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PubMed1989

Effects of pretreatment with propranolol on potassium, calcium, and magnesium shifts after ventricular fibrillation in dogs.

Hypokalemia and other electrolyte changes have been observed after resuscitation from ventricular fibrillation. We studied the effect of propranolol on postresuscitation electrolytes in a canine model of ventricular fibrillation and cardiac resuscitation by randomizing 40 anesthetized dogs to four groups: ventricular fibrillation--no drug (VF), ventricular fibrillation--propranolol pretreatment (VF-prop), control-no drug (NoVF), control--propranolol (NoVF-prop). We measured serum electrolytes at baseline and periodically for 3 hours. In VF dogs, serum potassium decreased from 3.9 +/- 0.4 to 3.2 +/- 0.2 mEq/L 60 minutes after resuscitation (p less than 0.001). The decrease in potassium was prevented (p less than 0.001) by propranolol. Serum calcium decreased from 10.6 +/- 0.8 to 10.2 +/- 0.8 mg/dl in VF dogs 15 minutes after resuscitation (p less than 0.05); this decrease was not blocked by propranolol (p = NS). Serum magnesium increased from 1.5 +/- 0.2 to 1.8 +/- 0.1 mEq/L in VF dogs 7 minutes after resuscitation (p less than 0.001); this rise was partially blocked by propranolol (p less than 0.01). Serum glucose increased from 105 +/- 6 to 183 +/- 27 mg/dl in VF dogs 7 minutes after resuscitation (p less than 0.001); this increase was diminished by propranolol (p less than 0.001). Thus propranolol prevents the decrease in serum potassium after ventricular fibrillation in this canine model, providing evidence that postresuscitation hypokalemia is caused by the beta-adrenergic effects of catecholamines secreted in response to cardiac arrest. Propranolol blocks the rise in magnesium and glucose but does not block the decrease in calcium after resuscitation.

Animals↗
PubMed1986

Effects of propranolol on catecholamine synthesis and uptake in the central nervous system of the rat.

These studies were undertaken to determine the effects of propranolol on catecholamine synthesis and uptake in the rat central nervous system. The effects of propranolol on catecholamine synthesis were studied in vitro in striatal and hypothalamic synaptosomes, and also in vivo. In addition, the effects of propranolol on catecholamine uptake in striatal and hypothalamic synaptosomes were evaluated. Propranolol inhibited synaptosomal catecholamine synthesis and uptake in both tissues. Norepinephrine uptake in the hypothalamus was most sensitive to propranolol inhibition (IC50 = 5 microM). Dopamine synthesis in striatal synaptosomes was also inhibited markedly, with an IC50 = 8 microM. After in vivo administration, propranolol decreased the accumulation of dopa in the striatum, confirming propranolol's synthesis inhibiting effect in dopaminergic terminals. Studies of soluble striatal tyrosine hydroxylase revealed that propranolol has a direct inhibitory effect on the enzyme. These results indicate that propranolol administration may cause a potentiation of norepinephrine activity specifically at alpha receptors, due to concurrent beta receptor blockade and inhibition of norepinephrine reuptake and a decrease in dopamine activity at dopaminergic receptor sites due to an inhibition of dopamine formation.

Animals↗
PubMed1985

Effect of altered plasma protein binding on pharmacokinetics and pharmacodynamics of propranolol in rats after surgery: role of alpha-1-acid glycoprotein.

The pharmacokinetics and pharmacodynamics of propranolol in rats 2 days after laparotomy were compared to control animals. The apparent volumes of distribution and the systemic clearance of propranolol were decreased to about 20 to 40 and 70% of control values, respectively. The area under the blood concentration-time curve (AUC) of propranolol after p.o. administration showed a marked elevation after surgery and its availability increased about 2-fold at doses of 5.0 and 12.5 mg/kg. These changes were associated with a decreased plasma unbound fraction of propranolol after surgery. Immunological determination of alpha-1-acid glycoprotein (AGP) revealed a marked increase after laparotomy and a linear relationship was found between the plasma AGP concentration and the binding capacity of high-affinity binding site for propranolol in plasma (r = 0.961, P less than .001). AUC of p.o. administered propranolol was also correlated with plasma AGP concentration. The beta-blocking activity of propranolol assessed by the reduction in the isoproterenol-induced tachycardia was decreased in rats after laparotomy when it was evaluated in terms of the total plasma concentration of propranolol. In contrast, its activity evaluated by the unbound plasma concentration showed no difference between control and laparotomized rats, suggesting the dependence of the pharmacological activity of propranolol on its unbound level in plasma. Thus, laparotomy-induced changes in both pharmacokinetics and pharmacodynamics could be considered largely due to an increase in its binding to the increased plasma level of AGP.

Animals↗
PubMed1977

Effect of propranolol on platelet function.

Excessive reactivity of blood platelets may contribute to atherosclerotic vascular disease. Hence drugs which alter platelet function may be protective. Prompted by findings that propranolol therapy normalized hyperactive platelet aggregation in patients with coronary artery disease, we studied propranolol in vitro to assess its action on platelets. At concentrations similar to those achieved in vivo (0.1-1 muM), propranolol raised the thresholds for aggregation of some normal paltelets by adenosine diphosphate (ADP). At higher concentrations (10-50 muM), propranolol abolished the second wave of platelet aggregation induced by ADP and epinephrine, and inhibited aggregation induced by collagen, thrombin, and the ionophore A23187. Propanolol blocked the release of 14C-serotonin from platelets, inhibited platelet adhesion to collagen, and interfered with clot retraction. Propranolol blocked ionophore-induced uptake of 45Ca by platelets. Inhibition appeared unrelated to beta-adrenergic blockage, as d(+) propranolol (which lacks beta-blocking activity) was equipotent with 1(-) propranolol. Moreover, practolol, a beta-blockading drug which is nonlipophilic, did not inhibit platelet function. These studies suggested that propranolol, like local anesthetics, decreased platelet responsiveness by a direct action on the platelet membrane, possibly by interfering with calcium availability. Modulation of platelet function by propranolol may occur at concentrations achieved at usual clinical doses of the drug.

Blood Coagulation Tests↗
PubMed1988

Pharmacokinetic study of a new sustained release preparation of propranolol in normal healthy volunteers.

The pharmacokinetics of a sustained release (SR) propranolol (Betalong) were compared with conventional propranolol (Inderal) after single and multiple dosing in 8 normal healthy volunteers. The study was designed in a crossover fashion. SR propranolol 80 mg in a single dose maintained the plasma concentration of propranolol above the minimum therapeutic concentration up to 25 h. The steady-state propranolol concentration after 80 mg conventional propranolol twice daily and SR propranolol 80 mg daily was almost similar. The results indicate that Betalong (SR propranolol) satisfies the pharmacokinetic criteria expected of a sustained release preparation of propranolol and may be useful in single daily dose.

Adult↗
PubMed1988

Effect of altered serum protein binding on propranolol distribution into milk in the lactating rabbit.

A diffusional model for drug distribution between milk and plasma was developed recently and tested in lactating rabbits. The purpose of this study was to test the ability of the model to predict the milk to plasma drug concentration ratio (M/P) in vivo for propranolol under conditions in which propranolol plasma protein binding was altered. Five lactating rabbits were administered a 1.6-mg/kg loading dose of i.v. dl-propranolol, followed by a 1.02 mg/(kg/hr) maintenance infusion of propranolol. Four hours after the initiation of the infusion, an i.v. bolus dose of 40 mg/kg of bovine alpha-1-acid glycoprotein (AAG) was administered. Blood and milk samples were collected for up to 8 hr after the initiation of the propranolol infusion; plasma and whole milk propranolol levels were quantitated by high-pressure liquid chromatography. Serum and skim propranolol unbound fractions, as well as the skim to whole milk propranolol concentration ratio were determined in samples collected before and after AAG administration. AAG administration resulted in a 22% decrease in mean unbound fraction of plasma and a 52% increase in mean total plasma propranolol concentration (35% decrease in mean systemic clearance). Observed M/P values fell from 2.13 +/- 0.42 to 1.23 +/- 0.34) AAG administration, closely approximated M/P observed in vivo. Total milk levels, however, were unaffected by AAG. The results are indicative that the diffusional model also holds under conditions in which one of the model parameters, such as unbound fraction of plasma, is altered. The lack of effect on total milk levels illustrates the importance of both M/P and systemic clearance in controlling milk drug concentrations, hence neonatal exposure.

Animals↗
PubMed1987

Selective induction of propranolol metabolism by smoking: additional effects on renal clearance of metabolites.

The objective of this study was to examine the effect of cigarette smoking on the activities of the three primary pathways governing propranolol metabolism in human subjects, i.e., glucuronidation, side-chain oxidation and ring oxidation. A single 80-mg dose of propranolol p.o. together with 40 muCi of 4-[3H]propranolol was given to six smoking and seven nonsmoking, young, white, male subjects and the oral clearance of propranolol and the partial clearances through these pathways were determined. The oral clearance of propranolol was increased by 77% (P less than .02) in smokers compared with nonsmokers. This apparent induction of propranolol metabolism was due to a 122% increase in side-chain oxidation (P less than .001) and a 55% increase in glucuronidation (P less than .01). There was no significant effect of smoking on aromatic ring oxidation. Smokers had a 30% greater renal clearance of total metabolites (P less than .05), due mainly to a 53% greater renal clearance of the acidic propranolol metabolite naphthoxylactic acid (P less than .001). These data show a selective effect of smoking on propranolol metabolism and suggest that side-chain oxidation and glucuronidation are mediated by isoenzymes inducible by aromatic hydrocarbons. The selective effect of smoking on the renal clearance of the major propranolol metabolite naphthoxylactic acid may be due to induction of a renal transport protein.

Adult↗
PubMedDate not supplied

Anticonvulsant effects of propranolol and their pharmacological modulation.

The anticonvulsant activity of propranolol was investigated in mice and rats using the electroshock seizure test (MES) and in special cases the electrically evoked hippocampal afterdischarges as a model. The results show that racemic propranolol as well as the two enantiomers were effective against MES. (+)-propranolol, the isomer with negligible beta-adrenoceptor blocking capacity revealed the stronger effect, its efficacy was comparable with the potency of phenobarbital, an overadditive synergism could be demonstrated. Subchronic administration of the two enantiomers led to a significantly reduced ED50 value of (-)-propranolol 24 h after the last application, the (-)-isomer became more effective. The (+)-propranolol did not reveal significant differences. In unrestrained rats with chronically implanted electrodes propranolol increased the stimulation threshold and reduced the duration of electrically evoked hippocampal afterdischarges. Investigations with drugs affecting monoaminergic systems in the CNS demonstrated that the noradrenergic system might play a predominant role in modulating the anticonvulsant effectiveness of propranolol. Pharmacological suppression (6-hydroxydopamine, reserpine, phenoxybenzamine) or stimulation (maprotiline, yohimbine, clenbuterol) reduced or enhanced the activity of propranolol against MES. On the other hand, manipulation of the serotonergic or dopaminergic system seemed to be less effective. In general, the findings confirm the results of previous studies that the membrane stabilizing property and not the blocking action on beta adrenergic (or serotonergic) receptors accounts for the anticonvulsant activity of propranolol.

Animals↗
PubMed1982

Contractile actions of racemic and d-propranolol on isolated canine mesenteric and coronary arteries.

This investigation was undertaken to determine whether propranolol exerts a direct vasoconstriction action which contributes to the increased systemic and regional vascular resistance observed after its acute administration. Helically cut strips of canine mesenteric and coronary arteries were exposed to cumulative concentrations of racemic propranolol, d-propranolol, metoprolol and sotalol. Racemic and d-propranolol were equipotent in eliciting concentration-related increments in tension in the mesenteric (3 x 10(-6)-3 x 10(-5) M) and coronary (3 x 10(-7)-3 x 10(-5) M) arterial strips. Metoprolol and sotalol did not cause contractions in concentrations up to 10(-4) M. Phenoxybenzamine, 10-(-6) M, did not alter the contractile responses elicited by racemic and d-propranolol. Upon exposure of mesenteric strips to calcium-free media or 10(-6) M verapamil, the contractile responses to propranolol (3 x 10(-5) M) and KCl (30 mM) were markedly reduced (not significantly different), whereas norepinephrine (10(-6) M)-induced responses were inhibited to a significantly lesser degree. In coronary arteries exposed to calcium-free media or 10(-6) M verapamil, the responses to propranolol, KCl and methoxamine (10(-5) M) were all extensively decreased (not significantly different). These results indicate that propranolol exerts a direct contractile effect on canine mesenteric and coronary arteries, which is unrelated to its beta adrenergic blocking activity and is not mediated through action on alpha adrenergic receptors. The propranolol-induced contraction appears to be associated predominantly with an influx of calcium ion.

Adrenergic beta-Antagonists↗
PubMedDate not supplied

Stereochemical composition of propranolol metabolites in the dog using stable isotope-labeled pseudoracemates.

Previous studies have demonstrated a larger oral bioavailability of (+)- as compared to (-)-propranolol in the dog. The objective of the present study was to examine how this difference is reflected in the metabolism in the drug. The stereochemical composition of propranolol and its metabolites was, therefore, determined in the urine of four dogs after single 160-mg oral doses of stable isotope-labeled pseudoracemates of propranolol. All major metabolites, accounting for 84% of the dose excreted in urine, were isolated by solvent extraction or HPLC, glucuronic acid conjugates after enzymatic hydrolysis, and analyzed by GC/MS after chemical derivatization. Of the three primary metabolic pathways, glucuronidation of the parent drug, about 16% of the dose recovered in urine, was highly selective for (-)-propranolol, (-)/(+)-enantiomer ratio 3.5. In contrast, all of the side-chain oxidation metabolites, about 30% of the dose, were mainly derived from (+)-propranolol, (-)/(+)-enantiomer ratio ranging from 0.35 to 0.74. Ring oxidation, involved in the metabolism of the remainder of the dose studied, about 38%, was, however, also found to be selective for (-)-propranolol, with the greatest selectivity observed in 4'-hydroxypropranolol, (-/(+)-enantiomer ratio 1.49. There was an excellent mass balance for the enantiomers of the metabolites studied, i.e. the total (-)/(+)-enantiomer ratio was close to unity. The higher oral bioavailability of (+)-propranolol in the dog, well reflected in the stereochemical composition of unchanged propranolol in urine, is suggested to be due to stereoselective presystemic hepatic removal of (-)-propranolol by glucuronidation and ring oxidation.

Animals↗
PubMed1983

Possible role of an endogenous opioid in the antihypertensive action of propranolol in spontaneously hypertensive rats.

The effect on systolic blood pressure and heart rate of the acute and chronic intraperitoneal (i.p.) administration of d- and dl-propranolol was investigated on unanesthetised spontaneously hypertensive rats. The effect of naloxone on the propranolol induced hypotension was also studied to test the hypothesis that the antihypertensive effect of propranolol involves the release of an endogenous opiate. On i.p. administration, 3 mg/kg d-propranolol was inactive; 3 and 30 mg/kg dl-propranolol decreased blood pressure and heart rate in a dose-dependent manner. When the rats were pretreated with 2 mg/kg naloxone i.p., the effect of propranolol on the blood pressure was nearly completely abolished, while that on the heart rate was only partially blocked. Chronic administration of dl-propranolol (30 mg/kg b.i.d.) to spontaneously hypertensive rats from the age of 6 weeks (prehypertensive phase) for 29 days prevented the development of hypertension while the rats treated with physiological saline for 29 days (control group) developed hypertension. Naloxone (2 mg/kg i.p.) administered on the 29th day to chronically treated rats induced a reversal of the propranolol action on systolic blood pressure and heart rate, i.e., blood pressure and heart rate increased. Naloxone had no such effect in the control group. We suggest that the release of an endogenous opioid contributes to the acute and chronic antihypertensive action of i.p. propranolol in spontaneously hypertensive rats and that the secretion of endogenous opioids participating in the control of cardiovascular functions is influenced by adrenergic mechanisms.

Animals↗
PubMed1980

Effects of propranolol on aldosterone plasma concentration and aldosterone metabolic clearance in hypertensive patients.

Although propranolol administration produces a lowering of PRA, PAC does not decrease in a similar fashion. In the present study the effects of propranolol on the aldosterone MCR were examined. Eight patients with essential hypertension were studied while receiving treatment with a diuretic and again after propranolol (160 to 320 mg/day) was added to the therapeutic regimen. Propranolol therapy was associated with a 25% decrease in PRA (p less than 0.05) and changes in PACs that were variable but not significantly different from diuretic therapy alone. The aldosterone MCR decreased from 1420 +/- 120 to 1120 +/- 90 L/24 hr in response to propranolol (p less than 0.01). The average production rate of aldosterone (MCR X PAC) did not change after propranolol treatment despite a decrease in PRA. There were no changes in plasma concentrations of potassium or in ACTH secretion (as reflected by levels of cortisol) to explain a role for propranolol to sustain aldosterone secretion. Thus propranolol administered to hypertensive patients pretreated with a diuretic can affect circulating levels of aldosterone apart from changes in PRA. Propranolol therapy produces a moderate reduction in aldosterone MCR and appears to augment aldosterone production by a mechanism exclusive of known stimuli.

Adult↗
PubMed1980

Stereospecific assay for (-)- and (+)-propranolol in human and dog plasma.

Propranolol is a nonselective beta adrenergic blocking agent used clinically as the racemic mixture. Since (-)-propranolol is about 100 times more potent than its optical antipode, significant differences in their disposition may be important clinically, especially if affected by disease state. The present technique, for the first time, allows for the quantitation of both propranolol enantiomers after administration of the racemic mixture in man and dogs. Enantiomers are reacted with synthetically prepared and optically pure N-trifluoroacetyl-(-)-prolyl chloride, followed by high-performance liquid chromatographic separation of the diastereoisomers using fluorescence detection. Derivatization is quantitative (> 98%) from 2 to 1000 ng/ml; 4-hydroxy and N-desisopropyl propranolol, basic metabolites, do not interfere with the assay. (-)-Propranolol and (+)-propranolol and their corresponding glucuronide concentrations were determined in an angina patient taking 800 mg of propranolol daily and in two dogs given a single oral 80 mg dose. The ratio of the area under the plasma concentration-time curves for (-):(+)-propranolol, and for (-):(+)-propranolol glucuronide were 1.4 and 3.4, respectively, in man, and averaged 0.5, and 3.1, respectively, in dogs.

Animals↗
PubMedDate not supplied

Effects of propranolol on the disposition and negative dromotropic activity of diltiazem in the dog during multiple dosing.

The effects of propranolol coadministration on the disposition and negative dromotropic action of intravenous and oral diltiazem were studied in six dogs after 3 days pretreatment with diltiazem alone (2.5 mg/kg, every 8 hr) and with coadministration of oral propranolol (5 mg/kg, every 8 hr). Diltiazem and two of its metabolites, desacetyldiltiazem and demethyldiltiazem, were measured by HPLC. Propranolol coadministration had no significant effects on either the systemic clearance, the apparent volume of distribution, elimination half-life, or the blood binding of diltiazem. On the other hand, the oral clearance of diltiazem was significantly reduced by 51%, and its oral bioavailability was significantly increased by 48% during propranolol coadministration. The area under the plasma demethyldiltiazem concentration-time curve after oral diltiazem increased significantly during propranolol coadministration. This increase was in proportion to the increase in the plasma diltiazem area under the concentration-time curve, such that the ratio of the areas of demethyldiltiazem to that of diltiazem remained the same between control and propranolol coadministration. Propranolol coadministration increased the area under the negative dromotropic activity-time curve after both intravenous and oral diltiazem by 37 and 48%, respectively. Using a log-linear pharmacodynamic model to analyze the data, there were no significant effects on either the slope, y-intercept, or the estimated diltiazem concentration needed to increase the PR interval by 20% of either intravenous or oral diltiazem with propranolol coadministration. These data suggest that propranolol coadministration can result in an increase in the pharmacological activity of diltiazem due to a kinetic drug interaction by increasing its oral bioavailability.

Administration, Oral↗
PubMed1997

Pharmacokinetics of propranolol in healthy cats during euthyroid and hyperthyroid states.

OBJECTIVE: To examine the pharmacokinetic profile of propranolol in cats before and during experimentally induced hyperthyroidism. ANIMALS: 8 conditioned, random-source, young adult, female cats. PROCEDURE: Propranolol was administered i.v. as a single bolus and 72 hours later by mouth. Thereafter, the cats were dosed for 5 weeks with L-thyroxine (50 micrograms/kg of body weight, s.c., once daily) to induce hyperthyroidism (serum thyroxine concentration, 217 +/- 17 nmol/L). Blood samples were obtained at appropriate intervals before and during hyperthyroidism and were analyzed for plasma propranolol concentration by use of high-performance liquid chromatography. RESULTS: In all cats, a two-compartment model best described the control and hyperthyroid intravenous data. The change in thyroid status from euthyroid to hyperthyroid caused a significant (P < 0.05), but small reduction in propranolol area under the curve (19,932 +/- 7,900 min.micrograms/L vs 15,911 +/- 1,400 min.micrograms/L) after i.v. administration. In contrast, after oral administration during the hyperthyroid state, a twofold increase (P < 0.05) in propranolol area under the curve (105,430 +/- 57,600 min.micrograms/L vs 226,811 +/- 112,000 min.micrograms/L) and peak serum propranolol concentration (651 +/- 247 micrograms/L vs 1191 +/- 590 micrograms/L) were attributed to significant (P < 0.05) increase in propranolol bioavailability caused by increased fractional absorption (57 +/- 28% vs 137 +/- 73%) and decreased total body clearance (58 +/- 27 ml/min/kg vs 30 +/- 19 ml/min/kg). Mean arrival time after oral dosing was significantly lengthened by hyperthyroidism (100 +/- 38 minutes vs 157 +/- 71 minutes). CLINICAL RELEVANCE: Hyperthyroidism-induced changes in propranolol pharmacokinetics may signal the need to reduce doses of propranolol when they are orally administered to hyperthyroid cats.

Administration, Oral↗
PubMed1997

[The effect of hypolipemic treatment on the pharmacokinetics of propranolol].

The influence of elevated concentration of lipids in blood on the concentration of drugs in organism was observed in 1976. The following experiments have revealed that pharmacokinetics of lipophilic drugs in hyperlipidemia is altered. The purpose of this paper was to evaluate the effect of hypolipemic treatment on the propranolol pharmacokinetics, to take into account phenotype of hydroxylation and type of primary hyperlipidemia. The study was carried out on 37 patients (34 patients EM and 3 patients PM) with hypercholesterolemia, hypertriglyceridemia and mixed form of hyperlipidemia. Duration of hypolipemic therapy was 30 days. Pharmacokinetic studies were carried out twice i.e. at the onset of the study and following a 30-day period of hypolipemic treatment. Propranolol was given orally as a single dose 80 mg. Blood serum was sampled during administration. HPLC method was used to determine blood serum concentration of propranolol. The one-compartment model was applied for calculation of pharmacokinetic parameters. The obtained results have disclosed that hypolipemic therapy altered pharmacokinetic parameters of propranolol. Intensity and course of these changes depend on the type of hyperlipidemia. The most pronounced changes were observed in patients EM with hypertriglyceridemia. Lowering of propranolol concentration in blood, elevated penetration into tissues and accelerated elimination were revealed (Fig. 3, 4). Similar changes, but lesser intensity were observed in patients with mixed form of hyperlipidemia (Fig 5, 6). Alteration of pharmacokinetic parameters of propranolol in hypercholesterolemic patients were slight and contrasting the patients with hypertriglyceridemia and mixed form of hyperlipidemia. The lowering of cholesterol concentration in blood has slight influence on normalization of propranolol kinetics (Fig 1, 2). In patients with phenotype PM pharmacokinetic parameters of propranolol were changed, under used treatment too. Due to the limited number of patients, conclusions should be carefully drawn. The actual results have disclosed a decrease in lipids concentration, mainly triglycerides, which causes changes in pharmacokinetics of propranolol in patients with phenotype PM as well.

Administration, Oral↗
PubMed1998

Effects of intravenous propranolol on human ventricular strength interval curves.

BACKGROUND: Prior studies on the effects of propranolol on human ventricular refractoriness have yielded occasionally inconsistent results. Most prior studies have examined refractory periods at a single stimulus intensity and without using continuous pacing; thus, the effects of propranolol on repolarization may have not been completely defined. The purpose of the present study was to reevaluate the effects of beta blockade on the human ventricular effective refractory period. METHODS: Strength-interval curves were performed in duplicate in a group of 10 patients to demonstrate their reproducibility. Strength-interval curves were performed before and after intravenous propranolol administration in a second group of 10 patients who had no evidence of structural heart disease. RESULTS: Propranolol increased the absolute refractory period from 208 +/- 9 milliseconds to 212 +/- 10 milliseconds (p = 0.01). However, propranolol decreased the coupling interval at which the strength-interval curve began to show an increase in the stimulus intensity required for capture from 236 +/- 8 milliseconds to 232 +/- 9 milliseconds. This resulted in a decrease of the width of the strength-interval curve from 28.0 +/- 5.1 milliseconds to 20.4 +/- 5.5 milliseconds (p < 0.005). Propranolol also significantly increased the slope of a logarithmic fit of the strength-interval curves. CONCLUSION: Propranolol exerts complex effects on human ventricular refractoriness. Propranolol decreases the width and increases the slope of human strength-interval curve, rather than increasing or decreasing the refractory period. These results have potential implications for antiarrhythmic effects of propranolol.

Adrenergic beta-Antagonists↗
PubMed1997

A comparison of divalproex with propranolol and placebo for the prophylaxis of migraine without aura.

OBJECTIVE: To compare the efficacy of divalproex sodium (Depakote) with that of propranolol hydrochloride (and placebo) for the prophylaxis of migraine without aura. DESIGN: Single-investigator, randomized, single-blind, placebo-controlled study with 5 phases: baseline (weeks 1-4); placebo (weeks 5-8); first treatment, 1 agent (weeks 9-20); washout (weeks 21-24); and second treatment, crossover to other agent (weeks 25-36). SETTING: Private practice of a general neurologist with a special interest in headache disorders. PATIENTS: Of 37 patients (30 women and 7 men) selected, 32 completed the study. All received placebo, after which half were randomized to receive divalproex or propranolol, then crossed over after washout. INTERVENTION: Divalproex and propranolol doses were titrated during the initial 8 weeks of each 12-week treatment cycle. For divalproex, doses were titrated to 1500 mg/d in 23 patients, to 2000 mg/d in 2, and downward in 7; the mean valproate sodium trough level was 68.5 mg/L. Propranolol was titrated to 180 mg/d in 28 patients, to 240 mg/d in 1, and downward in 3. RESULTS: Migraine frequency was reduced in 19% (6/ 32) of placebo-treated, 66% (21/32) of divalproex-treated, and 63% (20/32) of propranolol-treated patients. Assessment of migraine-days per month revealed significant response to placebo in 22% (7/32) of patients, to divalproex in 66% (21/32), and to propranolol in 69% (22/32). When results were limited to the third month of each active-agent treatment phase, 75% (24/ 32) of patients receiving divalproex and 78% (25/32) of those receiving propranolol had reduction in migraine frequency. CONCLUSION: No significant difference was identified between divalproex and propranolol for the prophylaxis of migraine without aura.

Adolescent↗