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PubMed1989

Randomized controlled study of propranolol for prevention of recurrent esophageal varices bleeding in patients with cirrhosis.

A randomized controlled trial of propranolol was conducted in 36 adult cirrhotic patients after active esophageal variceal hemorrhage had been controlled. Seventy-eight percent of the 18 patients on propranolol and 72% of the patients on a placebo were of Pugh's class A. Of the patients treated with propranolol, 94%, 87%, 68% and 57% were free from rebleeding 6, 12, 18 and 24 months after entry, respectively. The corresponding figures in control patients were 81%, 59%, 30% and 15%, respectively. The percentages of patients free from rebleeding were significantly higher in the propranolol group than in the control group (P less than 0.05). No significant adverse effect was observed during the study, except for a patient who developed hepatic decompensation 14 months after propranolol therapy. It was concluded that propranolol was a safe and effective drug for the prevention of variceal rebleeding in patients with good liver functional reserve.

Adult↗
PubMed1982

Effect of propranolol on myocardial cell necroses and blood levels of catecholamines in pigs subjected to stress.

The degree of myocardial cell necroses in pigs exposed to stress induced by a myorelaxant (succinylcholine) for about 12 min. was investigated. The Beta-adrenoceptor block propranolol was given in varying doses prior to the induced stress. The degree of necroses in these pigs was evaluated according to a point scale, ranging from 0 to 6 points, and compared with the changes found in untreated controls following stress. The blood levels of noradrenaline and adrenaline were assayed before, during an immediately after the period of stress. No protective effect of propranolol on the cardiac lesions was found when the drug was administered intravenously in a single dose of either 1 mg or 3 mg per kg. During the period of stress the blood levels of noradrenaline were high, indicating a high degree of activity in the sympatho-adrenal system. Propranolol in a single dose of 10 mg per kg intravenously reduced the number and size of heart lesions, while the blood levels of the catecholamines were lower under stress than after administration of 1 and 3 mg propranolol. After oral treatment with propranolol, 120 mg three times a day for 6 or 7 days, an almost complete absence of heart cell necrosis after the stress was obtained. The activity of the sympatho-adrenal system was elevated, as reflected by the high blood levels of catecholamines. The results indicate that stress-induced heart cell necrosis is mediated via the activity of the sympatho-adrenal system. The difference between a single and repeated doses of propranolol in protecting the heart suggests a complex of the adrenergic Beta-receptor blocker.

Animals↗
PubMed1981

Effect of extracellular potassium on the loss of potassium from human red blood cells treated with propranolol.

The Ca++-dependent propranolol-induced increase of K+ permeability of human red blood cells, well documented in previous studies, was found to depend on extracellular K+. This was shown by studying the passive transport of 86Rb and the loss of bulk cellular K+ in both K+-free and K+-containing media. The maximal effect of propranolol was achieved with 5-10 mM K+ in incubation media. The external K+ could be substituted with Tl+, but not with Na+. When added after propranolol, extracellular K+ failed to initiate the effect of propranolol on membrane permeability. The cell/medium distribution of permeant 204Tl showed that the propranolol-induced increase of K+ permeability did not result in considerable hyperpolarization of the red blood cell membrane. The data obtained seem to be more consistent with a counter-transport model for explaining the propranolol effect than with a mechanism based on free diffusion of K+ through the membrane.

Cell Membrane Permeability↗
PubMed1984

Interaction between propranolol and electron donors in altering the calcium ion-dependent potassium ion-permeability of the human red blood cell membrane.

Both propranolol and the electron donors ascorbate plus phenazine methosulfate increase the K+-permeability of the red blood cell membrane. The present investigation examined whether these effects were additive. Contrary to expectations, propranolol added after electron donors sharply inhibited the K+ (86Rb) efflux induced by such donors, without forming new K4 channels analogous to those induced by propranolol in intact red blood cells. The inhibitory effect of propranolol may be due to generalized disturbances of membrane structures necessary for the functioning of the K+ channels organized in the presence of reducing agents. In contrast, the electron donors added after propranolol caused a further stimulation of the 86Rb loss from the propranolol-treated red cells. The combined effect of these drugs therefore depends on the order of their addition. The possible mechanism of their interaction is briefly discussed.

Ascorbic Acid↗
PubMed1996

Effects of hypertension and propranolol upon aneurysm expansion in the Anidjar/Dobrin aneurysm model.

Propranolol has been suggested to slow aortic aneurysm (AAA) expansion by a mechanism independent of simple blood pressure (BP) reduction. To investigate this hypothesis, we designed a series of experiments to examine the effects of hypertension and propranolol upon AAA expansion. Using an established animal model, we induced AAA in normotensive and genetically hypertensive rats by perfusion of the isolated infrarenal aorta with elastase for two hours. Systolic tail BP was monitored with a plethysmograph. AAA size was measured directly with a micrometer on postoperative days 7 and 14. All data are expressed as the mean +/- standard deviation (SD). BP (mmHg) was significantly higher in hypertensive rats: 164 +/- 15 versus 119 +/- 7 (p < 0.001). AAA were also significantly larger in hypertensive rats with a mean expansion rate (mm/day) nearly twice that of normotensive animals: 0.13 +/- 0.09 versus 0.07 +/- 0.03. In a second series of animals, propranolol treatment was compared to placebo. In those animals, hypertensive propranolol-treated rats had significantly smaller AAA than placebo-treated controls (p < 0.05). There was no difference in normotensive animals but these rats had an unexplained paradoxical rise in BP with treatment. In this model, hypertension increases the expansion rate of AAA. Propranolol reduced the size of AAA in hypertensive animals, at least in part because of a decrease in BP. Other possible mechanisms of propranolol's action may be operative and require further study.

Adrenergic beta-Antagonists↗
PubMed1976

The treatment of glaucoma with propranolol (Inderal). A clinical trial.

The effect of propranolol (Inderal) on the intraocular pressure (IOP) in glaucoma has been measured. Twenty-two patients completed the clinical trial. Propranolol in doses of 160 mg/d effectively lowered IOP in eyes with various types of open angle glaucoma. The test periods lasted from 4 to 6 days. The ocular hypotensive effect of propranolol was also registered in patients efficiently treated with pilocarpine and acetazolamide (Diamox), and in glaucomas not satisfactorily controlled by this therapy. High positive correlations between mean pretreatment pressure (P1), and pressure fall (delta P) were found (P less than 0.001), and the pressure decrease induced by propranolol treatment tended to be proportional to the pressure gradient between the anterior chamber and the episcleral veins. This pressure gradient was reduced by an average of about 50% following propranolol treatment. There was no change in scleral rigidity after propranolol.

Aged↗
PubMed1985

Effect of age on the hepatic clearance of propranolol in rats.

The effect of age on hepatic clearance of propranolol was investigated in male Wistar rats (3 to 104 weeks old). Pharmacokinetic analysis of the plasma propranolol data obtained after i.v. dosage (1.0 mg kg-1) indicated that both the elimination rate constant and the volume of distribution decreased with age between weeks 5 and 11, after when the distribution volume remained almost constant. The elimination rate constant was reduced consistently with age after 15 weeks. Total body clearance of the drug was reduced extensively with age between weeks 5 and 11 (94 to 43 ml min-1 kg-1) and decreased gradually thereafter. The plasma free fraction of propranolol also decreased with age, falling from more than 20% in 3 to 5 weeks-old rats to about 10% in rats of 52 to 104 weeks. In immature rats the renal clearance was approximately 5 to 12% of the total body clearance. Intrinsic hepatic clearance for unbound propranolol also decreased with age between weeks 7 and 24. As expected from the evidence that propranolol has a high extraction ratio, the extent of its hepatic clearance was significantly dependent on the liver blood flow. These data suggest that the age-dependent decrease in hepatic clearance of propranolol is largely due to a reduction of the elimination rate that might be accompanied by the age-dependent decrease in liver blood flow.

Administration, Oral↗
PubMed1988

Buffer and pH effects on propranolol binding by human albumin and alpha 1-acid glycoprotein.

Propranolol binding to isolated human alpha-1-acid glycoprotein (AGP) and human albumin (HSA) was studied by equilibrium dialysis at 37 degrees C. With AGP (0.067%) and HSA (4%), total propranolol concentration was varied from 0.7 to 93,000 ng mL-1. Over this concentration range the percentage drug bound to HSA declined from 49 to 39% while that to AGP declined from 68 to 4%. Two classes of sites were identified on AGP with n1k1 = 8.50 X 10(4) M-1 and n2k2 = 3.12 X 10(4) M-1. With a pH 7.4 phosphate buffer, propranolol binding to AGP was greatest when the protein was initially dissolved in pH 7.4 water compared with pH 7.2 water or the phosphate buffer. Thus, the method of AGP solution preparation affected propranolol binding by this protein. For both AGP and HSA, greater drug binding was noted with phosphate buffers in comparison with a physiological buffer. With phosphate buffers, decreasing pH from 7.4 to 7.0 decreased propranolol binding by AGP, while decreasing pH from 7.7 to 7.4 had little effect. With HSA, the percent propranolol bound consistently decreased on lowering pH from 7.7 to 7.0.

Buffers↗
PubMed1989

The effect of Miglycol 812 oil on the oral absorption of propranolol in the rat.

This work has examined the effect of Miglyol 812 oil and its composite fatty acids on the oral absorption of propranolol with reference to its intravenous (i.v.) pharmacokinetics. Propranolol hydrochloride, spiked with 4-(3) H labelled compound, was administered i.v. or orally to male Wistar rats and blood concentrations of parent material determined by liquid scintillation counting after extraction into toluene. An i.v. dose-linearity study indicated dose-independent pharmacokinetics for propranolol at 1-2 mg kg-1, with a mean Cls, Vss, MRTi.v. and t0.5 beta of 0.076 L min-1 kg-1, 4.74 L kg-1, 57.81 min and 47.10 min, respectively. At 5 mg kg-1, there was evidence of non-linearity with MRTi.v. increased by about 250%, Vss by 170% and t0.5 beta by 230% compared with the lower doses. After oral administration of propranolol (10 mg kg-1) in aqueous solution, with or without Tween 80 (6%), the mean absorption time (MAT) and terminal half-life were approximately 55 min and 86 min, respectively. The MAT for propranolol administered in a 50% octanoic and lauric acid (1:1 by weight) oil-in-water emulsion, stabilized with 6% Tween 80 (129-90 min), was significantly longer compared with that for a 50% Miglyol 812 oil-in-water emulsion containing the same surfactant (16.55 min). The terminal half-life of propranolol administered in the fatty acid formulation (128.96 min), unlike that for the Miglyol emulsion (54-37 min), was significantly longer compared with that observed after i.v. administration (t0.5 beta = 47 min).(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1969

Treatment of hypertension with propranolol.

When used in the treatment of hypertension propranolol is at least of similar potency to bethanidine, guanethidine, and methyldopa. Propranolol does not produce postural or exercise hypotension and it seems that it is often more acceptable to patients than conventional drugs. It usually produces the best control of the supine blood pressure.A series of 109 hypertensive patients was treated with propranolol; in nine the drug was withdrawn. In 92 of the patients a supine or standing blood pressure of 100 mm. Hg or less was achieved. Eighty of the patients had previously been treated with other potent drugs, and close comparisons and prolonged follow-up in 17 patients showed that diastolic pressures of 100 mm. Hg or less were achieved in more patients after propranolol than with guanethidine, bethanidine, or methyldopa.Sensitivity to propranolol varies widely, and dosage should be increased gradually. The hypotensive effect often takes six to eight weeks to reach its maximum. Propranolol reduces cardiac output but may also act by reducing the cardiac component of pressor stimuli; as a result the baroreceptors gradually regulate the blood pressure at a lower level. It is contraindicated in patients with obstructive airways disease or in uncompensated heart failure.

Blood Pressure↗
PubMed1975

Effect of propranolol on left ventricular function, segmental wall motion, and diastolic pressure-volume relation in man.

Precise quantitation of the effects of the non-selective beta adrenergic blocking drug propranolol (3.15 mg/kg body weight) on left ventricular function, segmental wall motion, and diastolic pressure-volume relation in man has been performed. High fidelity left ventricular pressure measurements and simultaneous single-plane angiocardiograms were recorded on a video disc and volumes calculated by a light-pen computer system. Systolic segmental wall motion was computer analysed using the long axis-quadrasection method. Patients were transvenously atrially paced to maintain a constant heart rate. The haemodynamic effects of propranolol may vary depending upon the extent of pre-existing myocardial disease. In some patients ventricular function, as measured by ejection fraction, may be reduced. This reduction in ejection fraction appears to result from overall reduction in segmental wall motion, but also from accentuation of segmental wall abnormalities. These results are consistent with the thesis that beta adrenergic blocking drugs may inhibit compensatory sympathetic mechanisms. The diastolic effects of propranolol may include quite substantial increases in ventricular volumes in those patients with impaired cardiac function. With respect to the intact human ventricle, propranolol may increase diastolic volume for a given level of ventricular pressure. Thus, in a static sense, the ventricle in these patients could be viewed as being more compliant after propranolol administration. However, the fact that the length-tension relation, as measured by the slope of the logarithmic pressure versus volume plot is unaltered by propranolol, suggests that the muscle comprising the ventricle itself exhibits no alteration in its passive elastic properties.

Angiocardiography↗
PubMed1985

Beneficial effects of diltiazem and propranolol, alone and in combination, in patients with stable angina pectoris.

The antianginal effects of diltiazem 180 mg/day and propranolol 240 mg/day, alone and in combination, were investigated in 15 patients with effort related angina in a double blind placebo controlled crossover trial, with each period of treatment lasting four weeks. Patients performed a symptom limited treadmill exercise test at the end of each period of treatment. Mean (SEM) time to onset of angina was increased from 293(32) s when receiving placebo to 347(38) s when receiving diltiazem alone, to 350(30) s when receiving propranolol alone, and further to 421(34) s when receiving diltiazem and propranolol combined. Similar changes occurred in the duration of exercise testing and time to 1 mm ST segment depression. The sum of ST segment depression at peak exercise was reduced by both diltiazem and propranolol alone compared with placebo, and combination treatment produced a further significant improvement. Rate pressure product was significantly reduced at rest and at peak exercise after propranolol alone and combination treatment. The study clearly showed the superior value of diltiazem and propranolol combined in effort related angina when compared with either drug used alone.

Aged↗
PubMed1988

Propranolol treatment in children with tetralogy of Fallot alters the response to isoprenaline after surgical repair.

When propranolol is given to prevent hypoxaemic episodes in children with tetralogy of Fallot who are awaiting operation it is advisable to continue the treatment until shortly before the induction of anaesthesia. Because catecholamines are often required to maintain adequate cardiac output after surgical correction the effect of preoperative treatment with beta blockers on the response to isoprenaline after the operation was investigated in nine children given propranolol before operation and nine who were not. They were studied three and 24 hours after cardiopulmonary bypass. The haemodynamic response to increasing doses of infused isoprenaline was monitored. Immediately after cardiopulmonary bypass the response to isoprenaline was significantly blunted in the patients who had been given propranolol before operation. Their dose-response curve lay to the right of that for patients not given propranolol, and this indicates competitive inhibition. Propranolol concentrations in the blood and myocardium correlated significantly with the heart rate response to isoprenaline. Twenty four hours after operation the isoprenaline response was similar in both groups and concentrations of propranolol in the blood were minimal or undetectable. beta Blockers given up to the time of operation significantly altered the postoperative response to catecholamines.

Blood Pressure↗
PubMed1984

Studies on the effects of magnesium ion and propranolol on iris muscle phosphatidate phosphohydrolase.

The properties, subcellular distribution, and the effects of Mg2+ and propranolol on phosphatidate phosphohydrolase (EC 3.1.3.4) from rabbit iris smooth muscle have been investigated. The particulate and soluble (0-30% (NH4)2SO4 fraction) enzymes were assayed using aqueous phosphatidate dispersions and membrane-bound phosphatidate as substrates, respectively. When measured with aqueous substrate, activity was detected in both the particulate and soluble fractions, with the highest relative specific activity found in the microsomal fraction. Maximum dephosphorylation by the microsomal enzyme was about 1100 nmol of inorganic phosphate released/h per milligram protein and occurred at pH 7.0-7.5. In general Mg2+ inhibited the phosphohydrolase activity of the microsomal fraction and stimulated that of the soluble fraction, and the effects of the divalent cation on both of these activities were reversed by propranolol. The microsomal enzyme was slightly stimulated by deoxycholate and inhibited by the divalent cations Mg2+, Ca2+, and Mn2+ at concentrations greater than 0.25 mM. In contrast, the soluble enzyme was stimulated by Mg2+. Inhibition of the microsomal enzyme by Mg2+ (0.5 mM) was reversed by both EDTA, which also stimulated at higher concentrations (1 mM), and propranolol (0.1-0.2 mM). The inhibitory effect of Ca2+ on the enzyme was not reversed by propranolol. In the absence of Mg2+, the microsomal enzyme was inhibited by propranolol in a dose-dependent manner, and both in the absence and presence of the divalent cation the soluble enzyme was inhibited by the drug in a similar manner. These data suggest that the cationic moiety of propranolol may act by competing at the Mg2+-binding sites.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Propranolol metabolism by isolated hepatocytes from normal and cirrhotic rat livers: the effect of albumin.

Several recent reports have shown that the hepatic uptake and subsequent elimination of some substrates is faster in the presence of albumin than in its absence, as if some of the substrate bound to albumin was also available for uptake. In the present study, we examined the effect of albumin on the clearance of propranolol by isolated rat hepatocyte suspensions. The clearance of total drug decreased progressively as albumin concentration increased. There was also a progressive decrease in the free fraction of propranolol and the net result was an increase in the clearance of unbound drug (+50% at 40 g/L albumin). This increase was not due to an oncotic pressure effect of albumin, nor to the presence of fatty acids bound to albumin. The clearance of propranolol by isolated hepatocytes from cirrhotic rats was decreased compared with controls (-50%), and albumin also increased propranolol free clearance, albeit to a lesser extent than in control animals. Our results indicate that albumin facilitates the elimination of propranolol by hepatocytes, possibly because of surface-mediated catalysis of the albumin-propranolol complexes.

Albumins↗
PubMed1990

Effect of acidosis on skeletal muscle metabolism with and without propranolol.

Does the stimulatory effect of circulating catecholamines counteract the inhibitory effect of acidosis on skeletal muscle metabolism? To investigate this possibility, we studied gastrocnemii in dogs breathing either air (n = 10) or 4% carbon dioxide in air (n = 10) at rest and during contractions. In five dogs from each group, we infused propranolol into the arterial supply of the right and left muscles for 40 min. After 30 min of infusion, the left muscle was stimulated at 3 Hz for 10 min. During the 10th min of contractions, we removed and froze both muscles in liquid nitrogen. Oxygen uptake and blood flow to the left muscle prior to or during stimulation was not affected by acidosis either with or without propranolol. Glycogen concentration in resting muscle was unaffected by acidosis with or without propranolol. There was an acidosis related decrease of approximately 50% in the glycolytic intermediates (glucose 6-phosphate, fructose 1,6-diphosphate, alpha-glycerol phosphate, and dihydroxyacetone phosphate) in unstimulated muscles without beta-blockade. At rest, acidosis decreased muscle lactate by 50% with and 64% without propranolol, but lactate release was decreased only with acidosis without propranolol (1.4-0.1 mumols/kg.s). Acidosis without propranolol had no effect on the changes in glycogen concentration or the change in the concentration of glycolytic intermediates resulting from contractions. In beta-blocked muscle, the difference between stimulated and unstimulated concentrations of glycogen and glycolytic intermediates including lactate was 20-50% smaller with acidosis. Thus, with beta-blockade, the acidotic effects at rest disappeared and an inhibition of the metabolic adjustment to contractions appeared, indicating that circulating catecholamines do modify some metabolic effects of acidosis.

Acidosis↗
PubMed1991

Opposed responses of large and small coronary arteries to propranolol during exercise in dogs.

This study was carried out to determine the relative role of alpha- and beta-adrenoceptors at the level of large epicardial and small resistance coronary arteries when sympathetic tone is increased by exercise. The responses of left circumflex coronary diameter and blood flow were examined at rest and during treadmill exercise in seven chronically instrumented dogs during control conditions (saline) and after propranolol administration (1 mg/kg) either alone or in combination with phentolamine (1.5 mg/kg). In control conditions, graded treadmill exercise (5, 10, and 12 km/h) resulted in a progressive increase in coronary artery diameter and decrease in coronary vascular resistance. After propranolol, coronary vascular resistance slightly increased at rest and then progressively decreased during exercise. Surprisingly, coronary artery diameter significantly decreased at rest as well as throughout the exercise period. Phentolamine significantly reduced the propranolol-induced effects on coronary arterial diameter but did not restore the exercise-induced dilation of the large coronary arteries observed during control conditions. In addition, phentolamine prevented the propranolol-induced increase in coronary vascular resistance at rest and reinforced the exercise-induced decrease in coronary vascular resistance observed under propranolol. Thus beta-adrenoceptors are essential in the mediation of exercise-induced dilation of large coronary arteries. In contrast, activation of beta-adrenoceptors is only partially responsible for the decrease in coronary vascular resistance during exercise. Finally, constriction of large coronary arteries after propranolol is mainly explained by the unmasking of alpha-adrenergic tone at rest, but other mechanisms are involved during exercise.

Animals↗
PubMed1990

Propranolol restores phosphaturic effect of PTH in short-term phosphate deprivation.

Phosphate deprivation causes a resistance to the phosphaturic effect of parathyroid hormone (PTH). The present study evaluated the role of the beta-adrenergic system in this resistance phenomenon. In clearance experiments performed on acutely thyroparathyroidectomized male Sprague-Dawley rats, the phosphaturic response to PTH was determined in the presence and absence of propranolol in rats fed a low-phosphate diet (LPD) for 0.5, 1, 2, 3, or 4 days. Fractional excretion of phosphate (FEPi) in control rats fed a normal-phosphate diet (NPD) increased from 4.37 +/- 1.6 to 38.5 +/- 3.4% in response to PTH infusion. Propranolol did not change FEPi in NPD animals in the absence or in the presence of PTH (2.0 +/- 1.1 vs. 36.7 +/- 1.6%). LPD resulted in a gradual decrease in the phosphaturic response to PTH infusion as compared with NPD animals. PTH increased FEPi to 24.2 +/- 6.0% after one-half day of LPD, but when the infusion was supplemented with propranolol, PTH increased FEPi to 38.0 +/- 4.7%, similar to that in NPD animals. In the group fed LPD for one day, PTH increased FEPi to 16.9 +/- 4.3%, whereas in the presence of propranolol FEPi was restored to a similar level as in the NPD group (36.0 +/- 5.9%). Two days of LPD markedly decreased FEPi in response to PTH to 7.9 +/- 3.8% as compared with NPD rats, and propranolol infusion did not change this value significantly. Three and 4 days of LPD induced complete resistance to the phosphaturic effect of PTH in the presence as well as in the absence of propranolol.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗