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At least 1,009 records · Page 56Linked to original sources
PubMed1979

[Pharmacological properties of dl-2-(3'-t-butylamino-2'-hydroxypropylthio)-4-(5'-carbamoyl-2'-thienyl) thiazole hydrochloride (S-596), a new beta-adrenergic blocking agent (author's transl)].

We developed a new beta-adrenergic blocking, antiarrhythmic compound S-596 and compared the findings with those of propranolol or practolol. S-596 antagonized the positive chronotropic and inotropic actions of adrenaline in isolated guinea-pig atria, and blocked the relaxant response to adrenaline of isolated guinea pig tracheal strips. In anesthetized mongrel dogs, S-596 given intravenously inhibited increases in heart rate and myocardial contractile force and decreases in systemic blood pressure induced by isoproterenol. In conscious dogs, the oral administration of S-596 reduced the isoproterenol induced tachycardia and the maximal effect was attained one hour after administration. In this regard S-596 was about 5 times more potent than propranolol, and S-596 was significantly longer-acting than propranolol. Thus, S-596 has greater beta-blocking activity than propranolol. S-596 has a lesser degree of myocardial depressant action than propranolol in spontaneously contracting rat or guinea pig atria and no intrinsic sympathomimetic activity in reserpinized rats. S-596 also has a weaker local anesthetic and antiarrhythmic activity than propranolol, as determined in guinea pigs and rabbits.

Adrenergic beta-Antagonists↗
PubMed1976

[Therapy of chronic ischemic heart disease and arterial hypertension by means of beta-receptor blockaders].

50 patients with stenocardias in persisting arterial hypertension, of them 33 manifest coronary diseases, were orally treated with doses of propranolol up to 400 mg/die during a longer period. In the majority of the cases a good to very good therapeutic effectivity was to be proved in hypertension as well as in chronic ischaemic heart disease. The own favourable results of the treatment justify the estimation that proporanolol may be regarded as therapeutic remedy of choice in patients with simultaneous hypertension and chronic ischaemic heart disease. Moreover, a collective of 45 patients with different cardiovascular diagnoses under the new selective beta-receptor blocker Bonnecor (practolol) was observed. It is reported on first experiences in the sense of an intermediate information.

Adult↗
PubMed1976

Adverse reactions to beta-blocking drugs: a review.

Adverse reactions may occur as a predictable or unpredictable drug-induced illness can be reduced if the awareness of the prescribing doctor of clinically relevant drug and patient factors, which affect the response to the drug, can be increased. However, unexpected and unpredictable adverse reactions, sometimes reported as a single case in an anecdotal case report, are more difficult to evaluate and explain. Beta-blocking agents such as propranolol, oxprenolol and practolol have been asssociated with numerous adverse reactions. The influence of drug factors, such as range of action, absorption, metabolism, excretion, interactions, and patient factors such as disease states, idiosyncrasy, and personality are discussed.

Administration, Oral↗
PubMed1980

Immunologically mediated toxicity.

A major consideration which precedes the release of a new chemical into the environment of human beings is the possibility of its producing an undesirable or toxic effect. Toxicity is the clinical end-point of a mechanism which results in tissue damage. One such mechanism is mediated via the immunological system. The effect of some chemicals on immunologically competent cells has been to induce perturbations of immunological competence. This is currently under debate as a toxic hazard, and the concept is explored here, particularly in relation to the action of alkyl tins. Hypersensitivity, which is tissue damage resulting directly from an allergic reaction, depends on a substance acting as an antigen. Since many compounds of toxicological interest have a molecular weight less than 5000, the ability to induce an allergic state is governed in part by factors that influence antigen formation, covalent interactions with macromolecules and metabolism. These factors, together with an analysis of 'immunological specificity', are illustrated by experimental work on practolol, which demonstrates that an antibody present in human sera reacts with a product of first-phase metabolism.

Animals↗
PubMed1985

Adrenergic beta receptors are not uniformly distributed in the cerebellar cortex.

The noradrenergic (NE) innervation of the cerebellar cortex is sparse, forming a broad plexus of radially oriented axons distributing throughout the granular and molecular layers. Autoradiographic studies of beta-adrenergic receptor distribution in the rat show the greatest density of silver grains in the molecular layer (Palacios and Kuhar, '82). In the course of studies of NE hyperinnervated structures, we found that beta receptors are nonhomogeneously distributed in the Purkinje cell layer, where they occur in "patches" overlying small groups of Purkinje cell somata. Tissue sections were incubated in 10 pM 125iodocyanopindolol (ICYP), which binds equally to beta1 and beta2 adrenergic receptors. Nonspecific binding was determined in sections incubated in 125ICYP and 1 microM dl-propranolol. Beta-adrenergic receptor patches are of irregular size and are most prominent in the vermis of lobules I-IX, although the medial cerebellar hemispheres also show areas of increased silver grains over Purkinje cells. In order to determine the subtype of beta receptors, adjacent sections were incubated with either 125ICYP and the beta 2-selective antagonist IPS-339, or 125ICYP and the beta 1-selective antagonist practolol. Patches were observed after each incubation procedure, indicating that they are composed of both beta1 and beta2 receptors. Patches are observed in normal animals and also in rats in which cerebellar NE content was increased 165% by neonatal treatment with 6-hydroxydopamine. This treatment does not alter the density of beta receptors. The cerebellar elements in which the beta receptors are located is not known. While silver grains accumulate over small groups of Purkinje cell somata, they are not coextensive with these cell bodies. The distribution of beta-adrenergic receptors does not parallel the arrangement of noradrenergic varicosities in the rat cerebellar cortex.

Animals↗
PubMedDate not supplied

Characterization of beta-adrenergic receptors in dispersed rat testicular interstitial cells.

Recent studies have shown that beta-adrenergic agents stimulate steroidogenesis and cyclic AMP formation in mouse Leydig cells in culture. To obtain information about the possible presence and the characteristics of a beta-adrenergic receptor in rat testicular interstitial cells, the potent beta-adrenergic antagonist [125I]cyanopindolol (CYP) was used as ligand. Interstitial cells prepared by collagenase dispersion from rat testis were incubated with the ligand for 2 h at room temperature. [125I]cyanopindolol binds to a single class of high affinity sites at an apparent KD value of 15 pM. A number of sites of 6,600 sites/cell is measured when 0.1 microM (-) propranolol is used to determine non-specific binding. The order of potency of a series of agonists competing for [125I]cyanopindolol binding is consistent with the interaction of a beta 2-subtype receptor: zinterol greater than (-) isoproterenol greater than (-) epinephrine = salbutamol much greater than (-) norepinephrine. In addition, it was observed that the potency of a large series of specific beta 1 and beta 2 synthetic compounds for displacing [125I]cyanopindolol in rat interstitial cells is similar to the potency observed for these compounds in a typical beta 2-adrenergic tissue, the rat lung. For example, the potency of zinterol, a specific beta 2-adrenergic agonist, is 10 times higher in interstitial cells and lung than in rat heart, a typical beta 1-adrenergic tissue. Inversely, practolol, a typical beta 1-antagonist, is about 50 times more potent in rat heart than in interstitial cells and lung.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Characterization and localization of beta-adrenergic receptors in control and cryptorchidized rat testis by in vitro autoradiography.

beta-adrenergic receptors were localized and characterized in control and cryptorchidized rats to investigate further their role in testicular function. Slide-mounted cryostat sections were incubated with [125I]cyanopindolol, a specific ligand for beta-adrenergic receptors. The subtypes were characterized by the displacement of [125I]cyanopindolol binding by practolol, which binds preferentially to the beta 1 subtype, and zinterol, which is preferential for beta 2 receptors. Labeling was detected by autoradiography, first by exposing sections to Ultrofilm (LKB) and second by dipping slides in NTB-2 Kodak photographic emulsion. The histologic distribution of receptors was analyzed by counting silver grains overlying the testicular structures. It was found that the vast majority of receptors were of the beta 2-subtype. In intact rats, the greatest density of receptors was found in interstitial cells, with some specific labeling over the seminiferous tubules. However, in cryptorchidized animals, the proportion of beta 2 receptors in tubules that contained mainly Sertoli cells appeared to be markedly increased. The results obtained suggest that catecholamines have multiple sites of action in the testis.

Animals↗
PubMed1980

Production and characterization of specific antibody for radioimmunoassay of procainamide.

The production and characterization of a specific antibody for use in the radioimmunoassay of procainamide are described. Cross-reactivity was measured by a nonequilibrium competitive procedure. Procainamide analog concentrations resulting in 50% inhibition were: procainamide, 1.59 nmoles/ml; N-acetylprocainamide, 3.55 nmoles/ml; a propyl analog of procainamide, 398 nmoles/ml; procaine, 316 nmoles/ml; lidocaine, greater than 8000 nmoles/ml; and practolol, greater than 16,000 nmoles/ml. Variations in the ability to inhibit binding of labeled procainamide were related to structural similarities and differences. The affinity constant of the antibody for procainamide was 2.9 x 10(8) liters/mole as measured from a Scatchard plot. The assay allows the direct measurement of procainamide in a 0.1-ml aliquot of diluted serum. The advantages of this method over currently available techniques are its sensitivity, specificity, and simplicity. Furthermore, prior extraction of serum samples is not required. As little as 1 ng of drug/ml of serum can be detected by this method. The accuracy and precision were determined by adding known amounts of procainamide to human serum and then assaying five replicates of each concentration. The within-day and between-day coefficients of variation were 2 and 5%, respectively. The proposed method was used to determine the serum concentration after an intravenous dose of procainamide. A comparison of the radioimmunoassay results with values obtained by a GLC procedure showed excellent agreement.

Adult↗
PubMed1981

High-pressure liquid chromatography of nadolol and other beta-adrenergic blocking drugs.

A high-pressure liquid chromatographic assay was developed for the analysis of the beta-adrenergic blocking agent nadolol as a bulk material or formulated in a tablet. Other beta-adrenergic blocking drugs such as acebutolol, alprenolol, atenolol, metoprolol, oxprenolol, pindolol, practolol, propranolol, sotalol, and timolol can be chromatographed in this system. An ethylsilane column and a mobile phase consisting of 35% methanol-65% aqueous 0.0005 M hydrochloric acid-0.05 M sodium chloride are used. Detection is either at 254 nm with a variable-wavelength detector. As exemplified by nadolol, the drug content can be quantitated with or without atenolol as an internal standard.

Adrenergic beta-Antagonists↗
PubMed1986

Control of the heterogeneity of O2 saturation in small myocardial veins.

There is a wide variability in the measured O2 saturations (SvO2) of small myocardial veins (20-100 microns). The purpose of the present study was to examine several factors that contributed to this variability. Studies were conducted on anesthetized open-chest dogs. The role of beta-adrenoceptors and flow in the control of the heterogeneity of SvO2 was assessed. The hearts were quick-frozen in liquid N2 and the SvO2 in the subepicardial and subendocardial (ENDO) regions of the left ventricule was determined by microspectrophotometry. Under control conditions, ENDO SvO2 averaged 35% with a variance of 337. The control variance was much more than that of the methodological errors. With propranolol or practolol, variance was reduced by about half, e.g. ENDO SvO2 variance was 145 with propranolol. This reduction in SvO2 variance could be prevented by isoproterenol. When flow is reduced by partial occlusion the SvO2 values were skewed toward lower saturations. When nitroglycerin is administered during this partial occlusion, the SvO2 distribution is restored toward normal. It can be concluded that some of the variability of SvO2 in the heart is control by beta 1-adrenoceptors. There also appears to be an inverse relationship between coronary blood flow and SvO2 heterogeneity. Further work is necessary to determine what other factors control the variability of SvO2.

Animals↗
PubMed1988

Involvement of the sympathetic nervous system in the cardiovascular effects of ACTH-(1-24) during hemorrhagic shock in rats.

In urethane-anesthetized rats, removal of about 50% of the total blood volume over a period of 25-30 min caused hypovolemic shock, with extreme hypotension (MAP = 18-25 mm Hg and death of all animals within 22 +/- 5 min. The i.v. injection of ACTH-(1-24) in the dose range of 40-160 micrograms/kg induced a sustained, dose-dependent, and, at the highest dose used, an almost complete recovery of blood pressure, and 100% survival, at least for 2 h after treatment. The effect of ACTH-(1-24) was completely prevented by reserpine (5 mg/kg) and clonidine (0.1 mg/kg), significantly reduced by prazosin (0.1 mg/kg), dibenamine (15 mg/kg) and i.v. yohimbine (1 mg/kg) and unaffected by i.c.v. yohimbine (0.2 mg/kg) and i.v. practolol (15 mg/kg). These data suggest that the effect of ACTH-(1-24) in hypovolemic shock depends on the functional integrity of the sympathetic nervous system and is mediated through an activation of peripheral alpha-adrenoceptors.

Animals↗
PubMed1981

Temperature related effects on the binding characteristics of beta-adrenergic receptor agonists and antagonists by rabbit lung.

The effects of incubation temperature on binding characteristics of beta-adrenergic receptor agonists and antagonists were examined in rabbit whole lung membrane fragments. [3H] Dihydroalprenolol ([3H] DHA) exhibited single component, non-cooperative binding at 37 degrees C and 25 degrees C with characteristics representative of beta-adrenergic receptors. Inhibition of [3H] DHA binding by l-propranolol showed single component binding at either incubation temperature, but with slightly higher affinity at 25 degrees C, when analyzed by Hofstee plots. The binding of l-isoproterenol, l-epinephrine and l-norepinephrine were changed qualitatively, as well as quantitatively, by incubation temperature. Hofstee plot analysis of l-isoproterenol inhibition curves showed a linear plot at 37 degrees C and a curvilinear plot at 25 degrees C, whereas l-epinephrine and l-norepinephrine showed curvilinear plots at both temperatures, but with different relative distributions and affinities of the components. The binding characteristics of several selective beta 1- and beta 2-agonists and antagonists were also influenced by incubation temperature. Practolol and prenalterol, beta 1-selective agents, exhibited multiple component binding at 25 degrees C, but only single component binding at 37 degrees C. In contrast, salbutamol, a beta 2-selective agonist, showed single component binding at 25 degrees C and apparent multiple component binding at 37 degrees C. Such temperature-related changes in binding characteristics were not consistent with receptor subtype interconversion and were not restricted to either agonists or antagonists. These studies suggest that the choice of incubation temperature may result in different binding characteristics of various beta-adrenergic receptor ligands. These effects are especially important when binding studies are designed to determine the classification and density of beta-adrenergic receptor subtypes in individual tissues.

Adrenergic beta-Agonists↗
PubMed1977

Analysis of the beta-receptor mediated effect on fast-contracting skeletal muscle in vitro.

Subtetanic contractions of the isolated extensor digitorum longus (EDL) of the guinea-pig, a fast-contracting muscle, were evoked by transmural field stimulation. Isoprenaline, adrenaline, terbutaline, and noradrenaline each caused a dose-dependent increase in the force of contraction, their potencies decreasing in that order. Tyramine was without effect in this respect. Curare depressed the contractions of EDL by about 20% but did not appreciably change the response to the beta-adrenoceptor agonists. The effects of isoprenaline and noradrenaline were blocked by propranolol (unselective) and H 35/25 (1-(p-tolyl)-2-isopropylamino-1-propanol, beta2-selective) but not by practolol (beta1-selective). Moreover, the increase in the force of subtetanic contractions of EDL produced by noradrenaline was unaffected by phentolamine. It is concluded that the adrenoceptor mediating the increase in the force of contraction of the isolated EDL is of the beta2-type and that the site of action is direct on the muscle. Its similarity to the receptor mediating the inverse effect on the slow-contracting soleus-muscle is pointed out.

Adrenergic beta-Antagonists↗
PubMed1984

Endothelial cells contain beta adrenoceptors.

The direct identification of beta adrenoceptors in endothelial cell cultures has not been possible until the advent of a new beta-adrenergic radioligand, [125I]iodocyanopindolol ([125I]ICYP). Using [125I]ICYP, we report the successful identification of a beta adrenoceptor in cultured bovine aortic endothelial cells. At 37 degrees C, specific binding is saturable, stable and reversible. There is a single class of binding sites (21,500 +/- 2,900 sites/cell) with an equilibrium dissociation constant (Kd) of 109 +/- 26 pM. The rate constant of association, k1, is 1.22 X 10(9) M-1 min-1 and of dissociation, k-1, is 0.01 min-1. Binding studies on monolayers of endothelial cells grown in microtiter plates yield similar data (Kd = 53 +/- 9 pM, Bmax = 20,000 +/- 1,900 sites/cell). Stereoselectivity of binding for the (-)-isomer is demonstrable for both agonists and antagonists. A series of adrenergic agonists competes with [125I]ICYP for binding with an order of potency suggesting beta 2 subselectivity ; isoproterenol (0.73 microM) greater than epinephrine (15 microM) greater than norepinephrine (71 microM). Furthermore, the beta 2 inhibitor butoxamine is more potent than the beta 1 inhibitor practolol (7.7 microM vs 22 microM respectively). The GTP analogue, Gpp(NH)p, reduces isoproterenol affinity to 1.9 microM and increases the Hill coefficient from 0.62-0.90.

Adrenergic beta-Agonists↗
PubMed1981

Interaction of beta-adrenoceptor agonists with the serotonergic system in rat brain. A behavioral study using the L-5-HTP syndrome.

The effect of beta-adrenoceptor agonists on the behavioral effect of L-5-HTP in rats and mice was studied. All beta-agonists potentiated the behavioral syndrome elicited by L-5-HTP. However no indication for a correlation between their potencies to stimulate peripheral beta-receptors and their potencies to enchance L-5-HTP effect was found. The potentiating effect of salbutamol in rats was intensified by the MAO A inhibitor clorgyline, completely inhibited by (+/-)-propranolol and partly inhibited by WB-4101, while practolol was without effect. Lesions of 5-HT pathways by i.c.v. injections of 5,7-DHT impaired the potentiating effect of salbutamol in rats. In contrast, 6-OHDA lesions or alpha-methyl-p-tyrosine pretreatment were without effect. A central site of action of salbutamol is suggested by the fact that it intensified L-5-HTP effects also after i.c.v. administration. Therefore the results suggest that salbutamol facilitates 5-HT transmission in rat brain probably via stimulation of central beta receptors.

5,7-Dihydroxytryptamine↗
PubMed1979

Pharmacological characteristics of beta-adrenoceptor binding sites in intact and sympathectomized rat spleen.

[3H]-(--)-Dihydroalprenolol ([3H]-DHA) binds to rat spleen membranes with a dissociation equilibrium constant (KD) of about 0.7 nM and a maximal number of binding sites of 272 fmoles x mg protein-1. Approximately 90% of the sites labelled by 1 nM [3H]-DHA possess classical properties of beta-adrenoceptors. The labelled ligand is stereospecifically displaced by the isomers of propranolol and the order of potency of agonists is: isoprenaline greater than adrenaline greater than noradrenaline. Highly selective beta 1 antagonists such as practolol and atenolol displaced [3H]-DHA from spleen membranes in a biphasic manner indicating the co-existence of beta 1 and beta 2 sites (30--35% beta 1; 65--70% beta 2) in this tissue. Support for this classification was provided by the binding of the beta 2 agonist procaterol to spleen membranes. This drug possessed high affinity only for those sites that have low affinity for the beta 1 selective agents. Chemical sympathectomy induced by chronic 6-hydroxydopamine administration did not alter the number or the pharmacological properties of beta-adrenoceptor binding sites. The results suggest that both beta 1 and beta 2 adrenoceptors are probably postsynaptic in spleen.

Alprenolol↗
PubMed1975

The beta-adrenergic receptor-adenyl-cyclase system of rat reticulocytes: effects of adrenergic stimulants and inhibitors.

Non-nucleated red blood cells from rats contain adenyl cyclase, the activity of which is predominantly localized in the reticulocytes. Basal enzyme activities in membrane preparations from reticulocyte-rich blood (pretreatment of rats with acetyl-phenylhydrazide: about 60% reticuloytes) are about 5 times higher than in preparations from reticulocyte-poor blood (untreated animals: 2-3% reticulocytes). The enzyme activities are stimulated 10-fold by sodium fluoride (10(-2)M) and 6 to 8-fold by isoprenaline (10(-4)M). Adenyl cyclase activities in membrane preparations from reticulocyte-rich and reticulocyte-poor blood can be ascribed to identical enzymes since identical apparent Km (ATP; 3 times 10(-4)M, Ka (isoprenaline; 3 times 10(-6)M) and Ki (propranolol vs. isoprenaline; 3 times 10(-7)M) values were obtained in both preparations. Besides NaF, only phenylethanolamine derivatives with beta-adrenergic receptor stimulant properties were effective as stimulators of adenyl cyclase activity. The affinities (apparent Ka values) of the investigated compounds decreased in the order isoprenaline--hexoprenaline--fenoterol--salbutamol--adrenaline--terbutalin--noradrenaline--phenylephrine. For maximal intrinsic activity, the catechol structure was essential; the relative intrinsic activities of resorcinol derivatives did not exceed 0.6. The isoprenaline-stimulated adenyl cyclase activities in erythrocyte membrane preparations were competitively inhibited by beta-adrenergic blocking drugs, the affinities (apparent Ki values) decreasing in the order prindolol--penbutolol--propranolol--practolol. The dextrorotatory enantiomers of penbutolol and propranolol were 1/100 to 1/200 as active as the resp. levorotatory enantiomers. From experiments with alpha-adrenergic agonists (e.g. phenylephrine) and antagonists (e.g. phentolamine), it is concluded that alpha-adrenergic receptors do not interfere with the beta-adrenergically-mediated cAMP formation in these particular membranes. A variety of hormones and drugs known to stimulate denyl cyclase activities in various tissues, e. g. ACTH, glucagon, STH, erythropoietin, prostaglandin E1 etc. did not affect adenyl cyclase activity in reticulocyte-rich erythrocyte membrane preparations. In contrast to adenyl cyclase activity, phosphodiesterase activities in erythrocyte membrane and cytoplasmic fractions were only twice as high in reticulocyte-rich as in reticulocyte-poor preparations. From the experiments described, it is obvious that the adenyl cyclase of the rat reticulocyte is subject to monovalent-hormonal, i.e. beta-sympathomimetic stimulation. Moreover, the premature red blood cell provides a useful model for quantitative studies of the interaction of drugs with the beta-adrenergic receptor.

Adenosine Triphosphate↗
PubMed1980

Stimulant and depressant effects of beta-adrenoceptor blocking agents on isolated heart muscle. A positive inotropic effect not mediated through andrenoceptors.

The chronotropic and inotropic effects of fourteen beta-adrenoceptor blocking agents were studied in vitro on preparations of isolated heart muscle from kittens and guinea pigs. Most of the agents exert negative inotropic and chronotropic effects that increase rapidly with concentration above 10(-6) M. Exceptions are the closely related compounds practolol and atenolol, which have minimal depressant effects in concentrations as high as 2 X 10(-3) M. Dose-response relations for the depressant effects are similar for pacemaker frequency and for tension development in atrial and papillary muscle. The cardiodepressant effects of beta-blockers are non-stereospecific and are apparently unrelated to the actions of the drugs at beta-adrenoceptors. Many beta-blockers exert positive inotropic and chronotropic effects at concentrations lower than those that depress. The stimulant effects are slow in onset and do not fade. In most instances these effects are blocked by propranolol and may therefore be considered to be mediated throught beta-adrenoceptors; (-)-enantiomers are more potent than (+)-enantiomers as adrenoceptor stimulants. Adrenoceptor-mediated inotropic effects are usually more pronounced in atrial than in ventricular muscle. Certain beta-blockers, notably INPEA and sotalol, exert positive inotropic effects that are not blocked by propranolol or phenyoxybenzamine. The effects are very slow in onset and offset, and are accompanied by the development of contractions with a late tonic component which coincides with a greatly prolonged action potential. Unlike the adrenoceptor-mediated effect, the non-sympathomimetic inotropic effect is more pronounced in ventricular than in atrial muscle, and is not stereospecific. Pindolol also causes the development of a late tonic component, but the accompanying positive inotropic effect is overcome by the simultaneous development of the depressant action of the drug.

Adrenergic beta-Antagonists↗