Effect of different beta-blocking drugs and adrenaline on the conversion of thyroxine to triiodothyronine in isolated rat hepatocytes

The in vitro effect of various selective and non-selective beta-blocking drugs and adrenaline on the conversion of thyroxine (T4) to triiodothyronine (T3) was studied in suspensions of isolated rat hepatocytes after 90 min of incubation. Compared with the untreated controls propranolol caused a dose-related inhibition of the T4 to T3 conversion in conc of 100, 200 and 400 microM. The other beta-blocking drugs studied, timolol, oxprenolol, atenolol and metoprolol, were without any effect on this in vitro conversion. Propranolol did not interfere with the cellular association of T4 or the degradation of T4 and T3. Adrenaline 200 microM caused a small decrease of T3 in the medium and a corresponding increase in the intracellular content of T3. The inhibitory effect of propranolol 200 microM was not antagonized by equimolar concentrations of adrenaline. Our study suggests that the inhibitory effect of propranolol on the conversion of T4 to T3 in hepatocytes is caused by a direct chemical effect of the drug unrelated to its beta-blocking and membrane stabilizing properties.     

Atenolol,sustained-release oxprenolol,and long-acting propranolol in hypertension.

The effect of once-daily atenolol, sustained-release oxprenolol (a new formulation of oxprenolol presented as a compressed tablet in a waxed matrix), and long-acting propranolol (a new formulation presented as spheriods in a capsule) was studied in a double-blind crossover trial in 23 carefully selected hypertensive outpatients. After a run-in period with matching placebo each patient received atenolol (100 mg/day), sustained-release oxprenolol (160 mg/day), long-acting propranolol (160 mg/day), and placebo according to a randomised sequence. After four weeks'' treatment with sustained-release oxprenolol blood pressure in the two to four hours before the next dose was not significantly lower than after placebo. The effectiveness of atenolol and of the new formulation of propranolol in reducing blood pressure was confirmed. These results suggest that the present formulation of sustained-release oxprenolol should be reconsidered.     

Metabolic and hormonal response to physical exercise during beta 1-selective and non-selective beta-blockade

The effects of a beta 1-selective (metoprolol, 150 mg per day) and a non-selective beta-blocking agent (propranolol, 120 mg per day) on metabolic and hormonal responses to physical exercise (a 30 min bicycle ergometer test) were investigated against placebo in seven healthy male volunteers with a double blind cross-over design. The blood glucose level remained unchanged during placebo, it tended to increase during metoprolol, whereas it decreased during propranolol. Both metoprolol and propranolol counteracted the exercise-induced increase in plasma free fatty acids and caused a slight decrease in muscle glycogenolysis. The increase in blood lactate concentration during exercise was not influenced by beta-blockade. The secretion of glucagon and cortisol was not modified significantly by beta-blockade, whereas the growth hormone response to exercise was promoted equally by both beta-blocking agents. It has been assumed previously that, during treatment with beta-blocking agents, diminished hepatic gluconeogenesis, caused by the lack of lactate or free fatty acids, may result in a decline in blood glucose levels. The present results indicate that an inhibition of beta 2-mediated hepatic glycogenolysis by propranolol may also influence blood glucose homeostasis during exercise.     

Comparison of Adrenergic Beta-blocking Drugs in Angina Pectoris

The symptomatic, electrocardiographic, and haemodynamic effects of two adrenergic beta-blocking drugs, oxprenolol and propranolol, have been compared in equipotent intravenous doses in six patients with uncomplicated angina pectoris during treadmill exercise. The method of comparison included double-blind assessment and analysis with placebo control and randomized serial comparison in each patient. Both drugs produced an equal amelioration in symptoms in most of the patients. This was closely correlated with improvement in the electrocardiographic changes and a significant reduction in the exercising heart rate and systemic arterial pressure. This method of double-blind combined subjective and objective assessment carries distinct advantages in the comparative assessment of drug treatments in angina pectoris.     

Raynaud's phenomenon as side effect of beta-blockers in hypertension.

A series of 102 hypertensive patients were assessed for the frequency of symptoms of Raynaud''s phenomenon and absent peripheral pulses. Out of 21 patients receiving methyldopa alone only one had cold hands and feet whereas among patients on beta-blockers the incidence was 50%. The frequency of both symptoms and absent pulses was highest in patients taking propranolol compared with those taking atenolol or oxprenolol. Patients without a foot pulse were much more likely to have cold hands. A change from propranolol to oxprenolol in some symptomatic patients resulted in improvement. In two patients the skin temperature fell after an 80-mg dose of propranolol. The mechanism by which beta-blockers induce Raynaud''s phenomenon is still not clear.     

The effect of oxidized isoprenaline on the chick embryonic heart

Intra-amnial administration of isoprenaline (IPRO) to chick embryos induces a number of myocardial lesions. The purpose of the present study was to investigate whether similar changes may also be induced after injection of spontaneously oxidized isoprenaline and commercially obtained adrenochrome. Cardiotoxicity of these substances has been demonstrated in adult animals. IPRO, oxidized IPRO, or adrenochrome were administered intra-amnially to 10-day-old chick embryos at doses of 0.1, 1.0, 10.0, and 100.0 mg X kg-1. Parallel experimental groups received propranolol at a dose of 1 mg X kg-1, 15 s before injection of IPRO or oxidized IPRO. The cAMP level in the heart was determined by radioimmunoassay 2 and 30 min after administration of IPRO, oxidized IPRO, or adrenochrome at a single dose of 10.0 mg X kg-1. It has been found that in embryos the effect of IPRO and oxidized IPRO is dose dependent. The rise in mortality and development of cardiomegaly together with increased hydration and disturbances of the development of coronary vascularization were highly significant starting from the dose of 10 mg X kg-1. Furthermore, both drugs significantly increased cAMP levels in the embryonic heart. On the other hand, the administration of adrenochrome was without any effect. The changes induced by IPRO were prevented by the administration of the beta-blocking agent propranolol; the lesions induced by spontaneously oxidized IPRO were, however, prevented only partially.     

Comparative cardiovascular effects of propranolol and practolol in puppies.

The present results indicate that in 3-4-weeks-old puppies propranolol induces a significant depression of cardiovascular function expressed by a decrease in heart rate, myocardial contractility, and cardiac output, and an increase in systemic vascular resistance, in doses beyond beta-blocking levels. In contrast, practolol, in the same dose range, did not induce further cardio-circulatory depression, as shown by levels of heart rate, myocardial contractility, and cardiac output similar to the values obtained with beta-blocking doses of this agent. The cardio-depressant activity observed in puppies with doses of propranolol beyond blocking levels is thought to be due to direct negative inotropic and chronotropic effects of this agent, not related to influences on beta receptor sites. Such effect not observed with practolol at doses well beyond beta-blocking levels suggests that this drug exerts a more selective influence on cardiac sympathetic beta receptors.     

Role of transmembrane ion currents in the mechanism of action of beta-adrenoblockers

The effects of propranolol, oxprenolol, pindolol, labetalol, and atenolol on the isoproterenol-stimulated slow calcium current as well as on spontaneous slow calcium and fast sodium currents were studied in frog trabeculae by the double sucrose bridge technique. Administration of beta-adrenoblockers in low doses (10(-7)-10(-6)M) antagonized the stimulatory effect of isoproterenol on the slow calcium current (pindolol greater than oxprenolol greater than or equal to propranolol = labetalol greater than atenolol). When administered in high doses (2 X 10(-6)-10(-4)M) the beta-adrenoblockers reduced the slow calcium current. Meanwhile, some of them (propranolol, oxprenolol, labetalol) suppressed the fast sodium current.     

Effect of beta-adrenoblockaders on the smooth muscles of the trachea and bronchi

It has been shown in experiments on anesthetized guinea-pigs that (+/-) and (+) propranolol produced a dose-dependent increase in the resistance of the air ways. Meanwhile oxprenolol, trimepranol and atenolol had a poor bronchoconstrictor effect, and labetalol evoked no changes in the tone of the bronchi. On an isolated trachea of the guinea-pig both forms of propranolol, as well as trimepranol and oxprenolol produced contractions, atenolol did not cause any changes in the tone of the smooth muscles, while labetalol made the smooth muscles relax. It has been also demonstrated on an isolated trachea that pretreatment with atropine, diphenhydramine, and diethylamide of lysergic acid did not lead to any noticeable changes in the bronchoconstrictive action of propranolol. At the same time verapamil and Ca2+-free Krebs solution reversed the propranolol effect.     

Propranolol in the Treatment of Migraine

Beta-blocking drugs that prevent cranial vasodilatation are potentially valuable in the prophylaxis of migraine. Forty-nine patients with either classic or common migraine were treated with propranolol 160 mg/day for an average of six months. The first 30 of the patients to respond well to this treatment then participated in a double-blind cross-over trial with a placebo and propranolol. The mean frequency of headache attacks was significantly reduced by propranolol. None of the patients expressed a preference for placebo. Propranolol seems to be an effective prophylactic for common and classic migraine but the antimigraine properties of the various beta-blocking agents probably differ.     

Stereoselective pharmacokinetics of oxprenolol,propranolol, and verapamil: Species differences and influence of endotoxin

The influence of endotoxin-induced inflammation was studied on the pharmacokinetics of the enantiomers of the racemic drugs oxprenolol, propranolol, and verapamil in rabbits and dogs. Enantioselective pharmacokinetics were seen for oxprenolol and propranolol in the rabbit and for propranolol and verapamil in the dog. In the dog, the enantioselective differences in plasma concentrations are due to differences in both protein binding and metabolism, whereas in the rabbit the differences are due solely to differences in metabolism. In both species endotoxin treatment increases the plasma concentrations of the enantiomers of the three drugs; both protein binding and metabolism are influenced. In rabbits and in dogs, the influence of endotoxin on the disposition of the three drugs is less enantioselective than was previously observed in the rat. © 1995 Wiley-Liss, Inc.     

Influence of the Beta-Adrenergic Antagonists Propranolol, Practolol and Oxprenolol On the Proliferation of Rat Jejunal Crypt Cells

Abstract. Beta-adrenergic blockade by quite large doses of propranolol, practolol and oxprenolol, once or continuously applied, does not influence jejunal crypt-cell proliferation in the rat. After a single i.p. injection of 20 mg/kg propranolol or practolol and even of 100 mg/kg practolol, the mitotic index, the labelling index and the duration of the S phase do not differ between treated and untreated control animals nor between animals treated with the different drugs. Continuous application of 30 mg/kg/d propranolol, practolol or oxprenolol for 7 or 14 days does not affect the mitotic and labelling indices either, nor does it change the duration of the cycle of the jejunal crypt cells and its phases as determined by the percent labelled mitoses method. These results are in contrast to those reported previously by Tutton & Helme (1974).     

Different effect of propranolol and verapamil on isoprenaline-induced changes in the chick embryonic heart

Isoprenaline (IPRO) has been reported to cause pathological lesions of the embryonic heart. The purpose of the present study was to ascertain whether the development of IPRO-induced changes can be reduced--similarly as in adults--by beta blockade or calcium antagonists. IPRO was administered to 10-day-old chick embryos intraamnially (i.a.) in a dose of 2 X 10 mg.kg-1 per 48 h; propranolol (Inderal) and verapamil (Isoptin) were injected i.a. in a dose of 1.0 or 10.0 mg.kg-1 before each injection of IPRO. It was found that propranolol completely blocked the cardiac IPRO-induced changes, i.e. cardiomegaly, avascular areas and elevation of cAMP. On the other hand, verapamil was found to have no protective effect in any dose used. Furthermore, it increased the mortality of experimental embryos. This fact support the hypothesis that cardiac sensitivity to calcium antagonists may differ during prenatal development.     

Observations on electrocardiogram and plasma catecholamines during dental procedures: the forgotten vagus.

Emotional stress is conventionally considered to be associated with tachycardia and enhanced sympathetic activity. The electrocardiogram and plasma catecholamine and lipid concentrations were observed in 21 young healthy women undergoing dental procedures. Ten of these received premedication with the beta-blocking agent oxprenolol and 11 with a placebo, administered on a double-blind randomised basis. Mild tachycardia occurred in the placebo group a few minutes before and a few minutes after dentistry, but there was a reduction in heart rate immediately before and during the procedure. The pattern was similar in the group who received oxprenolol, though the heart rates at each stage were lower. Plasma adrenaline concentrations were much higher in the samples taken during the procedure than in those taken shortly before and after it. Plasma noradrenaline and lipid concentrations remained unchanged. A decrease in heart rate in the face of intense emotional arousal and an increased plasma adrenaline concentration suggest that the expectation or experience of pain may be associated with parasympathetic dominance despite greatly enhanced sympathetic activity.     

Propranolol has direct antithyroid activity: Inhibition of iodide transport in cultured thyroid follicles

The effect of propranolol on the process of thyroid hormone formation was studied in a physiological culture system. Porcine thyroid follicles were preincubated with propranolol for 24 h. Iodide transport, iodine organification, and de novo thyroid hormone formation were measured by incubating these follicles with the mixture of carrier-free 0·1 μCi Na ¹²⁵I and 50 nM NaI for 2 to 6 h at 37°C. A concentration of propranolol greater than 100 μM inhibited iodide transport in a dose-dependent manner; this inhibition was non-competitive with iodide and independent of thyrotropin (TSH). Reduced iodine organification and thyroid hormone formation was seen with 150 μM propranolol or greater. The inhibitory action of propranolol was not caused by beta-blocking activity, since D -propranolol (devoid of beta-blocking activity) inhibited iodide transport, and other beta-blockers (metoprolol, atenolol, and labetalol) did not inhibit iodide transport. The inhibition of iodide transport was most likely caused by membrane stabilizing activity since quinidine, which possess the same membrane stabilizing activity as propranolol, also inhibited iodide transport. TSH-mediated cAMP generation and Na ⁺K⁺ ATPase activity, membrane functions for iodide transport, were unaffected by propranolol. Our study has shown, for the first time, that propranolol has a direct antithyroid action, namely inhibition of iodide transport in the intact thyroid follicle.     

Influence of the beta-adrenergic antagonists propranolol, practolol and oxprenolol on the proliferation of rat jejunal crypt cells

Beta-adrenergic blockade by quite large doses of propranolol, practolol and oxprenolol, once or continuously applied, does not influence jejunal crypt-cell proliferation in the rat. After a single i.p. injection of 20 mg/kg propranolol or practolol and even of 100 mg/kg practolol, the mitotic index, the labelling index and the duration of the S phase do not differ between treated and untreated control animals nor between animals treated with the different drugs. Continuous application of 30 mg/kg/d propranolol, practolol or oxprenolol for 7 or 14 days does not affect the mitotic and labelling indices either, nor does it change the duration of the cycle of the jejunal crypt cells and its phases as determined by the percent labelled mitoses method. These results are in contrast to those reported previously by Tutton & Helme (1974).     

Influence of endotoxin on the stereoselective pharmacokinetics of oxprenolol,propranolol, and verapamil in the rat

The influence of endotoxin-induced inflammation on the enantioselective pharmacokinetics of propranolol, oxprenolol, and verapamil, which bind to α₁-acid glycoprotein, was studied in the rat. The racemic mixtures were given orally. In the control animals, for propranolol and oxprenolol, the plasma concentrations of the (R)-enantiomer were higher than those of the (S)-enantiomer, while for verapamil the reverse was true. Protein binding and intrinsic clearance are the main factors responsible for this enantioselectivity. After endotoxin treatment, for the three drugs tested the plasma concentrations and the plasma binding of both enantiomers were significantly increased. This effect was more pronounced for (R)-propranolol, (R)-oxprenolol, and (S)-verapamil than for their respective antipodes. The enantioselective effect of endotoxin on the plasma concentrations of the drugs studied seems mainly due to the enantioselective increase in binding to α₁-acid glycoprotein. © 1994 Wiley-Liss, Inc.     

Influence of methylxanthines and local anaesthetics on the metabolism of muscle and associated changes in mitochondrial morphology

The influence of methylxanthines and of a number of local anaesthetics and adrenaline-blocking agents on the metabolism of the isolated rat diaphragm has been investigated. Both caffeine and theophylline inhibited protein synthesis in the tissue and enhanced its endogenous respiration. The latter effect was counteracted by several local anaesthetics (butacaine, cinchocaine, amethocaine and marcaine) and by certain β-blocking agents (propranolol, oxprenolol and alprenolol), but these compounds by themselves enhanced respiration and inhibited protein synthesis by the tissue. By contrast with other agents toxic to muscle, neither the methylxanthines nor local anaesthetics produced much stimulation of lactate production.The change in mitochondrial morphology after caffeine treatment differed from that produced by the other agents although all three types of compound similarly enhanced the rate of respiration. Under the conditions studied many deleterious effects on the tissue were seen, observable particularly where caffeine was used in conjunction with some β-receptor blockers. Some of the changes, which were often similar to those reported as due to different respiratory states, could be reproduced by different concentrations of the ionophorous agent, valinomycin. The mechanism of the effects is discussed in the context of the influence of both groups of drugs on uptake of calcium and other ions by sarcoplasmic reticulum and mitochondria.     

Pharmacodynamics of Propranolol in Renal Failure

The pharmacodynamics of propranolol were studied in patients with renal functional impairment. ¹⁴C-labelled propranolol was given either intravenously or by mouth and the disappearance rates of propranolol, 4-hydroxypropranolol, and total radioactive metabolites measured. The renal clearance of total radioactive compounds is directly related to renal function. The half-life of total radioactivity is greatly lengthened in the presence of severe renal failure while the half-lives of the pharmacologically active propranolol and 4-hydroxymetabolite are slightly reduced. There is a suggestion that the absorption of propranolol is delayed in renal failure. No known pharmacological action or side effects from the other metabolic products of propranolol have been recognized. There is still too little well-documented evidence concerning the beta-blocking activity of the unidentified major metabolites of propranolol to suggest any alteration in the dosage regimen used in renal failure.     

Hypothalamic cyclic AMP after the injection of ovarian steroids into ovariectomized rats

The effect of ovarian steroids on the concentration of adenosine 3',5'-cyclic monophosphate (cAMP) in the hypothalamus was studied in ovariectomized rats. Ovariectomized rats exhibited a lower cAMP concentration than intact rats. The administration of a single dose of estradiol benzoate (50 micrograms/kg body weight) resulted 3 days later in a rise of cAMP values, but levels did not reach those observed in estrous rats. Progesterone (2 mg/rat) injected 3 days after the priming dose of estradiol benzoate produced 4 h later no further changes in hypothalamic cAMP. The changes in hypothalamic cAMP concentration induced by estrogen treatment depend, at least in part, on noradrenergic inputs, since they were prevented by the injection of the norepinephrine synthesis inhibitor, diethyldithiocarbamate. In addition, administration of the beta-blocking agent, propranolol, to estradiol- and estradiol-progesterone-treated rats lowered the concentration of cAMP in the hypothalamus in a dose-dependent manner. In contrast, the administration of an alpha-blocking agent, phenoxybenzamine, had no effect at the tested concentration. The results of this study indicate that estrogen increases cAMP concentration in the hypothalamus by a noradrenergic mechanism involving beta-receptors. Moreover, the findings suggest that estrogen induces an increase in the number of beta-receptor sites, whereas progesterone increases the apparent propranolol sensitivity for these receptor sites.