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PubMed1984

Comparative effects of propranolol, timolol and metoprolol on myocardial infarct size after experimental coronary artery occlusion.

The effects of equiblocking doses of three beta-adrenergic blocking agents, propranolol, timolol and metoprolol, on myocardial infarct size were evaluated in 28 dogs after acute experimental coronary artery occlusion. Heart rate, arterial pressure and arterial free fatty acid concentration were measured in an attempt to evaluate their effects on the extent of myocardial injury. The zone at risk of infarction in each dog 1 minute after left anterior coronary artery occlusion was assessed by injecting highly radioactive albumin microspheres into the left atrium, and the hypoperfused zone was determined by autoradiography. After 15 minutes, the dogs were randomized into four groups: control dogs (n = 7), propranolol-treated dogs (1.2 mg/kg intravenously, n = 7), timolol-treated dogs (0.2 mg/kg intravenously, n = 7) and metoprolol-treated dogs (1.2 mg/kg intravenously, n = 7). After 6 hours, the dogs were killed. The left ventricle was sliced and stained with triphenyl-tetrazolium chloride for measurement on infarct size. The same slices were then autoradiographed for measurement of the hypoperfused zone. The percent of hypoperfused zone that evolved to infarction (the ratio of infarct size to hypoperfused zone) was 90.4 +/- 1.9% in the control group, 72.4 +/- 2.4% in the propranolol-treated dogs (p less than 0.05 versus control group); 57.9 +/- 4.4% in the timolol-treated dogs (p less than 0.01 versus control group; p less than 0.05 versus propranolol) and 54.4 +/- 3.7% in the metoprolol-treated dogs (p less than 0.01 versus control group; p less than 0.05 versus propranolol). Thus, propranolol, timolol and metoprolol reduced myocardial infarct size in dogs by 20, 36 and 40%, respectively, after experimental coronary artery occlusion. Metoprolol and timolol protected the ischemic myocardium more effectively than did propranolol.

Animals↗
PubMed1985

Double-blind crossover comparison of the antianginal effects of nifedipine and isosorbide dinitrate in patients with exertional angina receiving propranolol.

A double-blind crossover study was performed on 27 patients with proved fixed coronary artery disease and stable angina pectoris. The study was designed to compare the relative efficacy of two combination therapies, nifedipine plus propranolol and isosorbide dinitrate plus propranolol, in terms of antianginal response and effect on exercise tolerance by evaluation of treadmill testing. The combination of nifedipine and propranolol was superior to the combination of isosorbide and propranolol in reducing the number of anginal attacks (p = 0.03), increasing total exercise time (p less than 0.02), increasing oxygen consumption achieved at end of exercise (p less than 0.03), increasing time to onset of pain (p = 0.003) and increasing oxygen consumption achieved at onset of pain (p = 0.003). Analysis of the rate-pressure products suggests that the difference in these results may be explained by the greater effect of nifedipine on afterload reduction. Although nitroglycerin consumption was reduced from baseline levels during combination nifedipine therapy (p less than 0.001), there was no statistical difference between nifedipine combination therapy and isosorbide combination therapy. In conclusion, although both combination therapies were superior to propranolol therapy alone, the combination of nifedipine and propranolol was more effective than the combination of isosorbide and propranolol in reducing the incidence of angina and improving exercise performance. Side effects were experienced at a similar frequency during both combination therapies.

Adult↗
PubMed2001

Modulation by propranolol of the uptake of ethidium bromide by rat submandibular acinar cells exposed to a P2X(7) agonist or to maitotoxin.

We have compared the formation of pores in rat submandibular acinar cells in response to 2',3'-O-(4-benzoylbenzoyl) adenosine 5'-triphosphate (Bz-ATP) and maitotoxin. Bz-ATP (100 microM) permeabilized the cells to ethidium bromide. The uptake of ethidium increased to 29+/-1% of maximal uptake in 10 min. DL-Propranolol (300 microM) inhibited the Bz-ATP-induced uptake of ethidium bromide by 40% without affecting the P2X(7)-gated cation channel. The inhibitory effect of DL-propranolol on the formation of pores by Bz-ATP was reproduced by D-propranolol, an optical isomer with very poor beta-blocking activity. Tenidap, an antiinflammatory drug, enhanced the permeabilization in response to Bz-ATP. Propanolol inhibited the response to tenidap plus Bz-ATP. The effect of propranolol was reproduced by labetolol, a beta-adrenergic antagonist with membrane-stabilizing properties, but not by atenolol, which blocks beta-adrenergic receptors but has no effect on the stability of the membrane. In the presence of extracellular calcium, maitotoxin also increased the uptake of ethidium bromide. Tenidap had no effect on this response, which was delayed by propranolol. In conclusion, we have shown that propranolol, in a range of 10-300 microM, inhibits the pore-forming activity of the P2X(7) receptor without affecting the opening of the cation channel coupled to this receptor. This inhibition is not related to its beta-adrenergic blocking activity but rather to its membrane-stabilizing properties. Propranolol also delays the uptake of ethidium bromide in response to maitotoxin. This is in agreement with the current view that P2X(7) agonists and maitotoxin share a common pore.

Adenosine Triphosphate↗
PubMed2003

A multicenter randomized crossover multiple-dose comparison study of arotinolol and propranolol in essential tremor.

BACKGROUND: A new medication is needed to treat essential tremor. Preliminary evidence suggests that arotinolol may be effective in the treatment of this disorder. OBJECTIVE: To study the effect of arotinolol and propranolol in a crossover, multiple dose comparative trial of patients with essential tremor. PATIENTS AND METHODS: One hundred and seventy-five outpatients, with essential tremor were included in the study; 161 patients completed the study. Patients were identically evaluated at eight consecutive visits. The study consisted of two treatments, which were arranged according to a crossover design that evaluated the dose of each (arotinolol 10 mg per day and propranolol 40 mg per day, arotinolol 20 mg per day and propranolol 80 mg per day, arotinolol 30 mg per day and propranolol 160 mg per day). Each course of treatment lasted 6 weeks. Major outcome evaluations consisted of a self-reported disability scale, and motor performance score obtained before drug intake and 14 days after each treatment. The treatment effects were evaluated by analysis of variance using the Hills-Armitage test. RESULTS: Arotinolol was found to be as effective as propranolol at reducing tremor. Drug effects as evaluated using motor-task performance scores revealed that arotinolol had a more significant effect than propranolol. CONCLUSIONS: Arotinolol may be more useful than propranolol for the treatment of essential tremor.

Adrenergic beta-Antagonists↗
PubMed2005

Use of the chiral pharmaceutical propranolol to identify sewage discharges into surface waters.

The discharge of relatively small volumes of untreated sewage is a source of wastewater-derived contaminants in surface waters that is often ignored because it is difficult to discriminate from wastewater effluent. To identify raw sewage discharges, we analyzed the two enantiomers of the popular chiral pharmaceutical, propranolol, after derivitization to convert the enantiomers to diastereomers. The enantiomeric fraction (the ratio of the concentration of one of its isomers to the total concentration) of propranolol in the influent of five wastewater treatment plants was 0.50 +/- 0.02, while after secondary treatment it was 0.42 or less. In a laboratory study designed to simulate an activated sludge municipal wastewater treatment system, the enantiomeric fraction of propranolol decreased from 0.5 to 0.43 as the compound underwent biotransformation. In a similar system designed to simulate an effluent-dominanted surface water, the enantiomeric fraction of propranolol remained constant as it underwent biotransformation. Analysis of samples from surface waters with known or suspected discharges of untreated sewage contained propranolol with an enantiomeric fraction of approximately 0.50 whereas surface waters with large discharges of wastewater effluent contained propranolol with enantiomeric fractions similar to those observed in wastewater effluent. Measurement of enantiomers of propranolol may be useful in detecting and documenting contaminants related to leaking sewers and combined sewer overflows.

Chromatography, Gas↗
PubMed1984

The 3,4-catechol derivative of propranolol, a minor dihydroxylated metabolite.

The O,O-dibenzyl ether of the 3,4-catechol derivative of propranolol (11) was prepared to determine whether the catechol is a product of metabolic hydroxylation. 4-(Allyloxy)-1,2-naphthoquinone (5) was reduced with sodium dithionite and alkylated with benzyl chloride to produce ether 7. Osmium tetroxide oxidation of 7 afforded glycol 8. Subsequent monotosylation, oxirane formation with KOH, and opening with isopropylamine afforded benzyl ether 11. Although hydrogenolysis was successful, catechol 3 was rapidly oxidized to the corresponding o-quinone (12). Reduction of 12 with sodium bisulfite afforded 3, which was derivatized with N,O-bis(trimethylsilyl)trifluoroacetamide (BSTFA) to serve as a standard for the metabolic experiments. Gas chromatography-mass spectrometry of the Me3Si ethers of the products of metabolism of pseudoracemic propranolol (made up of equal molar (2R)-propranolol-d0/(2S)-propranolol-3',3'-d2) in the presence of the rat liver 9000g supernatant fraction showed four dihydroxylated metabolites, of which catechol 3 was in smallest amount, approximately 9% of the sum of dihydroxylated metabolites. Each of the four dihydroxylated propranolols arises stereoselectively from the 2R enantiomer of propranolol (by 1.15- to 2-fold), as determined by parent ion intensities at m/z 507 vs. 509. Quinone 12 was a nonselective competitive beta-adrenoceptor antagonist, being about 16-fold less potent than propranolol in both beta 1 and beta 2 assays.

Animals↗
PubMed1999

Synthesis, stereoselective enzymatic hydrolysis, and skin permeation of diastereomeric propranolol ester prodrugs.

Four diastereomeric propranolol ester prodrugs (1S2S, 1S2R, 1R2S, 1R2R) were synthesized by treating pure R- and S-propranolol hydrochloride with pure enantiomers R- and S-phenylbutyryl chloride. A HPLC technique using alpha-1 acid glycoprotein (chiral AGP) column was developed to study the racemization of propranolol enantiomers during synthesis and hydrolysis studies. A reversed phase HPLC method was also developed to simultaneously analyze propranolol and the ester prodrug. Hydrolysis of these esters was studied in different rat tissue homogenates, i.e., liver, intestine, plasma, skin, brain, and pure plasma cholinesterases, i.e., butyryl cholinesterase (EC 3.1.1.8) and acetyl cholinesterase (EC 3.1.1.7). In vitro percutaneous permeation studies across full thickness shaved rat skin were performed using standard side-by-side diffusion cells at 37 degrees C. The disappearance of the diastereomeric ester prodrugs in rat tissue homogenates followed apparent first-order kinetics and was stereoselective. The ratio of brain to plasma hydrolytic rate constants are 27.8, 5.58, 6.07, and 2.97 for 1S2S, 1R2R, 1R2S, and 1S2R esters, respectively. Hydrolysis of all four diastereomeric ester prodrugs was faster by acetyl cholinesterase than butyryl cholinesterase and is stereoselective. The permeability coefficients [Kp x 10(3) (cm h-1)] are 1.40 +/- 0.30, 1.41 +/- 0.27, 42.20 +/- 1.24, 29.26 +/- 3.41, 16.27 +/- 3.12, 12.99 +/- 2.84 for (R)-propranolol, (S)-propranolol, 1S2S, 1R2S, 1S2R, and 1R2R ester prodrugs, respectively. The results indicate that the 1R2S diastereomeric ester prodrug of propranolol shows greatest stability in liver and intestinal tissues while it exhibits fairly rapid conversion in plasma. The results also suggest the configuration on the second chiral carbon atom to be the determinant in the rate of hydrolysis of all the diastereomeric prodrugs in all biological media examined. The Kp of all four prodrugs markedly increased compared to that of the parent drug, with 1S2S showing a 30-fold increase in skin permeability, the highest among all four prodrugs.

Adrenergic beta-Antagonists↗
PubMed1980

Effects of thyroid dysfunction on propranolol kinetics.

Propranolol kinetics was studied in six hyperthyroid and six hypothyroid patients who received single oral and intravenous doses of propranolol when they had thyroid dysfunction and again when they had become euthyroid. Change in thyroid status from hyperthyroid to euthyroid produced no change in the elimination half-life (t 1/2) of oral propranolol (3.2 +/- 0.5 to 4.1 +/- 0.7 hr), the oral clearance (38.4 +/- 7.3 to 27.4 +/- 2.4 ml/min/kg), the elimination t 1/2 of intravenous propranolol (2.5 +/- 0.3 to 3.5 +/- 0.7 hr), and the apparent volume of distribution (4.8 +/- 0.4 to 3.8 +/- 0.5 l/kg). The systemic clearance of propranolol, however, was greater when the patients were hyperthyroid (20.8 +/- 2.5 ml/min/kg) than when they had become euthyroid (11.7 +/- 1.7 ml/min/kg). The elimination t 1/2 after oral propranolol was longer in the hypothyroid (3.7 +/- 0.5 hr) than in the euthyroid state (2.0 +/- 0.1 hr). No other changes were observed in the kinetic parameters measured when these hypothyroid patients had become euthyroid. Adequate beta-adrenoceptor blockade in hyperthyroid patients may require higher propranolol dosage than expected.

Adult↗
PubMed1980

Kinetic and clinical observations in cyanotic children on propranolol therapy.

The kinetics of propranolol and its metabolite 4-hydroxypropranolol were determined together with heart rate and blood pressure responses in five cyanotic children on long-term propranolol therapy and after abrupt withdrawal. The daily dose range of propranolol was 2.4 to 4.4 mg/kg. Mean steady-state plasma propranolol concentrations, 16.5 to 114 ng/ml, were linearly related to dose (r = 0.93; p < 0.02) above a threshold dose of 1.8 mg/kg/day. There was excellent correlation (r = 0.96; p = 0.01) between concentrations and reduction in heart rate (delta HR, 14 to 27.5 beats/min), which also suggested a maximum heart rate response at plasma propranolol concentrations of 80 to 100 ng/ml. There was an inverse relationship between the plasma concentrations of 4-hydroxypropranolol and dose. On abrupt withdrawal of long-term propranolol therapy, plasma levels declined with a propranolol half-life (t1/2) of 3.9 to 6.4 hr, which correlated with the hemoglobin value. The 4-hydroxypropranolol t1/2 was 5.2 to 7.5 hr. Heart rates returned to normal after approximately 36 hr. Changes in blood pressure were minimal.

Child↗
PubMed1980

Effect of propranolol on plasma norepinephrine during sodium nitroprusside-induced hypotension.

The possibility of an action of propranolol which reduces traffic in the sympathetic nervous system and/or reduces release of norepinephrine at sympathetic nerve endings has been investigated in normal subjects. Plasma norephinephrine was measured in resting supine subjects before and during infusions of sodium nitroprusside which reduced the systolic blood pressure by approximately 10 and later by 20 mm Hg. In 5 subjects these observations were repeated 2 hr after a single 200-mg oral dose of propranolol and in 3 they were repeated after 2 to 8 wk of propranolol 320 mg twice daily. In the control experiments, plasma norepinephrine increased from 0.22 up to 0.74 ng/ml when the blood pressure was reduced by 17/15 mm Hg. Corresponding figures 2 hr after 200 mg propranolol were an increase of plasma norepinephrine from 0.30 or 0.79 ng/ml with a reduction of blood pressure of 19/15 mm Hg. After long-term treatment with 640 mg propranolol daily, a similar reduction of pressure with sodium nitroprusside increased plasma norepinephrine from 0.24 to 0.68 ng/ml. There was no significant alteration in the elevation of plasma norepinephrine following blood pressure reduction with nitroprusside after either short- or long-term treatment with propranolol. These experiments do not suggest a significant role for a nervous system effect of propranolol in modifying sympathetic activity.

Adult↗
PubMed1981

Propranolol and sotalol as antagonists of isoproterenol-enhanced physiologic tremor.

Six normal subjects were studied after graded bolus injections of isoproterenol. Log dose-response curves for increases in both heart rate (mostly beta 1), and amplitude of physiologic tremor (beta 2) were constructed for each subject in the control state and 2 hr after 10 or 40 mg propranolol, 200 mg sotalol, or placebo. All heart rate curves were shifted to the right in an approximately parallel fashion by all active treatments (40 mg propranolol greater than 200 mg sotalol greater than 10 mg propranolol). The tremor curve was also shifted to the right by 10 mg propranolol in an approximately parallel fashion and to the same extent as the heart rate curve (both dose-ratios = 6.1), but the tremor curves after both 40 mg propranolol and 200 mg sotalol appeared to be flattened as well as shifted laterally. We conclude that whereas it may be possible that 10 mg propranolol acts as a competitive antagonist of isoproterenol at beta 2-sites in skeletal muscle, 40 mg propranolol and 200 mg sotalol must have additional actions in reducing isoproterenol tremor. The possibilities are discussed.

Administration, Oral↗
PubMed1981

Plasma propranolol before, during, and after cardiopulmonary bypass.

We evaluated changes in propranolol plasma levels before, during, and after cardiopulmonary bypass (CPB). Two groups of patients were studied, all of whom had been on long-term propranolol and had received their last oral dose 10 to 15 hr before surgery. Approximately 100 min before CPB began group 1 patients (n = 7) received 0.1 mg/kg propranolol intravenously while group II patients (n = 7) received a placebo. Before CPB the plasma propranolol levels fell in accordance with published descriptions for nonsurgical patients receiving oral and intravenous propranolol. Thereafter, the changes in the plasma levels were much the same in both groups. With the onset of CPB, the plasma levels decreased by approximately 50%. There was an insignificant fall in plasma levels during CPB, but the most interesting observation was made after : in each patient, the plasma levels obtained 5, 60, 120, and 240 min after CPB were higher than the last level during CPB. Mean plasma levels did not decline in either group during the 4-hr period. Although the reason for the sustained rise in the propranolol levels after CPB is not known, we suggest that it is due to the redistribution of propranolol from the lungs of the plasma coupled with reduction in hepatic elimination.

Administration, Oral↗
PubMed1984

Propranolol disposition after acute myocardial infarction.

Serum propranolol concentration, elimination t 1/2, and protein binding were studied after a combined intravenous/oral regimen in 20 subjects with myocardial infarction (MI) and 15 with chest pain (CP). There was 1000% interindividual variation in propranolol concentrations in each group. In the MI group, mean total serum propranolol concentrations were greater than 100 nmol/l, except at 7 hr, when there was a trough not present in subjects with CP. Mean elimination t 1/2 s in subjects with MI (7.2) and CP (7.4 hr) did not differ. There were significantly higher alpha 1-acid glycoprotein concentrations and reduced percent unbound propranolol 27 hr after infarction. Free propranolol concentrations were lower 7 and 11 hr after dosing in the MI group, but concentrations thereafter were of the same order as those in subjects with CP. The only significant difference in any of the hemodynamic measurements was at 7 hr, when blood pressure was higher in the MI group. We conclude that propranolol kinetics were altered in subjects with MI and suggest that the regimen could be improved by increased propranolol dosage at commencement of therapy.

Administration, Oral↗
PubMed1984

Propranolol interactions with diazepam, lorazepam, and alprazolam.

Healthy subjects received single doses of diazepam (5 to 10 mg iv), lorazepam (2 mg iv), or alprazolam (1 mg orally) on two occasions, once in the control state and once with propranolol, 80 mg three times a day. Compliance with the propranolol regimen was verified by measurement of serum propranolol levels (overall means: 100 ng/ml) and by reduction in sensitivity to intravenous metaproterenol to one-thirtieth that of the control value. Propranolol prolonged diazepam elimination t1/2 (58 and 49 hr), reduced its clearance (0.20 and 0.24 ml/min/kg), and increased the 168-hr AUC for desmethyldiazepam, the major metabolite of diazepam (5.63 and 4.81 micrograms/ml . hr). Propranolol had no significant effect on lorazepam t1/2 (13.2 and 12.7 hr) or clearance (1.33 and 1.36 ml/min/kg), nor on alprazolam t1/2 (15.9 and 18.5 hr) or clearance (1.1 and 0.8 ml/min/kg). Thus propranolol induces a small but significant reduction in clearance of diazepam, biotransformed mainly by the oxidative reaction of N-demethylation. Propranolol does not impair lorazepam clearance by glucuronide conjugation nor that of alprazolam by aliphatic hydroxylation.

Adolescent↗
PubMed1984

Mechanism by which hydralazine increases propranolol bioavailability.

Five healthy subjects were given oral 14C-propranolol (10 microCi, 40 mg) alone and in combination with hydralazine, 25 and 50 mg. Hydralazine increased propranolol peak concentrations from 25 +/- 7 ng/ml to 61 +/- 10 and 85 +/- 11 ng/ml, reduced time to peak concentrations from 2.2 +/- 0.2 hr to 0.7 +/- 0.1 and 0.8 +/- 0.1 hr, and increased area under the propranolol concentration: time curves from 153 +/- 38 ng X ml-1 X hr to 246 +/- 64 and 324 ng X ml-1 X hr (in all cases P less than 0.05). Hydralazine did not change the fraction of the 14C-propranolol dose recovered in the urine as basic, acidic, and polar metabolites: 0.28 +/- 0.2, 0.27 +/- 0.03, and 0.44 +/- 0.03. The urinary excretion rate of radioactive metabolites of propranolol in acid, basic, and residue fractions increased in the 0 = to = 2-hr time interval after hydralazine but there was no change in the relative proportion of each metabolite fraction at any time. Similar results were obtained by HPLC. Studies with radioactive propranolol indicate that a major acid and basic metabolite remains to be defined in addition to unextracted polar metabolites. Our data indicate that hydralazine increases propranolol bioavailability by its hemodynamic actions rather than by inhibition of its metabolism.

Administration, Oral↗
PubMed1987

The interactions of propranolol and ketanserin.

Ten healthy volunteers received a single 10 mg intravenous dose of the 5-hydroxytryptamine-2 serotonin antagonist ketanserin in the control state and again during coadministration of propranolol, 80 mg b.i.d. There were no differences between control and propranolol treatment conditions in ketanserin volume of distribution (5.2 vs. 3.8 L/kg), elimination half-life (6.6 vs. 4.7 hours), clearance (9.7 vs. 10.0 ml/min/kg), or 72-hour excretion of intact ketanserin (0.7% vs. 0.7% of dose) or ketanserinol (21.8% vs. 24.9% of dose). In a second study, eight volunteers received a 160 mg oral dose of propranolol hydrochloride in the control state and again during treatment with ketanserin, 40 mg b.i.d. There were no significant differences between control and ketanserin conditions in the time of peak serum propranolol concentration (2.1 vs. 1.5 hours after dosage) or elimination half-life (3.8 vs. 4.1 hours). However, ketanserin increased peak serum propranolol concentrations (169 vs. 233 ng/ml) and reduced oral clearance (39 vs. 27 ml/min/kg); the differences were not statistically significant (0.05 less than P less than 0.1) with a sample size of eight. Thus therapeutic doses of propranolol in healthy volunteers do not alter the kinetics of a single dose of ketanserin. Therapeutic doses of ketanserin may impair oral clearance of propranolol, leading to increased area under the serum concentration curve and higher peak serum levels.

Adult↗
PubMed1988

Pharmacokinetic and pharmacodynamic interactions between nisoldipine and propranolol.

The pharmacokinetic and pharmacodynamic effects of nisoldipine, a 1,4-dihydropyridine calcium entry blocker, and the lipophilic beta-adrenoceptor blocker propranolol were assessed alone and in combination in 12 healthy men. Oral nisoldipine, 20 mg, or placebo was followed 1 hour later by propranolol, 40 mg, or placebo using a randomized, crossover, double-blind design. Nisoldipine significantly increased the AUC (+43%) and peak plasma drug concentration (Cmax) (+68%) of propranolol resulting in a higher degree of beta-adrenoceptor blockade (as assessed by isoproterenol). Conversely, nisoldipine's AUC (+30%) and Cmax (+57%) were increased with concomitant administration of propranolol. Nisoldipine did not affect blood pressure but caused significant decrease in total peripheral resistance (TPR) and increases in plasma catecholamines and cardiac index. Forearm vascular resistance and blood flow changed more markedly than did TPR and cardiac index. In contrast, propranolol had little effect on forearm hemodynamics despite significant decreases in cardiac index and increases in TPR. The data are compatible with changes in hepatic blood flow, accounting for the pharmacokinetic interaction of nisoldipine and propranolol. Different vascular beds appear to contribute to the effects of nisoldipine vs. propranolol on peripheral resistance.

Adult↗
PubMed1990

Pharmacodynamics of propranolol on left ventricular function: assessment by Doppler echocardiography.

The relationship of left ventricular systolic function and heart rate to serum l-propranolol concentrations was determined in 10 healthy male volunteers during maximal exercise treadmill testing. Peak aortic blood flow acceleration (ACL), measured by Doppler ultrasonography, was used to evaluate left ventricular systolic function. Repeated exercise testing was performed on two separate days after long-term oral administration of 40 mg propranolol or placebo every 6 hours in a randomized, double-blind, crossover fashion. Pharmacodynamic relationships were determined by fitting percent change in ACL and heart rate at maximal exertion with 1-propranolol with the Emax model (maximal effect) and nonlinear regression. Reductions in systolic function and heart rate during exercise were related directly to 1-propranolol. Propranolol was significantly (p less than 0.05) more potent in reducing heart rate (EC50, 10.6 +/- 9.2 ng/ml) compared with ACL (EC50, 19.2 +/- 8.9 ng/ml). However, Emax of propranolol for reducing ACL was significantly greater than that for reducing heart rate (-46.7% +/- 6.9% versus -29.5% +/- 15.9%; p less than 0.05). These data indicate that the concentration-effect relationship for 1-propranolol and its negative inotropic effect differ from its negative chronotropic effect.

Adult↗