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PubMed1991

Differential effects of propranolol on responses to receptor-dependent and receptor-independent stimuli in human neutrophils.

Recent evidence suggests that the hydrolysis of phosphatidylcholine (PC) by phospholipase D (PLD) may mediate superoxide anion (O2-) production in human neutrophils. To define the role of the PC-specific PLD products phosphatidic acid (PA) and diacylglycerol (DAG) in O2- production in response to agonists which activate the PLD pathway, we blocked the metabolism of PA to DAG with propranolol, an inhibitor of PA phosphohydrolase. Propranolol (150 microM) enhanced the production of O2- in response to the receptor agonists n-formyl-methionyl-leucyl-phenylalanine (FMLP, 292 +/- 94% of controls), platelet-activating factor (PAF, 932 +/- 215%) and leukotriene B4 (LTB4, 1305 +/- 475%). In the presence of propranolol, total O2- production in response to PAF and LTB4, which are potent priming stimuli but very weak direct agonists, was similar to that obtained with FMLP. IN contrast, responses to receptor-independent agonists phorbol myristate acetate (PMA) and ionomycin were inhibited (81 +/- 8% and 87 +/- 5% inhibition, respectively). The effects of propranolol were demonstrable in the absence of cellular calcium and were shared by both stereoisomers of the drug. These data are consistent with the hypothesis that PA produced through the hydrolysis of PC by PLD is an important mediator of O2- production in response to receptor-dependent agonists. However, the inhibitory effects of propranolol on receptor-independent stimuli suggest that PA generated through the PLD pathway plays a different role in the signal transduction mechanisms of these agonists or that propranolol may have additional effects beyond inhibition of PA phosphohydrolase.

Calcium↗
PubMed1983

Case report of propranolol (Inderal) pharmacotherapy for neuroleptic-induced akathisia and tremor.

This case report describes a schizophrenic patient who developed akathisia and tremor following neuroleptic pharmacotherapy with fluphenazine decanoate. The patient also suffered from familial (benign essential) tremor. The patient's neuroleptic-induced extrapyramidal side effects were not relieved by anticholinergic antiparkinson drugs or by phenobarbital. The patient was started on propranolol 10 mg b.i.d. She was also started on diazepam 5 mg t.i.d. for anxiety. The diazepam dose was held constant and propranolol was gradually increased to 40 mg q.i.d. The patient's extrapyramidal symptomatology gradually resolved over the course of one month, during which time the propranolol dose was being steadily increased. Propranolol also effectively controlled her familial tremor. After nine months as an outpatient, during which time the patient was neuroleptic-free, she developed psychotic decompensation for which she was treated with thiothixene. Akathisia or tremor did not develop, possibly because the patient was taking propranolol simultaneously. Propranolol may be useful for treating neuroleptic-induced akathisia. This requires systematic investigation with open and controlled trials.

Aged↗
PubMed1988

Stimulation of inositol phosphate production by propranolol in human neutrophils.

1. Propranolol has been reported to be beneficial in treating patients suffering from a variety of diseases including migraine, psychosis and schizophrenia. The mode of action of propranolol in the treatment of the above diseases is not clear. 2. An investigation into the possible effect of propranolol on receptor activated inositol phospholipid hydrolysis was carried out using human neutrophils. Receptor activated inositol phosphate production by formyl-methionyl-leucyl-phenylalanine has also been studied. 3. DL-propranolol caused a time and concentration dependent increase in inositol phosphate generation which was similar to that obtained for chemotactic peptide in neutrophils. The EC50 for propranolol was 2 microM compared to 0.5 microM for chemotactic peptide. 4. These results indicate the possibility that propranolol has a direct action on inositol phospholipid hydrolysis in addition to its beta-blocking effect.

Adult↗
PubMed1993

Synthesis and pharmacological evaluation of the antifibrillatory effect of fluorinated derivatives of carazolol and celiprolol: comparison with propranolol.

1. The effects of carazolol, celiprolol and their respective fluorinated derivatives (FD) on electrical stimulation threshold (EST) and ventricular fibrillation threshold (VFT) were compared with those of propranolol and propranolol-FD in Langendorff-perfused rabbit hearts. 2. Carazolol, carazolol-FD, propranolol and propranolol-FD produced significant dose-dependent elevation of both EST and VFT at all tested concentration levels. In contrast, celiprolol and celiprolol-FD did not produce a significant change in either threshold. 3. On a dosage basis, the order of antifibrillatory potency of these compounds is: carazolol-FD > propranolol-FD > carazolol > propranolol > celiprolol-FD > celiprolol. 4. The results of this study seem to indicate the importance of membrane stabilizing effect for a potent antifibrillatory action of beta-adrenoceptor blocking agents. Furthermore, fluorination is demonstrated to produce more potent antifibrillatory activity than that of the parent drugs.

Adrenergic beta-Antagonists↗
PubMed1995

High-performance liquid chromatographic determination of (S)- and (R)-propranolol in human plasma and urine with a chiral beta-cyclodextrin bonded phase.

The determination of propranolol enantiomers in microsamples of human plasma and urine by HPLC using a chiral stationary phase is described. After extraction from 200 microliters of plasma or urine with racemic alprenolol as internal standard (I.S.), the enantiomers are separated on a beta-cyclodextrin column with a polar organic mobile phase and determined by fluorescence detection. The retention times of I.S. and propranolol enantiomers are about 12-13 min and 16-18 min, respectively. Peak resolutions are 1.4 for I.S. and 2.2 for propranolol. The use of alprenolol as I.S. improves significantly the coefficients of variation (C.V.: 0.6-4.2%). Sensitivity is approximately 1.5 ng/ml per propranolol enantiomer. The assay is applied to pharmacokinetic studies of racemic propranolol in human biological fluids. The (S)-propranolol levels are always higher than the (R)-antipode concentrations in plasma and urine.

Chromatography, High Pressure Liquid↗
PubMed1994

Direct enantioselective determination of (R)- and (S)-propranolol in human plasma. Application to pharmacokinetic studies.

In order to examine possible drug interactions of (R)- and (S)-propranolol a randomized, double blind, crossover study has been performed, administering orally single doses of 40 mg (R,S)- and of 20 mg (S)-propranolol. HCl three times daily over a week to reach steady state conditions. After the first single dose of 40 mg (R,S)-propranolol. HCl, the AUC0-infinity and Cmax values of the (S)-isomer were greater than those of the (R)-isomer: the ratio of AUC(S) over AUC(R) was 1.77 (P < 0.05) and that of Cmax 1.57 (P < 0.01). When (S)-propranolol.HCl was given as a single 20 mg dose, the AUC(S) value was a factor of 0.55 lower than that administration of 40 mg (R,S)-propranolol.HCl. At steady state, the AUC of (S)-propranolol was 1.52 times higher (P < 0.01) than that of the (R)-isomer after administration of 40 mg racemate, and comparing the (S)-isomer, the ratio was 1.21. Following administration of the first single dose of 40 mg of the racemate, the mean (SD) clearance of the (R)- and (S)-isomers was 110 (84) and 61 (37) ml min-1 kg-1, respectively; at steady state these values were 89 (55) and 57 (37) ml min-1 kg-1, respectively. Respective values for (S)-propranolol after single isomer administration (20 mg) were 86 (36) and 57 (25) ml min-1 kg-1 in single dose and steady state situations. The data are based on the quantitative analysis of (R)- and (S)-propranolol in plasma.(ABSTRACT TRUNCATED AT 250 WORDS)

Chromatography, High Pressure Liquid↗
PubMed1995

The secretion of propranolol enantiomers in human saliva: evidence for active transport?

To study the possible transport routes which may lead to the presence of a drug in saliva, the concentration-time curves of the separate enantiomers of propranolol were measured in human saliva and plasma after oral administration of 10 mg of propranolol hydrochloride. Saliva samples were taken with the Salivette device. Plasma and saliva concentrations of the enantiomers of propranolol were determined by HPLC with fluorescence detection. The transport of propranolol from plasma to the salivary gland appears to be not stereospecific and not saturable. Therefore, there is no indication that the transport of propranolol to the salivary gland is active. The concentrations of both enantiomers of propranolol in saliva, however, were higher than those of both enantiomers in venous plasma. In the past this phenomenon was interpreted as an indication of active transport, but it could be explained by the fact that salivary concentration more closely reflects the central compartment than that of peripheral venous blood.

Adrenergic beta-Antagonists↗
PubMed1992

Response of angina and ischemia to long-term treatment in patients with chronic stable angina: a double-blind randomized individualized dosing trial of nifedipine, propranolol and their combination.

Seventy-four patients with chronic stable mild angina, mild coronary artery disease (83% had one- or two-vessel disease) and normal left ventricular function were studied to measure the response of treadmill exercise performance and painful and silent ischemia in the ambulatory setting to randomly assigned treatment with nifedipine or propranolol and their combination; titration to maximal tolerated dosages was performed in double-blind manner. At 3 months both nifedipine and propranolol reduced the weekly angina rate (p less than 0.05); during treadmill exercise testing, increases (p less than 0.05) were noted in time to angina and total exercise time and decreases in maximal ST depression at the end of exercise. There were no differences between the responses to nifedipine and propranolol and no significant additional changes were seen after another 3 months of therapy. The combination of nifedipine and propranolol reduced the number of patients with angina on exercise treadmill testing from 64% to 38% (p less than 0.05). During ambulatory electrocardiographic monitoring before treatment, there were 1.4 +/- 2.4 (mean +/- SD) episodes/24 h of painful ischemia and a very low silent ischemia frequency: mean 1.1 +/- 2.7 episodes/24 h, mean duration 16 +/- 25 min/24 h. Treatment with propranolol and nifedipine resulted in reduction of episodes and duration of painful and painless ischemia; approximately 77% of patients were free of all ischemic episodes. It is concluded that patients with chronic stable mild angina have a low incidence of silent ischemia. Nifedipine or propranolol alone, titrated to individualized maximally tolerated dosages, are equally effective in long-term control of painful and painless ischemia, anginal episodes and exercise-induced ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Angina Pectoris↗
PubMed1990

Propranolol-sensitive and phenoxybenzamine-insensitive binding of norepinephrine to endogenous lipid droplets from rat adipocytes.

Norepinephrine, epinephrine, and isoproterenol at concentrations of 5.5 x 10(-8) M were found to elicit lipolysis in a cell-free system containing lipid droplets from fat cells and lipase solution. In the cell-free system, the beta-blockers propranolol and dichloroisoproterenol at concentrations of 1 microM inhibited lipolysis induced by norepinephrine, whereas similar concentrations of the alpha-blockers phenoxybenzamine and yohimbine did not inhibit lipolysis. The binding of norepinephrine to endogenous lipid droplets was inhibited by propranolol, but not by phenoxybenzamine. We concluded that the propranolol-sensitive, phenoxybenzamine-insensitive binding of norepinephrine to endogenous lipid droplets is involved in lipolysis in fat cells. Treatment of endogenous lipid droplets with phospholipase C, but not phospholipase D, trypsin, chymotrypsin, or neuraminidase, inhibited the propranolol-sensitive binding of norepinephrine to the droplets. These results suggest that the phosphate group of phospholipid in endogenous lipid droplets may be the site of propranolol-sensitive binding of norepinephrine. The physiological significance of the propranolol-sensitive binding is discussed.

Adipose Tissue↗
PubMed1991

Propranolol preserves ultrastructure in adult cardiocytes exposed to anoxia/reoxygenation: a morphometric analysis.

The protective effect of d,l-propranolol was studied using freshly isolated canine ventricular cardiocytes (1.5 x 10(6)/mL) exposed to 30 min anoxia (95% N2/5% CO2) and 0, 3, 20, and 45 min of reoxygenation (95% O2/5% CO2). In addition to preventing lipid peroxide formation, propranolol maintained cellular viability, and minimized ultrastructural alterations. In the absence of propranolol, the outer mitochondria become swollen and rounded up within the first few minutes of reoxygenation. The perinuclear mitochondrial area increased only slightly. We observed that the cellular injury process proceeded differentially from the exterior to the interior, with a mitochondrial area increase and outer membrane rupture. Sarcolemmal damage was also observed with prevalent blebbing and membrane loss. The Z-lines became wider and more diffuse with reoxygenation. Injury to the nuclear double membrane was observed. Incubation with propranolol showed significant protection during postanoxia reoxygenation. In contrast, the more water soluble beta-blocker atenolol only exhibited slight protection. In addition, d-propranolol (the non beta-blocking isomer) and the antioxidant enzymes, SOD and catalase, showed significant protection. These data support previous findings concerning the antioxidant properties of propranolol which appear to be independent of beta-receptor blockade.

Animals↗
PubMed1991

Hepatic beta-adrenoceptor adaptation during propranolol administration is impaired in aging rats.

Aging has been associated with changes in beta-adrenoceptor responses and adaptation to prolonged removal of catecholamine stimulation. We have examined the effect of chronic propranolol administration on rat hepatic membrane beta-adrenoceptor density, agonist affinity and response in young (6-7 months) and old (26-7 months) male Wistar rats. Propranolol administration via miniosmotic pumps for 7 days resulted in similar and sustained plasma propranolol levels (approximately 100 ng/ml) in old and young rats. Pretreatment beta-adrenoceptor responses to isoprenaline were significantly higher in old rats. Propranolol administration was associated with significant increases in beta-adrenoceptor response and density (Bmax) in young rats only. Cyclic adenosine 3',5'-monophosphate (cyclic AMP) responses to prostaglandin E1 (PGE1), guanosine triphosphate (GTP), 5'-guanyl-imidodiphosphate (Gpp(NH)p), forskolin and Mn2+ were not significantly different between young and old rats and were not affected by propranolol administration. Neither aging or propranolol administration was associated with a change in beta-adrenoceptor agonist affinity. These findings demonstrate elevated hepatic beta-adrenoceptor response and impaired hepatic beta-adrenoceptor adaptation to beta-adrenoceptor blockade in aging rats.

Adaptation, Physiological↗
PubMed2004

Porcine FAD-containing monooxygenase metabolizes lidocaine, bupivacaine and propranolol in vitro.

Lidocaine, bupivacaine and propranolol are amines that can be expected to act as substrates for FAD-containing monooxygensae (FMO) (EC 1. 14. 13. 8). We found that FMO metabolizes lidocaine, bupivacaine and propranolol. The Km and Vmax values of lidocaine, bupivacaine and propranolol for FMO are 143, 408 and 210 microM, and 145, 119 and 135 nmol/min/mg FMO protein, respectively. The lipophilicity of the drugs decreased in the following order: lidocaine>propranolol>bupivacaine, under our experimental conditions. Furthermore, the metabolic products of FMO were separated by high-performance liquid chromatography and analyzed by gas chromatography-mass spectrometry, and were found to be the N-oxides and N-hydroxylamines of the respective drugs. These findings suggest that lidocaine, bupivacaine and propranolol are substrates for FMO, and the enzymatic toward lidocaine or bupivacaine may be inhibited exclusively and competitively by propranolol.

Animals↗
PubMed1996

Effects of verapamil, propranolol, and procainamide on adenosine-induced negative dromotropism in human beings.

Adenosine, verapamil, propranolol, and procainamide are widely used antiarrhythmic drugs. The interactions among them are still not known in human beings. Adenosine-induced negative dromotropic effects were assessed by rapid bolus injection of adenosine during constant high right atrial pacing in each patient. The initial dose of adenosine was 0.5 mg and was followed by a stepwise increment of 0.5 mg until atrioventricular (AV) nodal block occurred. The negative dromotropic actions of adenosine were examined in the control state and in the following three protocols in three groups of patients: (1) In 12 patients (group 1), intravenous verapamil, 0.15 mg/kg, was given; (2) In 12 patients (group 2), intravenous propranolol, 0.1 mg/kg, was given; and (3) in 10 patients (group 3), intravenous procainamide, 15 mg/kg, was given. The dose-response curves of adenosine on AV nodal conduction were almost identical in the control state and after verapamil, propranolol, or procainamide injection. However, verapamil, in contrast to propranolol, significantly reduced the dose of adenosine required to produce AV nodal block, from 4.4 +/- 0.7 mg to 2.7 +/- 0.3 mg (p < 0.01). Of note, procainamide exerted no significant effects on adenosine-induced negative dromotropism on AV nodal conduction or AV nodal block. In conclusion, the negative dromotropic effects of adenosine are preserved and independent even in the presence of verapamil, propranolol, or procainamide. Both verapamil and propranolol can exhibit additive effects with adenosine in prolonging AV nodal conduction time; however, only verapamil can reduce the dose of adenosine required to produce AV nodal block. This finding indicates that the dose of adenosine may be reduced for patients who have already been treated with verapamil.

Adenosine↗
PubMed1984

Perioperative beta blockade with propranolol: reduction in myocardial oxygen demands and incidence of atrial and ventricular arrhythmias.

To determine the effect of beta blockade with propranolol on myocardial oxygen demands and postoperative arrhythmias in patients having coronary bypass operations, 50 patients with chronic stable angina undergoing operation were randomized in a double-blind fashion to receive either propranolol (60 mg every 6 hours) or a placebo. Drug administration began 24 to 48 hours prior to operation and continued through the operative period and for one month after operation. There were no deaths. Two perioperative myocardial infarctions occurred, both in patients receiving a placebo. Myocardial oxygen demand as measured by the rate-pressure product (heart rate X mean arterial pressure) was significantly reduced during induction of anesthesia (7,658 +/- 451 versus 5,786 +/- 340; p less than 0.002) and during sternotomy (8,400 +/- 550 versus 6,756 +/- 384; p less than 0.02) in propranolol-treated patients. In the first two postoperative days, nitroprusside was required for control of hypertension of 10 patients in the placebo group but in only 3 patients given propranolol (p less than 0.05). Postoperatively, 15 of the 26 patients who received a placebo had 45 episodes of arrhythmia. Seven of the 24 propranolol-treated patients had 17 episodes (p less than 0.04). We conclude that propranolol given perioperatively in doses large enough to induce beta blockade significantly reduces myocardial oxygen demands in the vulnerable period during induction of anesthesia and sternotomy, reduces the need for antihypertensive therapy in the immediate postoperative period, and causes a marked reduction in the incidence and frequency of both supraventricular and ventricular arrhythmias in the postoperative period.

Angina Pectoris↗
PubMed1999

Propranolol for the prevention of postoperative arrhythmias in general thoracic surgery.

BACKGROUND: Prevention of postoperative arrhythmias in patients undergoing general thoracic surgery is desirable to prevent morbidity. METHODS: A randomized, double-blind, placebo controlled trial of propranolol (10 mg every 6 hours) for 5 days was undertaken in patients undergoing major thoracic operations to determine whether arrhythmias requiring treatment could be reduced. Secondary outcomes included overall arrhythmia rate, adverse events, and length of stay. Arrhythmias were assessed by 72-hour Holter monitoring. Patients with a history of heart failure, asthma, advanced heart block, preexisting arrhythmias, sensitivity to propranolol, or use of antiarrhythmic drugs were excluded. RESULTS: Using the intention-to-treat principle there was a 70% relative risk reduction from 20% to 6% in the rate of treated arrhythmias with propranolol (p = 0.071, 95% confidence interval 0.6% to 27.2%). Overall arrhythmias were common but usually benign. Adverse effects were common, although generally mild with hypotension and bradycardia being reported more often in the propranolol group. Length of stay was not different. CONCLUSIONS: There was a trend to a reduction in the risk of perioperative arrhythmias with propranolol. Moreover, propranolol was well tolerated showing a slight increase in minor adverse events.

Aged↗
PubMed2001

Ca(2+)-dependent production of reactive oxygen metabolites by human neutrophils in response to fluorinated propranolol analogues.

Fluorinated analogues of propranolol, namely trifluoroethyl propranolol (F3), pentafluoropropyl propranolol (F5), and heptafluorobutyl propranolol (F7), were found to induce reactive oxygen metabolite (ROM) production in human neutrophils in a dose-dependent manner. Preincubation of neutrophils with the calcium chelator BAPTA-AM or the tyrosine kinase inhibitor genistein inhibited this ROM production. Direct measurements of intracellular calcium revealed that these analogues caused a transient increase in intracellular calcium. In addition, these fluorinated analogues of propranolol caused a transient increase in actin polymerization. The effects of these compounds were found to be dependent upon the degree of fluorination of the parent compound. Propranolol, on the other hand, had no direct effect on ROM, calcium, or actin polymerization when added alone to neutrophils, although it did modify responses of cells to various stimuli. Whereas ROM production induced by the chemotactic peptide formyl-methionyl-leucyl-phenylalanine was enhanced in a dose-dependent manner, the response to the particulate stimulus, latex beads, was abolished.

Actins↗
PubMed1996

Interaction of propranolol with S100 proteins of the cardiac muscle.

The cardioprotective activity of propranolol is believed to be independent of its beta-adrenoceptor antagonistic effect. Propranolol exerts this effect through a direct effect on the cardiac muscle, but the precise mechanism remains unclear. In this work, we demonstrated that propranolol binds to S100ao and S100L proteins with ED50 of approximately 1.0 microM without cation dependency and that this binding changes the conformation of these S100 proteins. Propranolol, however, was found to bind to and to change the conformation of S100C protein in the presence of Mg2+ or Zn2+ with ED50 of approximately 1.0 microM. No change was observed in the presence of Ca2+. Moreover, in the presence of Mg2+, the ED50 of L- and D- propranolol were approximately 0.8 and 2.0 microM, respectively. This study demonstrated for the first time, that the S100 proteins of the cardiac muscle are intracellular targets of propranolol, and that Mg2+ is a modulator of the cardioprotective activity of S100C protein.

Animals↗
PubMed1984

Differential inhibition by propranolol of feeding induced in rats by various stimuli.

Opiate receptor blockade, or forced imbibition of 2% NaCl to deplete pituitary dynorphin decreases 2-deoxy-D-glucose (2-DG), but not insulin-induced hyperphagia, indicating a possible role for dynorphin in the eating associated with endogenous opiates. Beta-adrenergic receptor blockade decreases vasopressin release induced by 2-DG but not by insulin. Because vasopressin and dynorphin are sometimes co-localized, it was hypothesized that naloxone-sensitive feeding might be selectively inhibited by beta-adrenergic blockade with propranolol. Propranolol in doses as low as 2.5 mg/kg inhibited 4 hr feeding induced by 2-DG (400 mg/kg). Propranolol did not significantly affect feeding induced by ketocyclazocine administration (3.0 mg/kg) or by 24 hr food deprivation. Feeding stimulated by insulin (10 U/kg) was significantly inhibited by propranolol (2.5 mg/kg) only when the propranolol was reinjected during the period 2 hr after insulin injection, when the induced feeding was greatest. In summary, propranolol inhibited opiate-related (2-DG) as well as opiate-independent (insulin) hyperphagias. It also failed to inhibit food intake resulting from the opiate related stimulus of 24 hr food deprivation. Therefore, naloxone sensitive hyperphagias were not specifically inhibited by beta-adrenergic blockade, indicating that vasopressin-associated dynorphin is not involved in opiate related feeding.

Animals↗