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PubMed1990

Variable response to atrial pacing after intravenous propranolol in patients with stable exertional angina.

The effect of propranolol administration on regional coronary haemodynamics were investigated in 14 patients with stable exertional angina and isolated left anterior descending artery disease. Thermodilution was used to measure great cardiac vein flow (GCVF) and anterior regional coronary resistance (ARCR) under control conditions, at peak atrial pacing, after i.v. propranolol administration (0.1 mg kg-1) and at the peak of repeated atrial pacing. Propranolol did not change peak pacing heart rate, systolic blood pressure or double product. Peak pacing GCVF decreased slightly but non-significantly after drug administration from 84 +/- 20 to 79 +/- 24 ml min-1, while ARCR increased, but again non-significantly, from 1.36 +/- 0.44 to 1.45 +/- 0.45. Analysis of individual patient responses revealed that propranolol prolonged peak pacing time and hence peak pacing heart rate (from 126 +/- 24 to 140 +/- 23 beats min-1, P less than 0.05) in five patients. In such patients, peak pacing systolic blood pressure was lower than the pre-propranolol atrial pacing (145 +/- 35 vs 165 +/- 33, P less than 0.001) so that double product remained unchanged. Moreover, peak pacing ARCR did not change after propranolol (pre-propranolol 1.47 +/- 0.46, after propranolol 1.40 +/- 0.56 mmHg.ml-1.min, P = ns) while it increased significantly in the nine patients who did not improve after the drug (before propranolol 1.30 +/- 0.44, after propranolol 1.48 +/- 0.41 mmHg.ml-1.min, P less than 0.02). These data suggest that the response to atrial pacing after i.v. propranolol administration is variable as some patients tolerate higher heart rates while others do not.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed2000

Splanchnic organ blood flow during calcitonin gene-related peptide-induced hypotension with or without propranolol in dogs.

UNLABELLED: Propranolol has been used to attenuate reflex tachycardia during induced hypotension. The purpose of the current study was to determine whether propranolol can modify splanchnic organ blood flow during calcitonin gene-related peptide (CGRP)-induced hypotension in dogs anesthetized with 1.3% isoflurane in oxygen. After surgical preparation and hemodynamic stabilization, saline as a control, 0.5 mg/kg and 2.0 mg/kg propranolol (n = 10, each) were administered in a bolus injection 20 min before hypotension was induced. Mean arterial pressure was reduced to 60 mm Hg during 60 min of CGRP infusion. Renal blood flow (RBF), hepatic blood flow (HBF), and pancreatic blood flow (PBF) were measured using the hydrogen clearance method. Cardiac index did not change in all three groups, and heart rate in the control group remained unchanged. In the propranolol groups, however, heart rate decreased (P < 0.01). Plasma norepinephrine (NE), but not epinephrine (E), increased (P < 0.05) after propranolol administration. The NE and E increased (P < 0.01) during induced hypotension in all three groups. NE was higher in the 0.5 mg/kg propranolol group than in the control group. RBF in the control group remained unchanged throughout observation. RBF, HBF, and PBF decreased (P < 0.01) after propranolol and remained decreased during and after induced hypotension. The degrees of decreased HBF and PBF in the control group were less than those in the 2.0 mg/kg propranolol group. In conclusion, pretreatment with propranolol decreases splanchnic organ blood flow further during CGRP-induced hypotension, due in part to increased plasma catecholamine concentrations. IMPLICATIONS: The reductions in splanchnic organ blood flows during CGRP-induced hypotension with propranolol are due to a reflex augmentation in sympathetic vasoconstrictor tone caused by an increase in plasma catecholamine concentrations. These findings suggest that propranolol may impair splanchnic organ blood flow during CGRP-induced hypotension.

Adrenergic beta-Antagonists↗
PubMedDate not supplied

Effects of concentration and steric configuration of propranolol on AV conduction and ventricular repolarization in the dog.

To investigate the electrophysiological effects of propranolol in vivo over a wide range of plasma concentrations and to distinguish effects due to beta-blockade from those due to a direct membrane action, His bundle electrograms were recorded, and ventricular effective refractory periods (VERP) and monophasic action potential duration (MAP) were measured in anesthetized control dogs and in dogs given three graded infusions of d- or dl-propranolol. Dogs were excluded if the plasma concentrations attained did not fall in predefined ranges of 25--125, 125--700, and 700--3,000 ng/ml. Isoproterenol sensitivity tests were performed to determine the relative beta-blocking potency of the isomers at the three concentration ranges. The highest concentration of d-propranolol had approximately the same beta-blocking potency as the lowest concentration of dl-propranolol. Mean AH and HV intervals in the His bundle electrogram increased with the concentration of dl-propranolol, and the increase was greater than with d-propranolol (p less than 0.03) at the first and second concentration steps but not significantly different at the highest concentrations of d- and dl-propranolol. VERP and MAP increased directly with concentration of d- and dl-propranolol. Although the mean increases of VERP and MAP tended to be greater in the dl-propranolol group, the differences between d- and dl-propranolol were not statistically significant at any concentration. We conclude that prolongations of atrioventricular and His-Purkinje conduction are stereospecific responses and are due to beta-blockade. The specific mechanism for the prolongation of ventricular repolarization and refractoriness are effects of propranolol that could not be definitively classified in this study.

Action Potentials↗
PubMed1989

Pharmacodynamic and pharmacokinetic study of propranolol in patients with cirrhosis and portal hypertension.

1. The aim of this study was to investigate the pharmacokinetics and the beta-adrenoceptor blocking activity according to time of conventional (C) and long acting (LA) propranolol in cirrhotic patients. Twenty-four patients with alcoholic cirrhosis and oesophageal varices were randomly assigned to receive either 160 mg C propranolol, 160 mg LA propranolol or placebo acutely and then following repeated administration (acute and chronic phases). Thereafter propranolol concentrations and beta-adrenoceptor blockade (resting and exercise heart rates) were measured at different intervals. 2. The Cmax was significantly higher with C propranolol in both phases. The time of Cmax was significantly later with LA propranolol in both phases. The AUCs were significantly higher after chronic administration with both formulations of propranolol. 3. The exercise peaks of beta-adrenoceptor blockade were similar between the two formulations and between the two phases of administration of propranolol. The duration of effective beta-adrenoceptor blockade was significantly longer in the chronic phase and seemed to be longer with LA than with C propranolol although this was not significant (72 +/- 31 vs 48 +/- 18 h, respectively). 4. There was a significant correlation between the log propranolol concentration and exercise heart rate but not with resting heart rate. No correlation could be demonstrated between pharmacological data and the Child Pugh score. 5. We conclude that in cirrhotic patients exercise testing was a reliable method in the assessment of beta-adrenoceptor blockade. Pharmacology of propranolol was found to be different according to the formulation or to the phase of administration.

Adrenergic beta-Antagonists↗
PubMedDate not supplied

Vasorelaxing effects of propranolol in rat aorta and mesenteric artery: a role for nitric oxide and calcium entry blockade.

1. Propranolol has been prescribed successfully to patients with cardiovascular diseases, but the exact mechanisms by which it reduces peripheral vascular resistance have been poorly investigated. 2. The present study was designed to investigate the relaxing effects of propranolol in the rat isolated aorta and mesenteric artery, focusing on the contribution of the nitric oxide (NO)-cGMP pathway and calcium entry blockade. Relaxation responses to propranolol were obtained in precontracted rat aortic and mesenteric artery rings. 3. DL-Propranolol (10-100 micromol/L) produced concentration-dependent relaxations in the aorta and mesenteric artery rings with intact endothelium. The isomers D- and L-propranolol produced relaxation responses that were equipotent to the racemic mixture. 4. Metoprolol (10-100 micromol/L) produced slight relaxations, whereas atenolol (10-100 micromol/L) had no relaxant activity. 5. The NO inhibitor N(G)-nitro-L-arginine methyl ester (100 micromol/L) and the soluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (1 micromol/L), as well as removal of the endothelium, significantly reduced the relaxation responses induced by the lower concentrations of propranolol without affecting maximal responses. In addition, DL-propranolol markedly increased cGMP levels in endothelium-intact preparations. 6. In Ca(2+)-free Krebs' solution, DL-propranolol (10-100 micromol/L) caused marked rightward shift in the concentration-response curves to CaCl(2), with a decrease of maximal responses in tissues with either intact or denuded endothelium. Nifedipine (1 micromol/L) in combination with DL-propranolol virtually abolished the CaCl(2)-induced contractile responses. 7. The relaxation responses induced by DL-propranolol were significantly reduced in aortic and mesenteric rings precontracted with phorbol-12,13-dibutyrate (1 micromol/L). 8. In conclusion, DL-propranolol relaxes arterial smooth muscle by mechanisms involving activation of the NO-cGMP pathway and calcium influx blockade, independent of beta-adrenoceptor blockade.

Animals↗
PubMed2004

Acute administration of carvedilol is more effective than propranolol plus isosorbide-5-mononitrate in the reduction of portal pressure in patients with viral cirrhosis.

OBJECTIVE: Propranolol is known to decrease portal pressure in cirrhotic patients with portal hypertension; however, a substantial number of patients do not respond to propranolol administration. The addition of isosorbide-5-mononitrate may enhance portal pressure reduction in patients receiving propranolol. Carvedilol is a nonselective beta-blocker with alpha(1)-adrenergic blocking activity. It has been shown to decrease portal pressure in cirrhotic patients. Additionally, carvedilol has a greater portal hypotensive effect than propranolol alone in patients with cirrhosis. The current study is aimed at comparing the acute hemodynamic effects of carvedilol with the effects of propranolol plus isosorbide-5-mononitrate in patients with viral cirrhosis. METHODS: Patients with viral cirrhosis were randomly assigned to receive an oral administration of carvedilol of 25 mg (n = 11) or an oral administration of propranolol 40 mg plus isosorbide-5-mononitrate 20 mg (n = 11). Hemodynamic values were measured at basal and 90 min after drugs administration. RESULTS: Both carvedilol and propranolol plus isosorbide-5-mononitrate significantly decreased cardiac index, heart rate, and HVPG. The magnitude of changes in HVPG observed between the basal and after drugs administration was greater in patients receiving carvedilol than in those receiving propranolol plus isosorbide-5-mononitrate (-18.6 +/- 3.6%vs-10.1 +/- 3.6%, p < 0.05). Hepatic blood flow increased following carvedilol administration but remained unchanged in patients receiving propranolol plus isosorbide-5-mononitrate. The magnitude of decrease in mean arterial pressure (MAP) did not differ between the two groups of patients. CONCLUSION: In our patients with viral cirrhosis, carvedilol is more effective than propranolol plus isosorbide-5-mononitrate in the reduction of HVPG. Carvedilol administration causes an increase in hepatic blood flow, but its systemic effects were similar to those of propranolol plus isosorbide-5-mononitrate.

Antihypertensive Agents↗
PubMed2006

Prominent but reverse stereoselectivity in propranolol glucuronidation by human UDP-glucuronosyltransferases 1A9 and 1A10.

Propranolol is a nonselective beta-adrenergic blocker used as a racemic mixture in the treatment of hypertension, cardiac arrhythmias, and angina pectoris. For study of the stereoselective glucuronidation of this drug, the two propranolol glucuronide diastereomers were biosynthesized, purified, and characterized. A screen of 15 recombinant human UDP-glucuronosyltransferases (UGTs) indicated that only a few isoforms catalyze propranolol glucuronidation. Analysis of UGT2B4 and UGT2B7 revealed no significant stereoselectivity, but these two enzymes differed in glucuronidation kinetics. The glucuronidation kinetics of R-propranolol by UGT2B4 exhibited a sigmoid curve, whereas the glucuronidation of the same substrate by UGT2B7 was inhibited by substrate concentrations above 1 mM. Among the UGTs of subfamily 1A, UGT1A9 and UGT1A10 displayed high and, surprisingly, opposite stereoselectivity in the glucuronidation of propranolol enantiomers. UGT1A9 glucuronidated S-propranolol much faster than R-propranolol, whereas UGT1A10 exhibited the opposite enantiomer preference. Nonetheless, the Km values for the two enantiomers, both for UGT1A9 and for UGT1A10, were in the same range, suggesting similar affinities for the two enantiomers. Unlike UGT1A9, the expression of UGT1A10 is extrahepatic. Hence, the reverse stereoselectivity of these two UGTs may signify specific differences in the glucuronidation of propranolol enantiomers between intestine and liver microsomes. Subsequent experiments confirmed this hypothesis: human liver microsomes glucuronidated S-propranolol faster than R-propranolol, whereas human intestine microsomes glucuronidated S-propranolol faster. These findings suggest a contribution of intestinal UGTs to drug metabolism, at least for UGT1A10 substrates.

Adrenergic beta-Antagonists↗
PubMed1988

Propranolol inhalation challenge in relation to histamine response in children with asthma.

The relation between airway responsiveness to propranolol and histamine was studied in 32 asthmatic children. Propranolol and histamine were given by nebuliser to a maximum dose of 16 mg/ml and 32 mg/ml respectively and the response was measured as the provocative concentration of agonist causing a 20% fall in FEV1 (PC20). A PC20 histamine value of less than 32 mg/ml was obtained in 24 of the 32 children, of whom 15 had a measurable PC20 propranolol (less than 16 mg/ml). In these 24 children the geometric mean PC20 histamine was 4.5 mg/ml and 14.4 mg/ml respectively in those with and without a measurable PC20 propranolol (p = 0.023). There was a linear relationship between histamine and propranolol PC20 values (r = 0.60), and between PC20 histamine and FEV1 % predicted (r = 0.43), but not between PC20 propranolol and FEV1 % predicted (r = 0.38). In an open time course study in 12 children with asthma recovery of FEV1 after inhaled propranolol was incomplete in seven of the children after 90 minutes. When inhaled propranolol was followed by inhaled ipratropium bromide in a further 11 children FEV1 had returned to baseline in all children after 60 minutes. Thus propranolol inhalation can be used in children with asthma to assess the contribution of the beta adrenergic system to the regulation of bronchial smooth muscle tone. The test has several disadvantages in comparison with histamine provocation-long duration, the prolonged action of propranolol, and the fact that only the children with substantial hyperreactivity to histamine react to propranolol.

Adolescent↗
PubMed1993

Serotonergic inhibition of rat Leydig cell function by propranolol.

The beta-adrenergic antagonist propranolol binds to serotonin (5HT) receptors (5HT1B > 5HT1A > 5HT2) in brain membranes. We have recently demonstrated that 5HT acts through 5HT2 receptors in rat Leydig cells to release CRF, which, in turn, inhibits hCG-stimulated cAMP production and steroidogenesis. These observations prompted us to study the effects of propranolol on CRF secretion and cAMP and testosterone production in cultured rat Leydig cells. Treatment with (-)propranolol increased CRF release and inhibited basal and hCG-stimulated cAMP and steroidogenesis, with effects evident at 0.1 microM, an IC50 of 6 microM, and reduction of stimulated levels to near basal at 100 microM. These effects of the drug were prevented by pretreatment of cultures with the 5HT2 receptor antagonist ketanserin or a CRF antagonist or antiserum. Furthermore, propranolol increased the level of 5HT in the incubation medium of cultured Leydig cells. The (+)isomer of propranolol had minor effects on these parameters. Increasing concentrations of (-)propranolol displaced the binding of [125I] +/- 1-[2,5-dimethoxy-4-iodophyryl]-2-amino propane hydrochloride (DOI), a selective 5HT2 ligand, to Leydig cell membranes (IC50, 0.2 microM), and (+)propanolol showed weaker potency. The inhibitory actions of propranolol were exerted through its blockade of the Leydig cell 5HT2 low affinity receptor, which has functional properties of an autoreceptor, with consequent increases in 5HT and stimulation of CRF release through 5HT action at the high affinity site. The serotonergic actions of propranolol were prevented by DOI, an inhibitor of 5HT actions at the high affinity site. In addition, the propranolol-induced blockade of the low affinity site further increased the cAMP and steroidogenic responses to gonadotropin over those observed with DOI treatment alone. These studies demonstrate that propranolol acts as an antagonist at the Leydig cell low affinity 5HT2 receptor and stimulates CRF release via a serotonergic mechanism, with consequent inhibition of cAMP generation and steroidogenesis. This serotonergic action of the drug could contribute to the impairment of sexual function reported during propranolol treatment in man.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1999

Effects of cyclosporin on the pharmacokinetics of propranolol after intravenous and oral administration to control rats and to rats with uranyl nitrate-induced acute renal failure.

The effects of cyclosporin on the pharmacokinetics of propranolol have been investigated after intravenous and oral administration of the drugs to control rats and to rats with uranyl nitrate-induced acute renal failure. The effects of intravenous cyclosporin, 30 mg kg(-1), on the pharmacokinetics of intravenous propranolol, 3 mg kg(-1), were significant both in control rats and in rats with uranyl nitrate-induced acute renal failure; after intravenous administration of cyclosporin plasma concentrations of propranolol were significantly lower, the area under the plasma concentration-time curve (AUC) for propranolol from time zero to time infinity was significantly smaller, and the time-averaged total body clearance of propranolol was significantly faster. The effects of oral cyclosporin, 100 mg kg(-1), on the pharmacokinetics of oral propranolol, 10 mg kg(-1), were also significant, both in control rats and in rats with uranyl nitrate-induced acute renal failure; after administration of oral cyclosporin plasma concentrations of propranolol were significantly higher and the AUC of propranolol was significantly greater. These data suggest that cyclosporin increases the elimination of propranolol, and that the first-pass effects of propranolol are reduced, or gastrointestinal absorption of propranolol is increased, or both, by cyclosporin.

Acute Kidney Injury↗
PubMed1990

Alteration of propranolol pharmacokinetics and pharmacodynamics by quinidine in man.

The effects of quinidine on pharmacokinetics and pharmacodynamics of propranolol were investigated in a double-blind, placebo-controlled design. Healthy subjects of group A (n = 5) and group B (n = 11) were given oral propranolol (dose: group A 10 mg, group B 20 mg) with placebo or propranolol with quinidine (dose: group A 100 mg, group B 200 mg) on separate occasions. Quinidine induced a significant rise in the plasma concentrations of propranolol, and the area under the propranolol concentration-time curves (AUC) was also increased about 3-fold in both groups, indicative of an alteration of propranolol pharmacokinetics. In order to estimate the pharmacodynamic action of the pharmacokinetic interaction, the change in the heart rate during treadmill exercise testing was studied in group A. A significant inhibition of exercise-induced tachycardia was observed after administration of propranolol alone, but in combination with quinidine an even greater suppression was evident. These results indicate that the coadministration of propranolol and quinidine provides not only the potentiation of quinidine action by propranolol, which has been reported, but also the enhancement of propranolol action by quinidine, due to an increased plasma concentration of propranolol.

Adult↗
PubMed1976

Effects of propranolol on renin release during chronic thoracic caval constriction or acute renal artery stenosis in dogs.

Dogs were given d,1-propranolol before and after thoracic inferior vena cava constriction (TIVCC) or renal artery constriction (RAC) to determine if the increase in plasma renin activity (PRA) and associated biological activity could be suppressed. Oral propranolol administration (240 mg twice daily) was begun at least 2 days prior to TIVCC in six dogs; heart rate was reduced from 133 to 95 beats/min but PRA did not change with propranolol administration. After TIVCC and during continued propranolol administration, daily renal sodium excretion fell from an average value of 50 to less than 3 mEq sodium/day and PRA was elevated two- to fourfold. With prolonged propranolol administration during TIVCC, PRA returned toward normal levels but renal sodium excretion remained low. At this time, hourly measurements of sodium excretion showed no change after a 240-mg oral dose or propranolol although very high plasma levels of propranolol were achieved; also, PRA was unchanged and low. The effects of RAC were studied before and during an intravenous propranolol infusion (0.2 mg/kg/hour) in conscious animals. Before propranolol administration, arterial pressure increased during RAC from 120 to 136 mm Hg and PRA doubled. Propranolol infusion lowered heart rate from 110 to 84 beats/min, but arterial pressure and PRA were not attentuated by propranolol during RAC. The data indicate that non-beta-adrenergic mechanisms are involved in renin release during TIVCC and RAC.

Animals↗
PubMed1990

Chronic treatment with propranolol enhances the synthesis of prostaglandins E2 and I2 by the aorta of spontaneously hypertensive rats.

The effects of treatment with dl, d- or l-propranolol (subcutaneously for 1 week) on arterial blood pressure and on 6-keto prostaglandin (PG) F1 alpha (stable metabolite of PGI2) and PGE2 production by aorta, renal medulla and renal cortex were examined in spontaneously hypertensive rats. dl-Propranolol and l-propranolol significantly (P less than .05) lowered blood pressures from 148 +/- 9/113 +/- 5 (n = 6) and 133 +/- 4/100 +/- 2 (n = 12) mm Hg to 112 +/- 3/80 +/- 3 and 121 +/- 3/81 +/- 3 mm Hg, respectively. Comparable treatment of spontaneously hypertensive rats with inactive d-propranolol was without effect. Basal immunoreactive (i) i6-keto-PGF1 alpha and iPGE2 production by isolated aorta, renal medulla and cortex was not different in vehicle compared to the dl-propranolol-treated rats. In contrast, norepinephrine (1 microM)-stimulated synthesis of i6-keto PGF1 alpha and iPGE2 by the aorta in the dl-propranolol-treated group was significantly (P less than .05) enhanced compared with the vehicle-treated group. Aortic i6-keto-PGF1 alpha and iPGE2 synthesis stimulated by norepinephrine in l-propranolol-treated rats was also significantly (P less than .05) higher than that observed in vehicle and d-propranolol-treated rats. dl-Propranolol treatment did not alter norepinephrine-stimulated renal cortical or medullary i6-keto-PGF1 alpha or iPGE2 synthesis. Indomethacin (5 mg/kg i.p.) given on the last 2 days of dl-propranolol treatment, significantly inhibited aortic i6-keto-PGF1 alpha and iPGE2 production and blunted the antihypertensive effect of dl-propranolol.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

A comparison of verapamil and propranolol for the initial treatment of hypertension. Racial differences in response.

We compared verapamil and propranolol hydrochloride for monotherapy of hypertension. Verapamil lowered blood pressure (BP) more effectively than propranolol in black and white patients. Verapamil was equally effective in blacks and whites, whereas propranolol was more effective in whites. Heart rate was reduced by 6.0 beats per minute by verapamil, and by 13.6 beats per minute by propranolol. In blacks, verapamil lowered systolic BP 16.9 vs 8.1 mm Hg for propranolol; verapamil reduced diastolic BP 12.8 vs 8.6 mm Hg for propranolol. In whites, verapamil lowered systolic BP 19.0 vs 12.7 mm Hg for propranolol; verapamil reduced diastolic BP 16.7 vs 12.3 mm Hg for propranolol. Increases in systolic BP were observed in 22% and 3.4% of patients receiving propranolol and verapamil, respectively. The PR interval was increased from 163.5 to 174.9 ms for verapamil vs 160.3 to 164.4 ms for propranolol. Constipation (15%) and headaches (10%) were most frequent complaints for verapamil vs fatigue (18%) and dizziness (7%) for propranolol. Changes in blood biochemistry values were of small magnitude. We conclude that verapamil monotherapy is a safe and effective means of achieving BP control in patients with essential hypertension.

Adult↗
PubMed1984

Effects of the (+/-)-, (+)- and (-)-forms of propranolol, timolol and metoprolol on noradrenergic transmission in the rat isolated right ventricle.

The effects of the (+/-)-, (+)- and (-)-forms of propranolol, timolol and metoprolol on noradrenergic transmission have been studied in the rat isolated right ventricle. (+)- And (-)-propranolol (10(-5) M) inhibited the accumulation of radioactivity from [3H]-noradrenaline. The decline in the spontaneous outflow of radioactivity, following loading of the tissue with [3H]-noradrenaline, was reduced by (+)- and (-)-propranolol (10(-5) M), (+)-timolol (10(-5) M), (-)-timolol (10(-6) - 10(-5) M) and (+)-metoprolol (10(-5) M). (+)-Propranolol, (+)-timolol (10(-6) M) and (+)- and (-)-metoprolol (10(-5) M) increased the decline in outflow of radioactivity evoked by field stimulation in the absence, but not in the presence, of lignocaine (10(-4) M), probably by decreasing nerve excitability. The ability of (-)-propranolol (10(-5) M) to increase the decline in evoked outflow was also reduced in the presence of lignocaine. (+)-Propranolol, (+)-timolol and (-)-metoprolol reduced the contractile response to field stimulation by a similar percentage in the absence or presence of lignocaine. The ability of (-)-propranolol and (+)-metoprolol (10(-5) M) to reduce contractile responses was decreased and abolished, respectively, by the addition of lignocaine. Evoked-outflow was not altered but contractile responses were inhibited by (-)-timolol (10(-7) - 10(-5) M) and (-)-metoprolol (10(-5) M). Contractile responses to isoprenaline were not altered by (+)-propranolol, (+)-timolol (10(-7) M) and (+)-metoprolol (10(-7) - 10(-6) M). (+)- Or (-)-propranolol (10(-7) M) and (+)-timolol (10(-6) M) had no effect on the rate of beating to isoprenaline but reduced the force whereas (+/-)-metoprolol (10(-7) M) had no effect on the force but reduced the rate of beating. The rate of beating and force responses to isoprenaline were reduced by (+/-)-, (+)-, (-)-propranolol (10(-6) M), (+/-)- or (-)-timolol (10(-7) - 10(-6) M), (+/-)-metoprolol (10(-6) M) and (-)-metoprolol (10(-7) - 10(-6) M). The data suggest that, in the rat isolated right ventricle, the (+)-isomers are active constituents of (+/-)-propranolol and (+/-)-timolol but not of (+/-)-metoprolol.

Animals↗
PubMed1983

Effect of experimental renal failure on the disposition kinetics of l-propranolol in rats.

The effect of uranyl nitrate-induced renal failure on the pharmacokinetics of the levo-isomer of propranolol in rats was investigated. The serum clearance of an i.v. dose of propranolol (1.5 mg/kg) in normal animals approached hepatic blood flow, suggesting that the systemic clearance of the drug is rate-limited by blood flow to the liver. Extensive first-pass metabolism was observed after oral administration of l-propranolol was only 7%. Renal failure had no apparent effect on the distribution and elimination of i.v. administered l-propranolol. In contrast, the area under the serum drug concentration time curve after oral administration was increased from 6.95 to 19.3 micrograms X min/ml, which corresponded to a 2.5-fold increase in the systemic availability of l-propranolol (from 7 to 18%). The gastrointestinal absorption of l-propranolol, as assessed by comparing the urinary recovery of radioactivity after i.v. and oral administration of l-[3H]propranolol, was complete in normal animals. Hence, an increase in the extent of absorption of l-propranolol in renal failure cannot be offered as a cause of increased systemic availability. Neither the in vitro nor the in vivo serum protein binding of l-propranolol differed between renal failure and control animals. The intrinsic metabolic clearance of unbound l-propranolol in renal failure rats is estimated to be about 60% lower than that in control rats. These results suggest that the previously reported increase in propranolol serum concentration after oral administration of the drug to uremic patients is due to decreased presystemic biotransformation of the drug.

Acute Kidney Injury↗
PubMed1984

Accumulation, subcellular localization and release of propranolol from synaptosomes of rat cerebral cortex.

Propranolol is accumulated at several adrenergic neuroeffector junctions after chronic oral administration in the dog, and is released subsequently during sympathetic nerve stimulation. In the present study, the accumulation, subcellular localization and release of propranolol was examined in rat cortical synaptosomes. Synaptosomal propranolol accumulation was rapid and attained equilibrium within 1 min. Propranolol uptake increased in a nonlinear manner with increasing drug concentration in the medium, but could not be fully saturated over the concentration range studied (10(-7) - 10(-3) M). Uptake was unaffected by cocaine or ouabain and showed no stereoselectivity. Subsynaptosomal fractionation of propranolol-loaded synaptosomes revealed that the drug was concentrated principally in fractions enriched in synaptic plasma membranes and synaptic storage vesicles. Exposure of propranolol-loaded synaptosomes to elevated potassium evoked a concentration-dependent increase in propranolol overflow, which was not seen in mitochondrial fractions, myelin fractions or in freeze-thawed synaptosomal preparations. Veratridine was also effective in promoting propranolol overflow in a concentration-dependent manner. The increase in propranolol overflow induced by elevated potassium was significantly reduced, but not completely inhibited, in a calcium-free, ethylene glycol bis(beta-aminoethyl ether)-N,N'-tetraacetic acid-supplemented medium. These results indicate that propranolol may be accumulated by neuronal tissue and stored at sites from which release may occur in response to depolarizing stimuli. The data further suggest that propranolol release in the synaptosome preparation may occur by both calcium-dependent and calcium-independent processes.

Animals↗
PubMed1982

Comparison of propranolol and hydrochlorothiazide for thr initial treatment of hypertension. I. Results of short-term titration with emphasis on racial differences in response. Veterans Administration Cooperative Study Group on Antihypertensive agents.

We compared hydrochlorothiazide and propranolol hydrochloride for monotherapy of hypertension by a double-blind study of 683 men who were titrated to less than 90 mm Hg diastolic BP or to 640 mg of propranolol or 200 mg of hydrochlorothiazide. Propranolol reduced systolic BP from 146.0 +/- 14.4 (SD) to 134.8 +/- 16.3 mm Hg and diastolic BP from 101.6 +/- 4.6 to 90.5 +/- 7.5 mm Hg. Hydrochlorothiazide lowered both systolic BP more effectively from 146.5 +/- 15.8 to 128.8 +/- 12.2 mm Hg and diastolic BP from 101.3 +/- 4.5 to 89.4 +/- 6.5 mm Hg. In blacks, hydrochlorothiazide lowered systolic BP 20.3 +/- 14.3 mm Hg v 8.2 +/- 12.2 mm Hg for propranolol; hydrochlorothiazide reduced diastolic BP 13.0 +/- 7.0 mm Hg v 9.5 +/- 7.0 for propranolol. In whites, the systolic BP reductions were 15.3 +/- 12.0 mm Hg for hydrochlorothiazide v 13.2 +/- 13.1 mmn Hg for propranolol; diastolic BPs were 10.9 +/- 5.7 mm Hg for hydrochlorothiazide and 12.6 +/- 6.6 mm Hg for propranolol. In blacks treated with hydrochlorothiazide, 71.3% achieved diastolic BP of less than 90 mm Hg, v 53.5% with propranolol. There was no racial difference in dose response to propranolol, but blacks required much less hydrochlorothiazide to achieve control. We conclude that in this short-term study propranolol was as efficacious as hydrochlorothiazide in whites, but the latter was more effective than propranolol in blacks.

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