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PubMed1986

Influence of propranolol on rhythmic electrocorticographic activity induced by metrazol in rats.

Influence of propranolol (5 mg/kg i.p.) on rhythmic metrazol activity (RMA) was studied in 11 male albino rats with chronically implanted cortical as well as subcortical (thalamic ventrobasal complex and dorsal hippocampus) electrodes. Metrazol was injected subcutaneously at a low dose of 30 mg/kg. Another group of five rats was used to study the action of propranolol on spontaneously appearing episodes of rhythmic spikes as well as on vigilance. The incidence of both rhythmic metrazol activity and episodes was significantly increased by propranolol. The latency to the first burst of rhythmic metrazol activity and to the maximum of its incidence was significantly shortened by propranolol. Propranolol also increased the incidence of relaxed wakefulness and delayed the appearance of slow wave sleep. The facilitation of RMA and spontaneous episodes could not be explained only by the increased amount of relaxed wakefulness, i.e. the vigilance level necessary for these two phenomena, because these changes did not coincide in time. In two animals, the combination of propranolol and metrazol led to the appearance of ictal activity which was sometimes accompanied by partial clonic convulsions. This phenomenon was never seen after metrazol alone (30 mg/kg s.c.) in control recordings. Propranolol was found to potentiate the possible models of human absences--spontaneous episodes, RMA and minimal clonic seizures.

Animals↗
PubMed1977

Levo-bunolol and propranolol: further evaluation of oral beta-blocking activity in conscious dogs.

The oral beta-adrenoceptor blocking activity of bunolol, propanolol, and their levo-isomers was compared against isoproterenol- and treadmill exercise-induced tachycardias in normal conscious dogs. Relative potencies against isoproterenol were (ascending order): propranolol=1, levo-propranolol=2, bunolol=40, and levo-bunolol=102. Large oral doses of levo-bunolol and propranolol suppressed exercise tachycardia by only 18% (range 10 to 22%). Compared to the isoproterenol response, the tachycardia associated with severe exercise in the healthy trained dog was largely resistant to beta-receptor blockade showing factors other than beta-receptor stimulation to be involved. Differences in duration of beta-blockade were observed at equiactive doses of levo-bunolol and propranolol. The isoproterenol response had returned to greater than 50% of control by 12 hr after propranolol but was less than 10% of control at 12 hr after levo-bunolol. The time to 50% recovery of the exercise tachycardia was 24 hr after levo-bunolol and 6 to 9 hr after propranolol. The results show oral levo-bunolol to be considerably more potent and to have a longer duration of action than propranolol in inhibiting both isoproterenol and exercise-induced tachycardias in conscious dogs.

Administration, Oral↗
PubMed1988

Alteration of the pharmacokinetics and metabolism of propranolol and antipyrine elicited by indwelling catheters in the rat.

It has been shown that catheter implantation in rats increases concentrations of propranolol and this is usually explained by the increased serum protein binding of propranolol, as a consequence of the higher serum alpha-1-acid glycoprotein concentration. We investigated in this study whether this increase in propranolol concentration after p.o. administration is not also due to a decreased first pass metabolism. We therefore studied in rats the pharmacokinetics and the in vitro metabolism by hepatocytes, of propranolol and antipyrine, 2 and 48 hr after catheter implantation. After p.o. administration of propranolol, the area under the serum concentration time curve 48 hr after catheter implantation was increased 4-fold as compared to 2 hr. As the unbound propranolol fraction was decreased only by a factor of two, it can be concluded that the hepatic intrinsic clearance was decreased, and this was confirmed by a decreased metabolizing activity in the isolated hepatocytes of these animals. After i.v. administration of antipyrine, the systemic clearance was decreased, the volume of distribution was unchanged and the half-life was increased 48 hr after catheter implantation. As antipyrine is a low extraction drug and is not bound to serum proteins, the decreased systemic clearance suggests a lower hepatic intrinsic clearance, and this was again confirmed by a decreased metabolizing activity in the isolated hepatocytes. These results confirm the important effect of the presence of indwelling catheters on the serum concentrations of antipyrine and propranolol, and suggest that this effect is the result of both an increased serum binding and a decreased hepatic metabolism.

Animals↗
PubMed1987

Effects of the non-steroidal anti-inflammatory drugs, piroxicam or sulindac, on the antihypertensive actions of propranolol and verapamil.

Twenty-five hypertensive patients participated in a randomized placebo-controlled study. After blood pressures were normalized with propranolol or verapamil alone over a 6-week period, patients were entered into a 4-week double-blind period where they received non-steroidal anti-inflammatory drug (NSAID) treatment (sulindac or piroxicam) or placebo treatment in addition to their antihypertensive therapy. There was a significant elevation in standing systolic blood pressure (P less than 0.05) with propranolol and sulindac, when compared with propranolol and placebo, but no significant changes were shown with propranolol and piroxicam. Systolic blood pressures on sulindac treatment were significantly lower (P less than 0.05) in both supine and standing positions during treatment of hypertension with verapamil compared with propranolol. Both supine systolic and diastolic blood pressures on piroxicam treatment were significantly lower (P less than 0.05) during treatment of hypertension with verapamil compared with propranolol. We conclude that NSAID transiently block the antihypertensive effect of propranolol, causing blood pressures to increase and side effects to improve. However, NSAID do not cause loss of antihypertensive control with verapamil.

Adult↗
PubMed1986

[Treatment of unstable angina. A randomized double-blind study of propranolol, diltiazem and molsidomine].

A randomized, multicentric, double blind study attempted to compare in 41 patients hospitalized for unstable angina, the efficacy of diltiazem (D) 240 mg/day, propranolol (P) 160 mg/day and molsidomine (M) 8 mg/day. The patients included in the study presented one or several spontaneous angina episodes accompanied by a transient and significant lowering of ST and/or an inverted T wave without necrosis. The evaluation criteria were the occurrence of new angina pain and electrical alterations on a continuous Holter for 5 days. 11 patients received diltiazem, 13 patients received propranolol and 15 patients received molsidomine (including an early death). Clinically, the number of painful episodes per day and per patient goes, in an average, from 1.2 to 0.23 diltiazem, from 2.2 to 0.44 for propranolol and from 2.2 to 0.45 for molsidomine. Pain disappeared on the 5th day in 54.5 per cent of patients under diltiazem, 58.8 per cent of patients under propranolol and 53.5 per cent of patients under molsidomine. Electrically, the number of ischemic accidents per day and per patient was 0.45 under diltiazem, 2.12 under propranolol (0.53 in excluding one patient with latent angina) and 0.81 under molsidomine. The number of patients without any ischemic accident was 63.6 per cent under diltiazem, 53.8 per cent under propranolol and 40 per cent under molsidomine. In conclusion, diltiazem, propranolol, and molsidomine have a comparable efficacy in unstable angina. The association of these medications could have a synergistic effect.

Angina Pectoris↗
PubMed1979

Propranolol and tienilic acid in essential hypertension.

Sixteen patients with moderately severe essential hypertension completed a double-blind crossover trial with four treatment periods each lasting for six weeks. They received in random order, placebo; tienilic acid 250 mg/day; propranolol 80 mg b.d.; and tienilic acid 250 mg/day and propranolol 80 mg b.d. in combination. Mean blood pressure in the lying position was 169/98 mmHg on placebo, 157/94 mmHg on tienilic acid, 159/90 mmHg on propranolol and 142/86 mmHg on the combination of tienilic acid and propranolol. The effects of tienilic acid and propranolol on blood pressure were additive and there was no evidence of any interaction. The onset of the hypotensive effect of tienilic acid was gradual while the effect of propranolol was maximal within 2 weeks of the start of treatment. Tienilic acid produced a significant reduction in serum urate from 0.33 mmol/l to 0.18 mmol/l. The combination of tienilic acid and propranolol in the doses used in the trial was effective and acceptable in the reduction of raised blood pressure.

Adult↗
PubMed1985

Monotherapy with labetalol compared with propranolol. Differential effects by race.

The antihypertensive effect of oral labetalol and propranolol were evaluated in 65 black and 75 white patients with mild to moderate hypertension (standing diastolic blood pressure (StDBP) of 90-115 mmHg) in a double-blind multicenter clinical trial. Following a 4-week placebo phase, labetalol (n = 70) or propranolol (n = 70) was randomly assigned. During a 5-week titration phase, labetalol could be increased from 100 mg BID to 600 mg BID to achieve a StDBP of less than 90 mmHg and a decrement of greater than or equal to 10 mmHg. Propranolol could be titrated from 40 to 240 mg BID. A 3-month maintenance phase was followed by an optional 8-month maintenance phase. Hydrochlorothiazide (HCTZ) could be added at any time during the maintenance phase. Supine and standing blood pressures were measured at each visit. Statistical analysis revealed significant (ANOVA, p less than 0.05) treatment by race effects. Therefore, the treatment groups were stratified retrospectively by race. This study demonstrated that labetalol is equally effective in white and black patients, whereas, propranolol is significantly (p less than 0.05) more effective in white than in black patients. Moreover, labetalol is significantly more effective than propranolol in lowering the standing systolic/diastolic blood pressure of black patients (p less than 0.02/p less than 0.001). These blood-pressure effects were accompanied by a significantly greater (p less than 0.04) reduction in heart rate with propranolol. Furthermore, significantly more (p less than 0.05) black patients treated with propranolol compared to those treated with labetalol required the addition of a diuretic for control of their blood pressure.

Adult↗
PubMed1985

Effect of nifedipine and propranolol on blood flow, venous compliance and blood pressure in essential hypertension.

To determine the efficacy of nifedipine combined with propranolol in the treatment of hypertension, 23 patients with essential hypertension uncontrolled while they were receiving propranolol, 120 mg/d, entered a dose response trial of four 8-week periods while continuing propranolol therapy. Therapy during the four periods consisted respectively of a placebo, 30 mg/d of nifedipine, 30 or 60 mg/d of nifedipine, and 30 or 60 mg/d of nifedipine along with only 60 mg/d of propranolol. Studies of forearm blood flow and venous compliance were carried out in nine of the patients. Ten patients dropped out after the first period. The mean blood pressures while the patients were recumbent after the first, second and third periods were 163 +/- 17/100 +/- 6, 147 +/- 13/89 +/- 10 and 141 +/- 19/84 +/- 10 mm Hg respectively. There was no evidence of tolerance in the four patients who received 30 mg/d of nifedipine during the third period. There was a significant dose-diastolic pressure response (p less than 0.0006) without a change in heart rate in the eight who received 60 mg/d of nifedipine during this period. After 16 weeks of therapy with nifedipine 11 patients had a diastolic pressure less than 90 mm Hg while recumbent. While mean blood pressure and heart rate for the group were not significantly increased at the end of the fourth period, in three of the patients the diastolic pressure while recumbent increased to over 90 mm Hg. This suggests that 120 mg/d of propranolol is the minimum dose required for concomitant therapy. Adverse symptoms were mild and transient. Forearm plethysmography showed that nifedipine induced arteriolar but not venous dilation and that propranolol attenuated the vasodilator effect of nifedipine. The author concludes that nifedipine was safe and effective in combination with propranolol in this group of patients with essential hypertension.

Adult↗
PubMed1985

Prolonged protective effects following propranolol withdrawal against isoproterenol-induced myocardial infarction in normotensive and hypertensive rats.

Young adult, male and female, normotensive Sprague-Dawley (S-D) and spontaneously hypertensive rats (SHR) were injected with propranolol three times daily for 3 weeks. None of the animals manifested signs of withdrawal when the injections were terminated. Seven days later, the animals were challenged with a dose of isoproterenol which would produce massive myocardial infarction and 50-60% mortality in non-treated animals. The propranolol pretreatment caused marked tranquilizing and blood pressure lowering effects in SHR exclusively. Despite the 7-day propranolol withdrawal period, very few animals died and myocardial damage was minimal. However, blood pressure levels dropped to shock-like levels, blood CPK and LDH levels showed dynamic increases, there was marked hypertriglyceridaemia, and plasma corticosterone rose to supranormal levels. Microscopically, the hearts of the propranolol pretreated animals showed little evidence of necrosis but the SHR hearts manifested large atrial and ventricular thrombi. It is suggested that in the rat, propranolol treatment causes positive myocardial protective effects mediated through hormonal and metabolic changes and propranolol withdrawal does not lead to hypersensitivity to catecholamines. In fact, the beta-blocking effects of propranolol remain effective for some time after withdrawal.

Animals↗
PubMed1985

Effect of propranolol on brain electrical activity during hyperbaric oxygenation in the rat.

The effect of 1, 2, and 5 mg/kg propranolol on the neuroelectrophysiological manifestations of CNS oxygen toxicity was studied in conscious rats. Cortical electrodes for electrocorticographic (ECoG) recording and femoral venous cannula for i.v. infusion were implanted 7 and 3 d, respectively, before the experiment. The rats were divided into 5 groups. Groups I to III were treated with 1, 2, and 5 mg/kg propranolol, respectively, and Group IV with saline. Groups I-IV were exposed to 5 ATA O2 until the appearance of the first cortical paroxysmal electrical discharges (FED), considered to be a preconvulsive electrophysiological manifestation of CNS oxygen toxicity. Rats in Group V were exposed to 5 ATA N2-O2 normoxia and treated with 5 mg/kg propranolol. After the hyperbaric exposures and the i.v. administration of propranolol a typical ECoG pattern consisting of frequent bursts of high amplitude spindle-like waves of 6-7 c/s activity was observed. In hyperbaric oxygen-exposed rats, the paroxysmal electrical discharges were always preceded by the propranolol-induced spindle wave activity (in theta range) and oxygen-induced slow wave activity (in delta range) in ECoG. Infusion of 2 and 5 mg/kg propranolol significantly delayed the time of onset of the oxygen-induced slow wave activity and the FED. It is suggested that the protective effect of propranolol against the neurological manifestations of oxygen toxicity, may be related to its multiple effects on physiological systems rather than beta adrenergic blocking action alone.

Animals↗
PubMed1979

Stereoselective oral bioavailability of (+/-)-propranolol in the dog. A GC-MS study using a stable isotope technique.

The disposition of (+)- and (-)-propranolol and their glucuronic acid conjugates, (+)-POG and (-)-POG, in plasma was determined in 5 dogs following single 160 mg oral doses of stable isotope labeled racemic propranolol. Each animal received one dose of the racemate with the (+)-isomer labeled with two deuteriums and one dose with the (-)-isomer labeled. The isomers were separated and measured by gas chromatography-mass spectrometry. No stable isotope effect was detected. The area under the plasma concentration - time curve (AUC) for (-)-propranolol was only 54 +/- 10 per cent (mean +/- SD; n = 10) of the AUC for (+)-propranolol. The AUC of (-)-POG exceeded the AUC of (+)-POG by 4.02 +/- 1.22 times (mean +/- SD: n = 10). The time to peak plasma concentration (3.9-4.3 hr) and the half-life (1.6-1.9 hr) were identical for both isomers of propranolol as well as of POG. These results demonstrate a significantly lower oral bioavailability of (-)- as compared to (+)-propranolol in the dog, which appears to be associated with stereoselective presystemic glucuronidation of (-)-propranolol.

Administration, Oral↗
PubMedDate not supplied

Myocardial sensitivity to isoproterenol following abrupt propranolol withdrawal in conscious dogs.

The sensitivity of the cardiovascular system to isoproterenol following abrupt cessation of propranolol administration was studied in chronically instrumented conscious dogs pretreated orally with propranolol for 14 days. The effects of intravenous isoproterenol on heart rate, blood pressure, and mean velocity of circumferential fiber shortening (Vcf) were determined before and during propranolol administration and then at 12 hr intervals following drug withdrawal. During propranolol administration, all dose-response curves to isoproterenol were predictably shifted to the right. Twenty-four hours following propranolol withdrawal, when plasma levels of drug averaged only 7 ng/ml, the chronotropic response to isoproterenol remained significantly inhibited. In contrast, the Vcf response recovered rapidly and at 24 hr equaled the pretreatment control response. Furthermore, between 36 and 60 hr, when plasma propranolol levels averaged less than 1 ng/ml, the Vcf dose-response curve to isoproterenol was shifted to the left of control prior to returning to the pretreatment level. This leftward displacement of the Vcf response curve was not accompanied by a parallel change in the heart rate response or in afterload. Plasma norepinephrine levels were measured throughout the study and were not altered during drug treatment or following withdrawal. Thus, the data indicate that abrupt cessation of propranolol administration is associated with a period of increased myocardial sensitivity to at least the inotropic effects of isoproterenol and that abrupt withdrawal does not result in acute changes in sympathetic nervous system activity.

Animals↗
PubMed1984

Effect of intraoperative propranolol on serum creatine kinase MB release in patients having elective cardiac operations.

Intraoperative beta blockade has been evaluated as an adjunct to hypothermic cold blood potassium cardioplegia by quantitating serum creatine kinase MB release. Randomization of 80 patients having coronary artery bypass grafting and 18 patients having valve replacement with or without bypass grafting resulted in 46 of the former and seven of the latter receiving propranolol 0.05 mg/kg 4 to 5 minutes before aortic cross-clamping. Among patients having bypass grafting, infarct size (in gram-equivalents) was 7.9 +/- 0.7 gm-Eq for the propranolol group and 10.3 +/- 0.8 (p less than 0.05) for the control group. Ischemic times were 71.6 +/- 2.8 and 78.3 +/- 3/4 minutes (p = NS), respectively. In valve replacement, infarct size was 9.9 +/- 1.9 gm-Eq for those receiving propranolol and 12.6 +/- 2.0 (p = NS) for the control subjects; ischemic times were 99.4 +/- 12.5 and 80.5 +/- 5.7 minutes, respectively. When the two groups receiving propranolol were combined, infarct size was 8.2 +/- 0.6 gm-Eq versus 10.9 +/- 0.7 (p less than 0.01). When ischemic time was plotted against infarct size, analysis by linear regression revealed a significant correlation for patients receiving propranolol and having bypass grafting (p less than 0.01) and for all patients receiving propranolol (p less than 0.01). These data demonstrate a modest reduction of infarct size with intraoperative propranolol as an adjunct to our standard management of patients having aortic cross-clamping. Quantitation of creatine kinase MB release is the best clinically available method for assessing alterations in techniques of myocardial preservation.

Coronary Artery Bypass↗
PubMed1983

Effects of propranolol therapy on renal function and body fluid composition.

Fourteen hypertensive men underwent assessment of renal function and body fluid composition following short-term (three to six weeks), long-term (five to six months), and withdrawal (two weeks) of propranolol hydrochloride monotherapy for the treatment of hypertension. Results indicate that propranolol had little effect on glomerular filtration rate (less than 10% decrease); changes that did occur were directly correlated with changes in effective renal plasma flow. Propranolol therapy decreased effective renal plasma flow 14% and renal blood flow 15% during long-term therapy; decreases in renal perfusion persisted following withdrawal of therapy. Propranolol therapy was neither antidiuretic nor antinatriuretic; propranolol had no effect on urine osmolality, free water clearance, sodium clearance, or fractional sodium excretion. Furthermore, propranolol therapy did not expand plasma volume, extracellular fluid volume, or total body water. Finally, propranolol therapy had no effect on the renal handling of potassium or on serum potassium concentration.

Blood Pressure↗
PubMed1982

The role of propranolol therapy and proteinuria in the etiology of post renal transplantation hyperlipidemia.

The effects of propranolol and proteinuria on the fasting lipoprotein profiles of 33 male renal allograft recipients have been studied. By isolating the two variables by division of the patients into four groups according to propranolol dose and proteinuria, i.e. 1. propranolol = 0 mg/24 hr, proteinuria; less than 0.5 g/24 hr; 2. propranolol less than 0 mg/24 hr, proteinuria; less than 0.5 g/24 hr; 3. propranolol = 0 mg/24 hr, proteinuria; less than 0.5 g/24 hr; and 4. propranolol greater than 0 mg/24 hr, proteinuria; greater than 0.5 g/24 hr, it has been shown that propranolol treatment elevates the very low density lipoprotein triglyceride and decreases the high density lipoprotein cholesterol and that proteinuria (greater than 0.5 g/24 hr) increases low density lipoprotein cholesterol. The possible significance of these results in terms of transplantee management is discussed.

Adolescent↗
PubMedDate not supplied

[Pharmacokinetics of propranolol, phenytoin and lidocaine in hypercholesterolemic rabbits].

1. The aim of this study was to investigate an eventual influence of hypercholesterolemia on drug kinetics in the rabbit. Pharmacokinetic of propranolol, phenytoin and lidocain was studied in groups of male "Fauve de Bourgogne" rabbits. Each compound was administered by intravenous single dose injection, dosage being 1 mg/kg for propranolol, 10 mg/kg for phenytoin, and 3,5 mg/kg for lidocain. Propranolol plasma levels were determined by spectrofluorimetric method; plasma concentrations of phenytoin and lidocain were determinated according to a gas chromatographic method. 2. Our data showed variations of pharmacokinetic parameters for propranolol and phenytoin only. For propranolol the total body clearance (0,178 +/- 0,064 and 0,115 +/- 0,048 l.kg-1.mn-1; p less than 0,05) and the volume of distribution (9,32 +/- 3,10 and 6,02 +/- 0,96 l.kg-1; p less than 0,01) were significantly diminished; half-life (40,25 +/- 19,45 and 45,62 +/- 32,20 mn) remained inchanged. For phenytoin, total body clearance (3,28 +/- 0,94 and 1,43 +/- 0,50 l.kg-1.mn-1; p less than 0,001) was significantly diminished; half-life (136,4 +/- 29,4 and 324,9 +/- 131,6 mn; p less than 0,001) significantly increased; volume of distribution (0,62 +/- 0,13 and 0,62 +/- 0,10 l.kg-1) remained unchanged. 3. These variations may be related to changes in the plasma binding for propranolol and in the hepatic metabolism for propranolol and phenytoin.

Animals↗
PubMed1983

Interactions of phenobarbital with propranolol in the dog. 2. Bioavailability, metabolism and pharmacokinetics.

This article describes the effects of chronically administered phenobarbital (180 mg/day p.o.) in dogs on the bioavailability of single 40-mg oral doses of propranolol and on the pharmacokinetics and the patterns of propranolol metabolism in urine after both oral (40 mg) and i.v. (6 mg) doses. Phenobarbital decreased the bioavailability of propranolol from 7.7 to 3.5%. By using a gas chromatography/mass spectrometry technique, the quantitative metabolic pattern of i.v. propranolol was unaltered by phenobarbital, but increases in hydroxylation and induction of new metabolites were observed for oral propranolol after phenobarbital treatment. Chronic phenobarbital treatment led to significant decreases in the half-lives of propranolol after both i.v. and oral doses. Little change was observed in the hepatic blood flow, systemic clearance or intrinsic oral clearance. These data demonstrate the completely nonrestrictive elimination of propranolol. With phenobarbital, both the extent of plasma protein binding and the distribution into erythrocytes change significantly, yet the overall clearance remains unaltered. The half-lives fell in responses to the binding-induced reduction in the apparent volume of distribution.

Administration, Oral↗
PubMed1981

Prevention of supraventricular tachyarrhythmia with low-dose propranolol after coronary bypass.

Eighty-five patients receiving long-term propranolol therapy were randomized after aorta-coronary bypass grafting either to receive minidose propranolol (Group I) or to serve as controls (Group II). They were compared with 18 patients (Group III) who did not receive beta blocking agents prior to operation but were given propranolol postoperatively. Poor-risk patients (those having left ventricular aneurysms, low ejection fraction, or congestive heart failure) as well as patients who required catecholamines postoperatively were included in the study. All three groups were comparable with respect to all risk factors. Propranolol (5 to 10 mg/6 hr) was started through a nasogastric tube 6 hours after operation and continued orally in all patients in Groups I and III. Supraventricular tachyarrhythmia appeared in two of 37 patients in Group I (5%), 19 of 48 patients in Group II (40%), and five of 18 patients in Group III (27%). The incidence of supraventricular tachyarrhythmia was significantly lower in Group I than in Groups II and III (p less than 0.001, Group I versus Group II; p less than 0.01, Group I versus Group III). In conclusion, low-dose propranolol is very effective in preventing supraventricular tachyarrhythmia following aorta-coronary bypass in patients receiving beta blockers preoperatively. The increased tendency for postoperative supraventricular tachyarrhythmia to develop in these patients is attributed to hypersensitivity to adrenergic stimulation after propranolol withdrawal. The tachyarrhythmia can be prevented by early reinstitution of propranolol in low doses after the operation.

Administration, Oral↗