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PubMed1978

Influence of (DL)-propranolol and Ca2+ on membrane potential and amino acid transport in Ehrlich ascites tumor cells.

(1) (DL)-Propranolol and Ca2+ are shown to alter the transmembrane potential difference of Ehrlich ascites tumor cells as measured by means of the cyanine dye, 3,3'-dipropyl-2,2'-thiodicarbocyanine iodide, whose fluorescent intensity changes as a function of membrane potential. (2) The changes in membrane potential elicited by these agents are dependent of the external K+ concentration in a manner which suggest that the potential changes result from a specific increase in the permeability of the plasma membrane to K+. (3) Na+-dependent amino acid transport in the presence of propranolol can be modulated by varying the external K+ concentration (K+o). The initial rate of uptake is stimulated by propranolol at low K+o and inhibited at high K+o. The change in transport rate is nearly directly proportional to the natural logarithm of [K+]o in the presence of propranolol. (4) ATP depletion of the cells by preincubation with rotenone abolishes the changes in fluorescence and amino acid uptake seen with propranolol as a function of K+o. Restoration of cellular ATP with glucose in presence of Ca2+ restores both fluorescence and amino acid transport changes which occur in response to propranolol. (5) The fluorescence changes and amino acid transport changes in response to propranolol are pH dependent, with little effect seen at pH6. (6) It is concluded that the rate of Na+-dependent amino acid uptake is a function of membrane potential and is dependent on the electrochemical potential difference for Na+.

Adenosine Triphosphate↗
PubMed1987

Inhibition of purified bovine milk lipoprotein lipase by propranolol and other beta-adrenergic blockers in vitro.

Numerous clinical studies have shown that propranolol administration causes hypertriglyceridemia and a decrease in high-density lipoprotein in man. Although these findings have been attributed to diminution of triacylglycerol-rich lipoprotein catabolism by lipoprotein lipase, biochemical studies of the effects of propranolol on lipoprotein lipase activity in vitro have not been previously reported. We purified lipoprotein lipase from raw bovine skimmed milk and examined the effect of propranolol using as substrate phospholipid-stabilized, triolein emulsions containing purified human apolipoprotein C-II. These studies demonstrate that propranolol inhibits lipoprotein lipase activity. The inhibition was found to be noncompetitive with a Ki for propranolol of 0.55 mM. In addition, propranolol was shown to bind to phospholipid-stabilized triolein emulsions reaching local concentrations at the particle surface many times higher than its bulk concentration. Metoprolol, timolol and practolol, which are less hydrophobic than propranolol, were less inhibitory. Atenolol was the weakest inhibitor of purified bovine lipoprotein lipase in vitro.

Adrenergic beta-Antagonists↗
PubMed1982

Effects of propranolol and a number of its analogues on sodium channels.

To assess the relative contributions that the sodium channel blocking activity of propranolol may play in a variety of its therapeutic applications, its effects were examined in vitro with a sodium channel specific 22Na+ uptake system, using rat brain membranes. Propranolol inhibited 22Na+ uptake in the rat brain membrane preparation by acting as a competitive inhibitor of the binding of the sodium channel opening agent veratridine, with an IC50 for this action of 6.5 microM. This is approximately one order of magnitude higher in concentration than that necessary for expression of the beta-adrenergic antagonism of propranolol. The binding of propranolol and its action to block sodium channels were demonstrably different from those of the neurotoxins tetrodotoxin and saxitoxin. Propranolol had effects on sodium channels that are similar, although not identical to those of the local anesthetics procaine and lidocaine. The concentrations of propranolol and a number of its analogues which produced 50% inhibition of 22Na+ uptake (IC50 values ranging from 4 to greater than 100 microM) were similar to the concentrations of these same analogues which were required to produce negative inotropic and antiarrythmic effects (ED40) on isolated rabbit atria [D. O. Rauls and J. K. Baker, J. med. Chem, 22, 81 (1979)]. These effects showed correlations of 0.945 and 0.936, respectively, with the 22Na+ uptake inhibition. It is concluded from this information that a substantial proportion of the negative inotropic and antiarrythmic effects of propranolol is due to its action on sodium channels.

Animals↗
PubMed1987

Irreversible binding and metabolism of propranolol by human liver microsomes--relationship to polymorphic oxidation.

Studies were performed to investigate the irreversible binding and oxidative metabolism of propranolol in human liver microsomes and the relationship of binding and metabolism to the polymorphic oxidation of debrisoquine. Incubation of microsomes with 14C-labelled propranolol in the presence of a NADPH-generating system gave rise to irreversible binding which increased linearly with time and became saturated at high substrate concentrations. The extent of binding was decreased by the exclusion of cofactors, boiling, anaerobic conditions, and the addition of reduced glutathione and SKF-525A. Trichloropropene oxide had a negligible effect on cofactor-dependent binding. However, debrisoquine, antipyrine and phenacetin decreased binding to a considerable extent. The latter compound abolished cofactor-dependent binding completely at the concentration used (1 mM). Electrophoresis of microsomes which had been incubated with tritiated propranolol revealed that binding was probably occurring to a large number of proteins particularly in the 40,000-90,000 molecular weight range. Glutathione, debrisoquine and antipyrine did not inhibit the 4'-hydroxylation and N-deisopropylation of propranolol. In contrast, phenacetin exerted a very potent inhibitory action on both routes of metabolism. It is concluded that a product or products of propranolol oxidation bind irreversibly but non-selectively to human liver microsomal protein, the enzyme system responsible for the activation of propranolol appears to be related more closely to the cytochrome P-450 system which metabolizes phenacetin than to that metabolising debrisoquine, and radiolabelled propranolol is not a sufficiently specific probe for studying these cytochrome P-450 systems.

Biotransformation↗
PubMed1989

Comparison of propranolol-binding plasma proteins in sheep with those in humans, dogs and rats.

Alpha 1-acid glycoprotein (AGP), a plasma protein responsible for the binding of a variety of basic lipophilic drugs including propranolol, is different from other plasma proteins in being nonprecipitable after treatment with 1.2M perchloric acid (PCA). To assess the contribution of AGP to drug disposition in sheep and three other species (rats, dogs, and humans), the binding of [3H]propranolol was measured before and after PCA precipitation. PCA precipitation reduced propranolol binding 14-fold in sheep, compared to 2- to 3-fold in the other species. This implied either that sheep AGP binds less propranolol than other species, or that the AGP in sheep is more precipitable. It was not due to inherently poor propranolol binding, as whole sheep plasma bound a higher fraction than the other species. When samples of PCA-precipitated sheep plasma were analyzed using polyacrylamide gel electrophoresis, the concentration of AGP was 10-20% that of the other species. Phenobarbital induction was used as a tool to examine the changes in the plasma protein profile. Phenobarbital induced propranolol binding and AGP along with two other proteins in sheep. One of these proteins migrated similarly to AGP deglycosylated by peptide-N-glycosidase F. It is postulated that the greater precipitability of propranolol binding in sheep is due to a less glycosylated form of AGP which is not important in other species.

Animals↗
PubMed1991

Differential effects of propranolol on the IgE-dependent, or calcium ionophore-stimulated, phosphoinositide hydrolysis and calcium mobilization in a mast (RBL 2H3) cell line.

Our previous studies demonstrated that propranolol, an inhibitor of phosphatidic acid phosphohydrolase (PAPase) (EC 3.1.3.4) blocks the IgE-dependent mediator release from a rat mast (RBL 2H3) cell line. To continue these studies, we examined the ability of propranolol to inhibit the IgE-dependent or ionomycin-mediated phosphoinositide hydrolysis and calcium mobilization in RBL 2H3 cells. RBL 2H3 cells, sensitized with mouse monoclonal anti-trinitrophenol IgE (anti-TNP IgE), were stimulated to release both histamine and peptidoleukotrienes (LT) in response to a suboptimal concentration of trinitrophenol-ovalbumin conjugate (TNP-OVA) or ionomycin. Preincubation of the cells with d,l-propranolol (300 microM) significantly (P less than 0.05) inhibited the effects of both TNP-OVA and ionomycin on histamine and LT release. There was no difference in potency for the different isomers of propranolol, indicating that these effects were not a consequence of an effect on beta 2-adrenergic receptors. TNP-OVA produced a rapid hydrolysis of phosphoinositides resulting in a time-dependent increase in mono- (IP1), di- (IP2), tri- (IP3), and total inositol phosphate production. Ionomycin also produced a rapid increase in total inositol phosphate production; however, this largely reflected an accumulation of IP1. Both secretagogues produced a rapid elevation in cytosolic free calcium ([Ca2+]i); however, the effect of ionomycin maximized within a much shorter time frame than the effect of TNP-OVA. The effects of TNP-OVA on phosphoinositide hydrolysis and increase in [Ca2+]i were inhibited by propranolol over exactly the same concentration range as the effects of this compound on TNP-OVA-stimulated mediator release. In contrast, propranolol had no effect on the increase in [Ca2+]i and phosphoinositide hydrolysis in response to ionomycin. Taken together, these results suggest that PAPase/phospholipase D (PLD) (EC 3.1.4.4) activation may be a prerequisite for both IgE-dependent and ionomycin-stimulated mediator release from RBL 2H3 cells. Although other explanations are possible, the data further suggest that receptor-mediated, but not ionophore-stimulated, phosphoinositide hydrolysis and [Ca2+]i in RBL 2H3 cells may be regulated by a propranolol-sensitive pathway involving possible activation of PAPase.

Animals↗
PubMed1993

Influence of human recombinant interleukin-1 beta on the enantioselective disposition of propranolol in rats.

The influence of i.v. administration of 10 micrograms/kg recombinant human interleukin-1 beta (rhIL-1 beta), a putative mediator of inflammation, on the pharmacokinetics and metabolism of the propranolol enantiomers was studied in rats aged 3, 12 and 24 months. After oral administration of rac-propranolol to control rats of the three age groups, the plasma concentrations of (R)-propranolol were higher than those of (S)-propranolol. Administration of IL-1 beta increased the plasma concentrations of the (R)-enantiomer markedly and significantly, those of the (S)-enantiomer only to a lesser degree. For both enantiomers an important increase in plasma binding was found in the IL-1 beta-treated rats, which was linked to the increase in alpha 1-acid glycoprotein levels. The in vitro clearance, measured in 3-month-old rats using the 9000 g liver fraction, was for neither of the propranolol enantiomers influenced by IL-1 beta treatment, which is in keeping with the unchanged cytochrome P450 content. The enantioselective influence of IL-1 beta treatment on the pharmacokinetics of propranolol was also present in 12- and 24-month-old rats, although somewhat less pronounced in the latter group. Our results show an enantioselective influence of IL-1 beta treatment on the pharmacokinetics of propranolol in the rat, favouring the (R)-enantiomer.

Aging↗
PubMed1975

Effect of propranolol on antinociceptive, tolerance- and dependence-producing properties of morphine in rodents and monkeys.

Since an abstinence syndrome may accompany the injection of opioids in addicts pretreated with propranolol the morphine antagonistic properties of this compound were investigated. Racemic propranolol did not significantly affect the antinociceptive ED50 of morphine in rodents and neither precipitated abstinence in morphine-dependent monkeys nor exacerbated the syndrome in 24 hr withdrawn monkeys. Multiple doses of propranolol did not alter the development of physical dependence on morphine in monkeys. Clinical narcotic antagonism would not be predicted from this profile. Evidence for a possible propranolol-morphine interaction came from studies using the mouse tail flick test. Thus, after 8 injections of propranolol (over 4 days) mice were tolerant to normally effective doses of morphine. Concurrent injections of naloxone antagonised this effect. When propranolol and morphine were administered concurrently the morphine ED50 (on day 5) was twice that of the group receiving morphine alone. Similar results were obtained with d-propranolol; practolol had a neutral effect.

Analgesics, Opioid↗
PubMed1979

Differential effects of d- and l-propranolol on dopamine turnover stimulated by oxotremorine in striatal and mesolimbic areas of rat brain.

The effects of l-propranolol, d-propranolol and clonidine on homovanillic acid (HVA) concentrations in the corpus striatum and nucleus accumbens of rats were studied under normal conditions and after treatment with oxotremorine or haloperidol. Thile propranolol and clonidine given alone had no significant effect on HVA levels in either area, l-propranolol (1--10 mg/kg) and clonidine (0.1 mg/kg), both significantly inhibited the elevation of striatal HVA, found 60 min after oxotremorine administration. Both l- and d-propranolol (2.5 mg/kg), reduced the effect of oxotremorine in the nucleus accumbens. Neither l-propranolol no clonidine affected the rise in HVA in either brain area seen after haloperidol. Our results suggest that propranolol may reduce cholinergic activation of dopaminergic pathways by two different mechanisms. One is stereospecific for the l-isomer and operates in the striatum and another, which is shared by both isomers, occurs in the nucleus accumbens.

Animals↗
PubMed1980

Increase of myocardial pH by 1- and d-propranolol during ischemia of the heart in dogs.

Myocardial pH was measured continuously with a micro pH electrode inserted into the left ventricular wall in dogs. Anterior descending coronary flow was reduced to about 1/3 of the original flow by partial occlusion of the coronary artery. Myocardial pH decreased from 7.50--7.60 to 7.06--7.24 after partial occlusion. Drugs were injected intravenously during ischemia of the heart caused by partial occlusion. l-Propranolol (1 mg/kg) reduced heart rate and increased the pH from 7.06 +/- 0.04 to 7.48 +/- 0.04 (P less than 0.01). d-Propranolol (1 mg/kg) reduced heart non-significantly and increased the pH from 7.24 +/- 0.05 TO 7.56 +/- 0.05 significantly (P less than 0.05). In other studies, the effect of l- and d-propranolol on both heart rate and metabolic responses to isoproterenol (500 micrograms/kg i.p.) was studied. Isoproterenol increased heart rate and also elevated the blood levels of glucose and lactate. l-Propranolol inhibited these responses to isoproterenol. d-Propranolol did not inhibit the heart rate response but inhibited the blood lactate response to isoproterenol significantly. The blood glucose response to isoproterenol was inhibited by d-propranolol non-significantly. The action of both l- and d-propranolol on ischemic myocardial pH may be related to their action on cardiac metabolism as well as to their local anesthetic action.

Anesthesia, Local↗
PubMed1983

Propranolol withdrawal supersensitivity in rat cardiovascular tissue, in vitro.

The purpose of the present study was to determine if propranolol withdrawal supersensitivity could be demonstrated under in vitro conditions. Rats pretreated for 14 days with propranolol were studied 24, 48, 72 and 96 h after propranolol withdrawal. Right atria, right ventricle strips and thoracic aortic strips were isolated for study under in vitro conditions. Dose-response curves and geometric mean ED50 values revealed the presence of supersensitivity to the chronotropic and inotropic effects of isoproterenol in vitro at 72 and 96 h after withdrawal. No change in sensitivity was found 24 or 48 h after propranolol cessation. In like manner, supersensitivity to the vasorelaxant action of isoproterenol was demonstrated in aortic strips precontracted with angiotensin II at 72 and 96 h after propranolol withdrawal. In contrast, subsensitivity to the contractile actions of methoxamine was observed 48 h after withdrawal. These data indicate that chronic propranolol pretreatment and withdrawal results in the unmasking of supersensitivity to both beta 1 and beta 2 adrenoceptor stimulation. There would also appear to be a compensatory change in alpha-adrenoceptor-induced responses in rat aorta following propranolol withdrawal.

Animals↗
PubMed1986

Stereospecific antibodies to propranolol.

The beta-adrenergic antagonist propranolol was activated through its side chain, coupled to bovine serum albumin, and injected into BALB/c mice. After fusion of the splenocytes from these immunized mice with the NS-1 myeloma cell line, two hybridomas, producing monoclonal anti-propranolol antibodies, were isolated. Clone P-49 was monospecific for propranolol, with a significant preference for the 1-stereoisomer, as compared to the d form. On the other hand, clone P-28 cross-reacted with alprenolol as well as some other beta-antagonists. Both classes of antibodies competed with A431 epidermoid carcinoma beta 2-adrenoceptors for the binding of [3H]propranolol. When ascites cells from clone P-28 were fixed with glutaraldehyde, the anti-propranolol monoclonal antibody became cell bound. These cell-bound P-28 antibodies bind propranolol and other beta-adrenergic ligands with a similar ranking order to the soluble monoclonal antibody. The cell-bound antibody displayed a 5-fold higher affinity towards 1-propranolol than the soluble monoclonal antibody. The practical implications of these findings are discussed.

Antibodies, Monoclonal↗
PubMed1987

Systemic and hepatic hemodynamics after variceal hemorrhage: effects of propranolol and placebo.

Hepatic and systemic hemodynamics were measured in 19 cirrhotic patients with variceal bleeding enrolled in a controlled trial of propranolol for the prevention of rebleeding. The patients were studied on three separate occasions. The first study was performed before randomization within 24 h of the bleeding episode, once hemodynamic stabilization had been achieved. The second study was performed after 10 days of treatment, and the third after 6 mo without rebleeding. Propranolol dosage was titrated according to blood levels. Wedged and free hepatic venous pressures and the hepatic venous pressure gradient were recorded. Hepatic blood flow and cardiac output were also measured. Before treatment, the groups of patients treated with propranolol (n = 11) or placebo (n = 8) were comparable according to clinical, biochemical, and hemodynamic parameters. After 10 days, hepatic venous pressure gradient decreased similarly in the two groups (-20% in the propranolol group, -25% in the placebo group). Cardiac output fell only in the propranolol group (-40%). Hepatic blood flow remained unchanged in either group. After 6 mo, hepatic venous pressure gradient remained lower than the values from the first (within 24 h of bleeding) study in both the propranolol group (n = 5) and the placebo group (n = 6). Our results suggest that portal pressure increases shortly after hemorrhage with a return to baseline values 10 days later, and that propranolol does not further magnify these changes. Spontaneous changes in hepatic hemodynamics after variceal hemorrhage must be taken into account when evaluating the effect of pharmacologic agents on portal pressure.

Adult↗
PubMed1990

Hemodynamic events in a prospective randomized trial of propranolol versus placebo in the prevention of a first variceal hemorrhage.

In a double-blind randomized trial, the hemodynamic events following the administration of propranolol (n = 51) or a placebo (n = 51) were prospectively studied in cirrhotic patients with esophageal varices. The hepatic venous pressure gradient, heart rate, and variceal size were determined at the baseline and 3, 12, and 24 months after the beginning of therapy. Baseline values were similar in both groups. At 3 months, the hepatic venous pressure gradient decreased significantly in propranolol-treated patients (from 18.1 +/- 4.2 to 15.7 +/- 3.4 mm Hg; P less than 0.05) but not in patients receiving the placebo (19.6 +/- 6.8 to 17.5 +/- 5.3 mm Hg; NS). At subsequent time intervals this gradient decreased significantly from the baseline value in both groups. Heart rate decreased significantly in the propranolol-treated group at all times (P less than 0.001). Variceal hemorrhage occurred in 13 patients (11 placebo-, 2 propranolol-treated; P less than 0.01), all of whom had a hepatic venous pressure gradient greater than 12 mm Hg. In 21 patients (14 propranolol-, 7 placebo-treated) the hepatic venous pressure gradient decreased to less than or equal to 12 mm Hg; none of them bled from esophageal varices, and their mortality rate also decreased. Because most of the bleeding events occurred during the first year (10 placebo-, 1 propranolol-treated; P less than 0.01), propranolol seems to have its protective effect during the period associated with the largest reduction in the hepatic venous pressure gradient. Because a reduction in the hepatic venous pressure gradient to less than 12 mm Hg protects from variceal bleeding and increases the rate of survival, this should be the aim of the pharmacological therapy of portal hypertension.

Adult↗
PubMed1989

Biphasic pattern of hypersensitivity following acute propranolol withdrawal in normal subjects.

The effect of abrupt propranolol withdrawal on exercise-induced changes in heart rate and blood pressure was studied in six normal volunteers. Response to exercise was measured on two occassions during propranolol treatment and 1, 2, 3, 4, 5 and 7 days after the last dose of propranolol. Exercise-induced changes in heart rate were significantly lower than control during propranolol treatment (p less than 0.005). Following propranolol cessation, all subjects showed a biphasic pattern of hypersensitivity. Heart rate response was significantly greater than control 2, 3 and 7 days after the last propranolol dose (p less than 0.05) and not significantly different from control 1, 4 and 5 days after the last dose of propranolol. Exercise-induced changes in pulse pressure showed a biphasic pattern similar to the changes in heart rate.

Adult↗
PubMed1983

Propranolol and hyperthyroidism: serum free fatty acids and glucose-induced insulin release in nondiabetic thyrotoxic patients during treatment to clinical compensation.

Glucose-induced insulin secretion was studied in 10 hyperthyroid patients, without personal or familial diabetic background, treated with increasing weekly doses of propranolol until clinical compensation was obtained. Intravenous glucose tolerance tests (25g) with concomitant determination of serum glucose, insulin and FFA were done before treatment, at 240 mg/day of propranolol and after clinical compensation. Patients were divided into two groups according to laboratory data and propranolol dosage needed for clinical compensation (group A: 240 mg/day; group B: 320-400 mg/day). Fasting serum insulin, glucose disappearance rate, and estimates of total insulin secretion after intravenous glucose did not change significantly during propranolol therapy and were within the normal range. Fasting FFA of untreated patients were significantly higher than control values (p less than 0.001), but a significant decrease was already seen at 240 mg/day of propranolol, even before clinical compensation. There was a marked difference in the insulin secretion pattern of thyrotoxic patients as compared to controls. Serum insulin and insulin:glucose ratios increased promptly, and at 5 min after glucose reached significantly higher levels than in normal subjects, before treatment as well as after clinical compensation with the propranolol therapy. Both the increased levels of FFA and of T3 could be involved in this pattern of the insulin response of nondiabetic thyrotoxic patients, since the secretion of insulin during the first 10 min after intravenous glucose was directly correlated to fasting serum FFA before propranolol, and serum T3 was directly correlated with total insulin response after clinical compensation. Furthermore the comparison of the results obtained in group A and group B patients raises the possibility that an increased beta-cell responsiveness to beta-adrenergic stimuli might also be involved in this pattern of insulin secretion.

Adult↗
PubMed1986

Effect of propranolol on cortical electrical activity in conscious and anesthetized rats.

The effect of propranolol on electrocorticographic (ECoG) activity was studied in conscious and anesthetized rats. Cortical electrodes and femoral venous cannulae were implanted 5 days before the experiments. The ECoG was recorded continuously and analyzed to different frequency bands, 2 hr before and 4 hr after the administration of propranolol. After a single infusion of 2 and 5 mg/kg or 5 consecutive daily doses of 2 mg/kg propranolol, frequent bursts of large amplitude 6-7 c/sec wave in the ECoG were observed. This ECoG phenomenon lasted between 60-100 min after the infusion of propranolol and was entirely abolished by pentobarbital anesthesia. Frequency analysis of the ECoG showed an immediate shift from predominantly delta (delta 0.5-4 c/sec) activity to overwhelmingly theta (theta 4-8 c/sec) activity following the infusion of propranolol. It is suggested that these changes in ECoG induced by propranolol are related to the sleep-enhancing and tranquilizing effects of propranolol.

Anesthesia, General↗
PubMed1983

Combined effects of propranolol and ethanol on human psychomotor performance.

Twelve male subjects were given placebo or 160 mg propranolol, in divided doses, during a 24-hr period before drinking a beverage containing 0 or 50 ml ethanol/70 kg body weight. Tests designed to measure mental and motor performance were administered 75 min after the last dose of propranolol. The tests performed included the wobble board (WB), pursuit meter (PM), delayed auditory feedback (DAF), pegboard (PB), tapping, time estimation (TE), and a modified Cornell medical index (CMI). A mean blood ethanol concentration of 48.0 +/- 9.1 mg/dl and a mean plasma propranolol level of 33.1 +/- 13.1 ng/ml were achieved. Ethanol alone significantly impaired performance in 12 out of 20 tests (p less than 0.05). Propranolol significantly (p less than 0.05) antagonized the decrement in psychomotor performance induced by ethanol on the PM. In all other tests, there was no significant interaction between ethanol and propranolol. Propranolol alone had no significant effect on the psychomotor tests. When the drugs were combined, the subjective symptoms, as measured by the CMI, showed a trend toward being additive. This study suggests that no adverse interaction occurs between therapeutic doses of propranolol and minimum impairment doses of ethanol.

Adult↗