of phospholipid acyl chains. The membrane-interacting characteristics differentiate beta-blockers as nonselective propranolol, alprenolol and oxprenolol vs. beta1-selective atenolol, metoprolol and esmolol. Such differentiation reflects not only the structural difference but also the beta-adrenoceptor-blocking difference. The membrane fluidization may be partly responsible for the nonselective blockade of beta-adrenoceptors.

Changes in butyrylcholinesterase activity and serum lipids after oxprenolol and glibenclamide treatments in non-diabetic rats.

The effects of chronic treatment with oxprenolol (CAS 6452-72-7, OXP, 15 mg/ kg/ day) or glibenclamide (CAS 10238-21-8, GL, 2.5 mg/kg/day), or their combination administered for 6 and 12 weeks, on the butyrylcholinesterase (BuChE) activity in plasma and liver and on the plasma levels of triglycerides, total cholesterol and high density lipoprotein (HDL)-cholesterol were studied in normal, non-diabetic female rats. In all treated groups a significant increase of plasma BuChE activity was obtained after 6 weeks of either OXP (46 %), or GL (36 %) treatment, or of their concurrent application (24 %). After 12 weeks of treatment, the increase in enzyme activity was significant only in the OXP group. The BuChE activity in the liver was increased (between 3-25 %) in all treated groups except in one during 6 and 12 weeks of treatment. These effects of either OXP or GL, or their combination on BuChE activity in liver suggest their stimulating effects on enzyme synthesis. The changes of total plasma cholesterol in all groups were insignificant. On the other hand, HDL-cholesterol was significantly decreased in all treated groups. After 6 weeks of treatment, GL, OXP, or their combination caused a decrease in plasma HDL cholesterol by 19, 50 or 22 % respectively, when compared with the control group. After 12 weeks of GL, OXP, or GL+OXP administration, HDL-cholesterol plasma levels in treated groups were 32, 25 and 22 % lower than in the control group. Treatment with GL, OXP, or GL+OXP during 6 weeks had no significant effect on triglycerides level. However, after 12 weeks of GL, OXP, or GL+OXP administration, the triglycerides levels were significantly increased (9, 47 and 36 %) when compared with the control group. These results showed that the increase in BuChE activity might be the first sign of altered triglyceride and lipoprotein metabolism.

Gastropods as an evaluation tool for screening the irritating potency of absorption enhancers and drugs.

PURPOSE: The objective of this study was to develop a simple alternative test using naked snails (slugs) for screening the irritating potency of chemicals on mucosal surfaces. METHODS: The effect of various absorption enhancers and two beta-blocking agents on the mucosal tissue was determined from the total protein and lactate dehydrogenase released from the foot mucosa after treatment. Additionally, mucus production and reduction in body weight of the slugs caused by the treatment were measured. RESULTS: According to the effects on the mucosal epithelium of the slugs the following rank order of increasing toxicity was established: PBS, HP-beta-CD (5%), beta-CD (1.8%) and oxprenolol hydrochloride (1%) < DDPC (1%) < STDHF (1%) < BAC (1%), SDC (1%) and propranolol hydrochloride (1%). The results of the present study are in agreement with other studies using the same compounds on other models. CONCLUSIONS: The results of this study indicated the mucosa of slugs can serve as a primary screening tool for the evaluation of chemicals on mucosal surfaces. By simply measuring mucus production and weight loss reliable toxicity information can be obtained. This demonstrates rapid screening tests can be carried out using simple toxicity endpoints.

Beta2-agonists prevent Th1 development by selective inhibition of interleukin 12.

Interleukin 12 (IL-12) plays a central role in the immune system by skewing the immune response towards T helper 1 (Th1) type responses which are characterized by high interferon-gamma and low IL-4 production. In this report we present evidence that beta2-agonists inhibit IL-12 production by both human monocytes in response to lipopolysaccharide (LPS) and dendritic cells stimulated via CD40. Inhibition of IL-12 production is selective, as other cytokines produced by monocytes are unaffected. IL-12 inhibition is dependent on beta2-adrenoceptor stimulation and correlates with increased levels of intracellular cAMP. In conjunction with their ability to suppress IL-12 production, when beta2-agonists are added at priming of neonatal T lymphocytes, they inhibit the development of Th1-type cells, while promoting T helper 2 (Th2) cell differentiation. Further, the in vivo administration of a therapeutic dose of salbutamol results in the selective inhibition of IL-12 production by whole blood lymphocytes stimulated in vitro with LPS. These findings provide new insight into the immunological consequences of the clinical use of beta2-agonists and may suggest new approaches for the treatment of Th1-mediated diseases.

Effects of oxprenolol treatment on pseudocholinesterase and lipids in rats.

The effect of chronic treatment with the non-selective beta-blocker oxprenolol (CAS 6452-71-7) administered orally in two different doses (15 or 30 mg/kg/day for 6, 10 and 12 weeks) on plasma cholinesterase (PChE) activity and on the plasma level of triglyceride and total cholesterol were studied in normal rats. In all treated groups a significant increase (approximately 27-51%) of PChE activity was obtained (p < 0.05 vs. control group). The plasma concentration of total cholesterol was significantly increased as well (21-48%, p < 0.05 vs. control) but oxprenolol exerted no significant effect on plasma triglyceride levels. The increase of enzyme activity and total cholesterol were not time- or dose-dependent. According to these results which showed a direct relationship between PChE activity and total cholesterol it is supposed that the increase of enzyme activity is initially due to the action of oxprenolol on total cholesterol metabolism but that it does not have a direct effect on the enzyme. The results contribute to the hypothesis that PChE plays a role in lipoprotein metabolism although this has not yet been proven.

Beta-blockers inhibit the modification of low-density lipoproteins by sodium hypochlorite in vitro.

The effect of beta-blockers (alprenolol, oxprenolol, atenolol, acebutolol) and the non-steroidal anti-inflammatory drug, diclofenac, on modification of low-density lipoproteins (LDL) by sodium hypochlorite (NaOCl) was investigated in vitro. Beta-blockers and diclofenac inhibit the formation of thiobarbituric acid reactive substances in LDL modified by NaOCl. Beta-blockers, but not diclofenac, inhibit the hypochlorite-induced aggregation of LDL which was determined by photon correlation spectroscopy. The intracellular accumulation of cholesterol esters in J774 macrophages is inhibited by addition of beta-blockers, but not diclofenac, to LDL prior to the addition of NaOCl. The modification inhibiting effect of beta-blockers is inversely correlated to the binding capabilities of these substances to LDL which were assessed by laser electrophoresis. Inhibition of LDL modification in vivo by beta-blockers may reduce the risk of atherosclerosis and, therefore, compensate for the cholesterol-raising effect of these drugs in human plasma.

Arrhythmogenic effect of beta-adrenoceptor-blocking drugs in Purkinje fibres of guinea-pig hearts.

The association between torsade de pointes and experimentally induced early afterdepolarizations in isolated fibres is well documented. The effect of eight beta-adrenoceptor-blocking drugs (sotalol, nifenalol, acebutolol, dichloroisoproterenol, propranolol, oxprenolol, pindolol, atenolol), and of amiodarone, was studied in isolated spontaneously beating guinea-pig Purkinje fibres by the intracellular microelectrode technique. Phase 3 early afterdepolarizations were initiated by nifenalol hydrochloride (n = 18; 10 mumol/l: 0/18, 40 mumol/l: 3/18, 80 mumol/l: 8/18, 160 mumol/l: 11/18), rac.-(+/-)-sotalol hydrochloride (n = 28; 20 mumol/l: 0/28, 40 mumol/l: 9/28, 80 mumol/l: 20/28), (R)(+)-sotalol hydrochloride (n = 12; 40 mumol/l: 1/12, 80 mumol/l: 4/12), and (S)(-)-sotalol hydrochloride (n = 10, 40 mumol/l: 1/10, 80 mumol/l: 4/10). The arrhythmogenic effect was reversible after a washout period of one hour and early after-depolarizations could be terminated by tetrodotoxin (0.4-1.6 mumol/l, n = 6). Amiodarone only induced early afterdepolarizations at a low extracellular potassium concentration of [K+]o = 1.35 mmol/l (n = 5; 150 mumol/l: 0/5, 300 mumol/l: 1/5). The initiation of early after-depolarizations by sotalol and nifenalol might be induced by an imbalance of sodium inward current and potassium outward currents, and early afterdepolarizations are blocked by tetrodotoxin.

Chronic administration of oxprenolol and metoprolol attenuate sympathetic cardiovascular responses only in non-adrenalectomized pithed rats.

1. Oxprenolol and metoprolol (30 mg kg-1) were injected intraperitoneally (i.p.) for 1 day (acute treatment) and 6 weeks (chronic treatment) to Sprague-Dawley rats. 2. Increases of mean blood pressure and heart rate to noradrenaline (0.1-10 micrograms kg-1) and to electrical stimulation (0.5 msec, supramax V, 0.25-5 Hz) of the entire sympathetic outflow were measured in non-adrenalectomized (acute and chronic) and adrenalectomized (chronic) pithed rats. 3. Acute beta-adrenoceptor antagonist administration was without effect on mean blood pressure and heart rate increases to noradrenaline and electrical stimulation. 4. Chronic administration with oxprenolol significantly diminished the stimulation-induced increases of mean blood pressure and heart rate in non-adrenalectomized pithed rats. 5. Increases in heart rate, elicited by stimulation of the entire sympathetic outflow in non-adrenalectomized but not in adrenalectomized pithed rats, were decreased by metoprolol treatment. Both treatments were without effect on noradrenaline responses. 6. These results indicate that chronic beta-adrenoceptor antagonist treatment is associated with a reduction in the cardiovascular responses to sympathetic nerve-stimulation. However, this mechanism only operates when adrenomedullary adrenaline is present to facilitate the noradrenaline release through activation of presynaptic beta 2-adrenoceptors.

Concentration-dependent binding of the chiral beta-blocker oxprenolol to isoelectric or negatively charged unilamellar vesicles.

Large unilamellar vesicles (LUVs) of different lipid compositions were used to study the type of binding of the beta-blocking cationic agent oxprenolol to the lipid matrix of biological membranes at a physiologic pH value of 7.4. When isoelectric membranes of pure egg lecithin or egg lecithin/cholesterol (7:3 mol/mol) were used, a linear relationship between membrane-bound and free oxprenolol indicated a constant molar partition coefficient of 54 or 44 between the liposomal and the aqueous phase over a wide concentration range of the drug up to 25 mM. This pointed to deep insertion of the drug molecules into the hydrophobic membrane interior. Drug binding to membranes of negatively charged phosphatidylserine from bovine brain was cooperative with a Hill coefficient h of 3.4 at concentrations below 0.5 mM and a molar ratio Re of bound drug per lipid of 1:10. Above drug concentrations of 2.5 mM and Re = 1:5, a constant molar partition coefficient of 33 could be estimated. R-oxprenolol or S-oxprenolol, as well as the racemic drug, showed no differences in membrane binding, even with egg lecithin LUVs containing 20 mol% of the negatively charged (2S, 4R)-N-(hexadecanoyl)-4-hydroxyproline, which has a pronounced chiral headgroup. Our results suggest that enantioselective interactions of the chiral oxprenolol with the chiral lipids of biological membranes can be excluded. Furthermore, surface adsorption of the drug is probable only on the negatively charged cytosolic side of biological plasma membranes, whereas on the isoelectric exterior the cationic drug is inserted deeply into the membrane.

[Proxodolol--a new beta- and alpha-adrenoblockader]. / Proksodolol--novyi (beta-, al'fa-)adrenoblokator.

The beta- and alpha-adrenoceptor blocking activity, the specificity of its beta-adrenoceptor blocking action, partial agonistic and membrane-stabilizing properties, as well as antihypertensive, antiarrhythmic, and anti-ischemic effects were studied. Proxodolol was shown to be superior to labetalol in its beta-adrenoceptor blocking action and similar to it in its alpha-adrenoceptor blocking agent. The drug has no a partial agonistic activity and produces a moderate membrane-stabilizing action. Proxodolol proved to be effective in treating experimental hypertension and arrhythmias. It exhibits anti-ischemic activity.

Regional differences in nitric oxide-mediated relaxation of the rabbit sphincter of Oddi.

We studied the role of the L-arginine-nitric oxide (NO) pathway in non-adrenergic, non-cholinergic (NANC) relaxation of the rabbit sphincter of Oddi by recording changes in isometric tension in response to electrical field stimulation in two series of experiments. In a first set of experiments, biliary sphincters of Oddi removed from New Zealand white rabbits were placed horizontally in an organ bath containing oxygenized, buffered (pH 7.4) Krebs solution. Contractile responses of the whole sphincter to field stimulation were determined. In the second set of experiments, sphincter of Oddi was divided into two parts and the effects of field stimulation were studied separately on areas close to the duodenal papilla (area I) and areas close to the common bile duct (area II). In the whole sphincter of Oddi, field stimulation induced an initial twitch-like contraction followed by relaxation proportional to the number of stimuli (3 and 10 stimuli at 20 Hz, 50 V, 0.1 ms). The magnitude of the contractile responses was considerably reduced by 1 microM atropine, phentolamine and oxprenolol (NANC solution). Field stimulation produced dose-dependent contractions of both segments of sphincter of Oddi in response to the same protocol as used with whole sphincter of Oddi. However, preincubation with NANC solution produced monophasic relaxations in response to field stimulation in area I, whereas area II preparations such as the whole sphincter of Oddi responded with contractions followed by minimal relaxations. Field stimulation failed to induce either contractions or relaxations in the presence of 1 microM tetrodotoxin.(ABSTRACT TRUNCATED AT 250 WORDS)

[A comparative evaluation of the antidepressive activity of different beta-adrenoblockaders]. / Sravnitel'naia otsenka antidepressivnoi aktivnosti razlichnykh beta-adrenoblokatorov.

A chronobiological evaluation of the forced swimming test in rats treated with propranolol has shown that beta-adrenoblockers have antidepressive properties. This is true for oxprenolol which shows less pronounced affects. Nadolol that does not readily cross the blood-brain barrier insignificantly changes swimming behavior in the animals.

The effect of oxprenolol dosage time on its pharmacokinetics and haemodynamic effects during exercise in man.

We have studied the effect of dosage time of oxprenolol (Trasicor) on its pharmacokinetics and pharmacodynamics in six healthy volunteers. The drug effects measured were heart rate and systolic blood pressure during exercise. Oxprenolol was taken orally at 08.00 h, 14.00 h, 20.00 h, and 02.00 h in randomized order, with 1 week between successive doses. There were differences in the pharmacokinetics of oxprenolol for the ratio between the apparent volume of distribution and systemic availability (P = 0.04) and for elimination half-life (P = 0.006). Both were lowest after administration at 14.00 h (163 (77) l and 1.2 (0.6) h; mean (SD)) and highest after administration at 02.00 h (229 (100) l, and 1.7 (0.6) h). The systolic blood pressure during exercise before oxprenolol did not vary with dosage time, but heart rate during exercise before intake was lowest before dosage time 08.00 h and highest before dosage time 20.00 h (P = 0.03). The time-course of heart rate during exercise after oxprenolol was described by a model that incorporated the factors drug concentration and spontaneous diurnal variation. EC50 and Emax did not vary between dosage times. The spontaneous diurnal variation in heart rate during exercise was unaffected by oxprenolol, leading to an apparently greater effect of oxprenolol during the night than during the day.

On the relationship between the inhibition of thrombin stimulated aggregation and thromboxane formation in isolated platelets treated with beta-adrenoceptor blocking drugs.

Thromboxane B2 (TXB2) formation in isolated, thrombin-stimulated rat platelets was time dependent and appeared after 5 s of incubation. Beta-adrenoceptor blocking (BAB) drugs inhibited thrombin-stimulated TXB2 formation in the following rank order of potency: metipranolol approximately alprenolol approximately propranolol > oxprenolol > practolol. Atenolol was ineffective in inhibiting TXB2 production in stimulated platelets. The inhibition of thrombin-stimulated TXB2 formation by BAB drugs correlated with their inhibitory effect on thrombin-stimulated platelet aggregation, arachidonic acid liberation from membrane phospholipids and with their membrane fluidization. The higher was the liposolubility of the beta-adrenoceptor blocking drugs investigated, the higher was their inhibition of stimulated TXB2 formation. Hydrophilic, selective atenolol and practolol revealed slight or no inhibitory effect on stimulated thromboxane production.

In vitro and in vivo evaluation of the genotoxicity of N-nitrosooxprenolol.

N-nitrosooxprenolol (NO-oxprenolol) might be formed in the stomach of patients taking the beta-adrenergic blocking drug, oxprenolol. This nitroso derivative has previously been shown to induce DNA damage and repair in both rat and human cultured hepatocytes. The results of the present study show that in the presence of co-cultured rat hepatocytes, 0.03 mM NO-oxprenolol produced a significant increase in the frequency of 6-thioguanine-resistant but not of ouabain-resistant mutants. No mutagenic activity was detected in the absence of metabolic activation. In mice, NO-oxprenolol (1 g/kg) increased the incidence of micronucleated cells in the liver but not in the bone marrow and the spleen. These results suggest that NO-oxprenolol, consistent with its chemical nature of nitrosamine, is biotransformed into short-lived reactive species.

Regulation of tumor necrosis factor production by adrenaline and beta-adrenergic agonists.

The effects of adrenaline and isoproterenol, a specific beta-adrenergic agonist, on TNF production were investigated. Both agents inhibited the production of TNF by human blood and THP-1 cells stimulated by LPS. The effect of adrenaline was prevented by a beta-receptor antagonist, but not by an alpha-receptor antagonist. Levels of TNF mRNA were not reduced by adrenaline. Inhibition of TNF production was observed only if cells were first exposed to adrenaline or isoproterenol at about the same time as to LPS; incubation of THP-1 cells with isoproterenol for 24 h before LPS stimulation dramatically increased response, and prevented suppression of TNF production by a second dose of isoproterenol. Intracellular cAMP levels were increased by adrenaline and isoproterenol, at concentrations that inhibited TNF production. However, prolonged incubation of THP-1 cells with isoproterenol resulted in depression of cAMP concentrations to below basal levels. These data suggest that TNF production can be regulated by beta-receptor stimulation, that such regulation is mediated by changes in intracellular cAMP concentrations and is exerted at a posttranscriptional level. Adrenaline may be an important endogenous regulator of TNF production in sepsis.

An interactive computer program for randomization analysis of response curves with facilities for multiple comparisons.

An interactive Fortran program, MUCRA, is presented. The program can perform randomization analysis of a completely randomized or randomized-blocks design extended to growth and response curves. A single-step Scheffé-type procedure as well as the Peritz's closed step-down procedure have been implemented which control the familywise type I error-rate. In general, MUCRA is suitable as a computer tool for a distribution-free analysis of variance with repeated measures. The use of MUCRA is demonstrated by analyzing the effects oxprenolol and atenolol have on exercise heart rate. Oxprenolol is a non-selective beta-blocker with moderate intrinsic sympathomimetic activity (ISA), given by the Oros delivery system. Atenolol is a beta 1-selective blocker without ISA. A randomized placebo-controlled crossover design was used to compare the effects of the beta 1-blockers on heart rate during a progressive maximal exercise test on a bicycle ergometer. Application of the Scheffé-type procedure showed that the two drugs significantly (alpha = .05) reduce the heart rate during the exercise test at the three prechosen times (2, 5, and 24 hr) after intake. The reduction from atenolol is more pronounced than from oxprenolol Oros at 2 and 5 hr.

Atypical beta-adrenergic receptor in 3T3-F442A adipocytes. Pharmacological and molecular relationship with the human beta 3-adrenergic receptor.

Expression of ligand binding properties for an atypical beta-adrenergic receptor (beta-AR) subtype was studied during the adipose differentiation of murine 3T3-F442A cells and compared with that of the human beta 3-AR expressed in Chinese hamster ovary cells stably transfected with the human beta 3-AR gene (CHO-beta 3 cells) Emorine, L. J., Marullo, S., Briend-Sutren, M. M., Patey, G., Tate, K., Delavier-Klutchko, C., and Strosberg, A. D. (1989) Science 245, 1118-1121). 3T3-F442A adipocytes exhibited high and low affinity binding sites for (-)-4-(3-t-butylamino-2-hydroxypropoxy) [5,7-3H]benzimidazole-2-one ((-)-[3H]CGP-12177) (KD = 1.2 and 38.3 nM) and (-)-[125I]iodocyanopindolol ([125I]CYP) (KD = 47 and 1,510 pM). The high affinity sites corresponded to the classical beta 1- and beta 2-AR subtypes whereas the KD values of the low affinity sites for the radioligands were similar to those measured in CHO-beta 3 cells (KD = 28 nM and 1,890 pM for (-)-[3H]CGP12177 and [125I]CYP, respectively). These low affinity sites were undetectable in preadipocytes but represented about 90% of total beta-ARs in adipocytes. The atypical beta-AR and the human beta 3-AR add similarly low affinities (Ki = 3-5 microM) for (+/-)-(2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino-3)-(4-(1-methyl- 4- trifluormethyl-2-imidazolyl)-phenoxy)-2-propanol methane sulfonate (CGP20712A) or erythro-(+/-)-1-(7-methylindan-4-yloxy)-3-isopropylaminob utan-2-ol (ICI118551), highly selective beta 1- and beta 2-AR antagonists, respectively, in agreement with the poor inhibitory effect of the compounds on (-)-isoproterenol (IPR)-stimulated adenylate cyclase activity. Atypical beta-AR and beta 3-AR had an affinity about 10-50 times higher for sodium-4-(2-[2-hydroxy-2-(3-chlorophenyl)ethylamino]propyl)phenoxyace tate sesquihydrate (BRL37344) than the beta 1-AR subtype. This correlates with the potent lipolytic effect of BRL37344 in adipocytes. The rank order of potency of agonists in functional and binding studies was BRL37344 greater than IPR less than (-)-norepinephrine greater than (-)-epinephrine both in 3T3 adipocytes and CHO-beta 3 cells. As in CHO-beta 3 cells, the classical beta 1- and beta 2-antagonists CGP12177, oxprenolol, and pindolol were partial agonists in adipocytes. Although undetectable in preadipocytes, a major mRNA species of 2.3 kilobases (kb) and a minor one of 2.8 kb were observed in adipocytes by hybridization to a human beta 3-AR specific probe.(ABSTRACT TRUNCATED AT 400 WORDS)

Personality. Type A behavior, and the effects of beta-blockade.

In a previous report, it was shown that a dimension of personality entitled dependence/independence could be used to distinguish the cardiovascular and catecholaminergic response to stress in type A individuals. This study is a continuation of the previous work. It examines the relative effects of beta-blockade on stress-induced changes in heart rate, blood pressure, and catecholamines in two groups of type A individuals who differ in reactivity. Sixty-six healthy, middle-aged men with type A behavior were classified as dependent (high reactivity) or independent (low reactivity). The effects of beta-blockade on the two groups were tested in a randomized, double-blind, crossover trial utilizing a mental stressor, a physical stressor, and work day monitoring. Results showed that, in comparison with the independent type As, those who had been classified as dependent had higher heart rates in all three stress conditions and had higher epinephrine levels during both the mental and physical stressors. For both groups, beta-blockade lowered the heart rate and systolic blood pressure but increased norepinephrine with the mental stressor and epinephrine and norepinephrine with the physical stressor. It also reduced the mean work day heart rate. For the dependent type As, the drug had a greater effect on increasing epinephrine during the physical stressor and by reducing the percent of the work day spent in high heart rate zones. The results are discussed from the point of view of identifying type As who may be particularly coronary prone and the potential effects of beta-blockade on the reactivity associated with type A behavior.