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Results for “Propranolol”

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At least 19 recordsLinked to original sources

PubMed1979

Propranolol glucuronide cumulation during long-term propranolol therapy: a proposed storage mechanism for propranolol.

The comparative disposition of propranolol glucuronide (PG) and propranolol was determined in 35 patients with hypertension or coronary artery disease during initiation of propranolol therapy, during steady-state conditions, and after discontinuation of propranolol (dose range, 40 to 960 mg daily, every 6 hr). The 2.3-fold PG cumulation in plasma was identical to propranolol cumulation. PG plasma levels were about 4 times as high as propranolol levels over the whole dose range. Unexpectedly slow terminal elimination rate of propranolol (t1/2 approximately 16 to 24 hr) on discontinuation of propranolol appeared to be related to equally slow PG elimination. PG and propranolol could be detected in plasma and urine up to 3 to 5 days after propranolol discontinuation. The PG formed in man was deconjugated to propranolol in the dog after intravenous administration, suggesting that PG may serve as a storage pool for propranolol. Observations consistent with systemic and enteric deconjugation of PG, including enterohepatic recirculation, may, at least in part, explain the observed propranolol cumulation as well as the slow elimination of propranolol after its discontinuation. PG renal clearance (29 to 70 ml/min) and PG plasma levels were highly dependent on glomerular filtration rate, suggesting that PG may cumulate abnormally in patients with severe renal disease.

Adolescent↗

PubMedDate not supplied

Pharmacokinetics of propranolol after single and multiple dosing with sustained release propranolol or propranolol CR (innopran XL) , a new chronotherapeutic formulation.

Blood pressure rises rapidly upon waking and may be responsible, in part, for the increased incidence of myocardial infarction and stroke during the morning hours. Current formulations and dosing of antihypertensive drugs do not provide maximum coverage during this vulnerable period. This study was performed to demonstrate that propranolol CR (Innopran XL), a novel chronotherapeutic formulation of propranolol designed for nighttime dosing, has appropriate pharmacokinetics to provide maximum cardioprotective effect in the morning. Pharmacokinetics of propranolol CR and sustained-release propranolol after single and multiple doses were determined in normal male volunteers in this open-label, 2-period crossover study. The drugs were dosed in the evening and serial blood samples were taken for determination of propranolol concentration the next 24 to 72 hours. After a single 160-mg dose of propranolol CR administered at 10 pm, absorption was delayed by about 4 hours, after which plasma concentration rose steadily, reaching a peak at about 10:00 am. In contrast, after dosing with sustained release propranolol, plasma levels of propranolol began to rise almost immediately, reaching a plateau between 4:00 am and 10:00 am. During multiple dosing, steady-state trough plasma concentrations were achieved after 2 days with either drug. After the final dose, the plasma profiles of both drugs were similar to those observed in the single-dose study. Bioavailability was similar for both formulations of propranolol. Propranolol CR exhibited appropriate pharmacokinetics for a chronotherapeutic approach to the treatment of hypertension.

1-Propanol↗

PubMed1992

Membrane antiperoxidative activities of D-propranolol, L-propranolol and dimethyl quaternary propranolol (UM-272).

With the isolated sarcolemmal membrane model, the antiperoxidative activities of D-propranolol, L-propranolol and the non-beta-blocker analogue UM-272 (dimethyl quaternary propranolol) were compared. Membrane lipid peroxidation induced by the Fe-catalysed, hydroxyl radical producing system (dihydroxyfumarate + Fe3+) was assessed by MDA formation. In the range of 10-200 microM, both D- and L-propranolol exhibited identical concentration-dependent inhibitory effects (20-70%), whereas UM-272 was about 2/3 as active as propranolol. In contrast, lignocaine (lidocaine), a well known membrane stabilizer, did not produce any effect. When purified rat hepatic microsomes were peroxidized by NADPH + Fe3+, comparable antiperoxidative effects were produced by the propranolol enantiomers and the dimethyl analogue. Thus, the antioxidant activities of these agents are related to their intrinsic chemical properties which might contribute to the reported beneficial effects of propranolol and UM-272 in models of ischaemia/reperfusion injury.

Animals↗

PubMed1978

Pathways of propranolol metabolism. Use of the stable isotope twin-ion GC-MS technique to examine the conversion of propranolol to propranolol-diol by 9000g rat liver supernatant.

The metabolic conversion of propranolol to propranolol-diol [1-(1-naphthyloxy)-2,3-propyleneglycol] by rat liver 9000g supernatant was demonstrated to proceed through the intermediate 3-naphthyloxy-2-hydroxypropionaldehyde. Using side chain deuterated propranolol-d5 as substrate, propranolol-diol-d4 was produced, indicating an obligatory aldehyde intermediate. Analysis of desisopropylpropranolol obtained in the same incubation showed no loss of deuterium indicating that the possibility of rapidly tautomerizing imine intermediate did not make a significant contribution in this metabolic conversion. Desisopropylpropranolol, added in small amounts to the incubation mixture is more rapidly converted to the propranolol-diol than is propranolol, indicating that the major pathway of conversion of propranolol to its diol metabolite is through the desisopropylpropranolol intermediate.

Animals↗

PubMed1986

Studies on the uptake and release of propranolol and the effects of propranolol on catecholamines in cultures of bovine adrenal chromaffin cells.

Uptake and release of [3H]l-propranolol and the effects of propranolol on the uptake and release of [3H]norepinephrine were studied in cultures of isolated bovine adrenal chromaffin cells. [3H]l-Propranolol uptake increased with increasing [3H]l-propranolol concentration from 10(-7) M to 10(-3) M and was not saturable in this concentration range. [3H]l-Propranolol uptake was equally inhibited by l- and d-propranolol, indicating that the uptake is not stereoselective. [3H]l-Propranolol uptake differed from [3H]norepinephrine uptake in two respects: [3H]l-propranolol uptake was 44-50 times greater than [3H]norepinephrine uptake at early non-equilibrium time periods, and [3H]l-propranolol uptake was not Na+ dependent and was not inhibited by desipramine, indicating that [3H]l-propranolol is not taken up by the biogenic amine transport system. In cells preloaded with [3H]l-propranolol, two agents, veratridine and tyramine, stimulated an increased release of [3H]l-propranolol into the medium. However, veratridine-induced [3H]l-propranolol release was inhibited only slightly by the Na+ channel blocker tetrodotoxin, and tyramine-induced [3H]l-propranolol release was not inhibited by desipramine. In addition, K+, carbachol and the physiological mediator of adrenal catecholamine release, acetylcholine, failed to evoke [3H]l-propranolol release. Therefore, it is unlikely that propranolol is released in response to physiological stimulation of adrenal chromaffin cells in animals administered propranolol in vivo. l-Propranolol inhibited [3H]norepinephrine uptake by chromaffin cells with an IC50 for l-propranolol of 5 X 10(-6) M; d-propranolol was equally potent for this effect at lower propranolol concentrations. By themselves, neither l- nor d-propranolol had any effect on [3H]norepinephrine release from the cells. However, l-propranolol inhibited carbachol-induced [3H]norepinephrine release with an IC50 for l-propranolol of 5 X 10(-7) M to 10(-6) M. At these lower concentrations, d-propranolol had no effect on carbachol-induced [3H]norepinephrine release, indicating that the inhibition by l-propranolol may be mediated via beta-adrenoceptors on chromaffin cells.

Acetylcholine↗

PubMed1985

Propranolol-verapamil versus propranolol-nifedipine in severe angina pectoris of effort: a randomized, double-blind, crossover study.

To compare a propranolol-verapamil with a propranolol-nifedipine combination in patients with severe angina of effort, 16 patients (11 men and 5 women, aged 56 +/- 8 years [mean +/- standard deviation]) with more than 5 episodes/week of angina and a positive exercise tolerance test despite propranolol (229 +/- 44 mg/day [range 180 to 360]) were maintained on this dose of propranolol and, in addition, received verapamil (360 mg/day) and nifedipine (60 mg/day) for 3 weeks each in a double-blind, randomized fashion. In comparison with propranolol alone, anginal frequency and nitroglycerin usage were reduced by propranolol-verapamil but not by propranolol-nifedipine. Exercise time (standard Bruce protocol) was similar for the 2 combinations (6.4 +/- 2.0 minutes with propranolol-verapamil, 6.6 +/- 2.1 minutes with propranolol-nifedipine, difference not significant), but the magnitude of ST-segment depression at peak exercise was less (p less than 0.05) during propranolol-verapamil (0.03 +/- 0.06 mV) than during propranolol alone (0.18 +/- 0.07 mV) and propranolol-nifedipine (0.08 +/- 0.07 mV). Left ventricular ejection fraction at rest was higher (p less than 0.05) with propranolol-nifedipine (0.62 +/- 0.10) than with propranolol-verapamil (0.58 +/- 0.10), but neither differed from ejection fraction at rest with propranolol alone (0.59 +/- 0.08). Ejection fraction at peak exercise was similar during all 3 periods. In 2 patients, verapamil caused weakness, lightheadedness, and severe sinus bradycardia (40 to 48 beats/min), and the dosage was reduced (blindly) to 240 mg/day, with the alleviation of bradycardia and associated symptoms.(ABSTRACT TRUNCATED AT 250 WORDS)

Angina Pectoris↗

PubMed1998

Propranolol plus prazosin compared with propranolol plus isosorbide-5-mononitrate in the treatment of portal hypertension.

BACKGROUND & AIMS: The association of prazosin to propranolol enhances the decrease in portal pressure but may cause hypotension and sodium retention. The aim of this study was to compare the portal pressure reduction and safety of the combination of propranolol plus prazosin with that of propranolol plus isosorbide-5-mononitrate (ISMN). METHODS: Fifty-six portal-hypertensive cirrhotics received randomly propranolol plus prazosin (n = 28) or propranolol plus ISMN (n = 28) orally for 3 months. Hemodynamics and liver and renal function were assessed at baseline and after 3 months. RESULTS: Propranolol plus prazosin caused a greater reduction in hepatic venous pressure gradient (HVPG) than propranolol plus ISMN (-24.2% +/- 11% vs. -16.1% +/- 11%; P < 0.01). A reduction in HVPG of > 20% was significantly more frequent in the propranolol plus prazosin group than in the propranolol plus ISMN group (85% vs. 53%; P < 0.05). Neither treatment modified hepatic blood flow, quantitative liver function test results, glomerular filtration rate, plasma renin activity, or plasma aldosterone level. Side effects occurred in 13 patients receiving propranolol plus prazosin compared with 7 receiving propranolol plus ISMN (P = 0.16). CONCLUSIONS: Propranolol plus prazosin has a greater portal pressure-lowering effect than propranolol plus ISMN. Both therapies were safe for liver and renal function. However, the combination of propranolol plus prazosin caused a greater decrease in arterial pressure and was less well tolerated than propranolol plus ISMN.

Adrenergic alpha-Antagonists↗

PubMed1992

Racemic (R,S)-propranolol versus half-dosed optically pure (S)-propranolol in humans at steady state: Hemodynamic effects, plasma concentrations, and influence on thyroid hormone levels.

In a randomized, double-blind, crossover study in 10 healthy volunteers the hemodynamic effects, drug plasma concentrations, and thyroid hormone profiles were compared after oral administration for 1 week of 40 mg t.i.d. racemic (R,S)-propranolol versus 20 mg t.i.d. optically pure (S)-propranolol. During exercise, both substances decreased heart rate (-14%, p less than 0.01), as well as the overall rate pressure product (-19%, p less than 0.01) to the same extent, indicating similar beta-blocking effects. After oral application of (R,S)-propranolol the maximal plasma concentration (Cmax) and the area under the plasma concentration-time curve (AUC) of (S)-propranolol were higher than those of (R)-propranolol (eudismic ratios (S)- over (R)-propranolol Cmax, 1.36 [p less than 0.01] and AUC, 1.42 [p less than 0.01]) despite dose-equivalence of both enantiomers in the administered racemic (R,S)-propranolol preparation indicating different pharmacokinetic properties. Mean values of Cmax and the AUC of (S)-propranolol did not differ significantly after 1 week of oral administration of 40 mg (R,S)-propranolol and 20 mg (S)-propranolol t.i.d., respectively. The ratio of triiodothyronine to thyroxine was decreased by (R,S)-propranolol (-25%, p less than 0.01) but not by (S)-propranolol, suggesting that only the (R)-enantiomer inhibits the conversion of thyroxine to triiodothyronine. Thus, half-dosed optically pure (S)-propranolol is an equally effective beta-adrenergic receptor antagonist compared with currently used racemic (R,S)-propranolol. By contrast, the conversion of thyroxine to triiodothyronine is inhibited by (R)-propranolol only.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗

PubMed1996

Propranolol plus molsidomine vs propranolol alone in the treatment of portal hypertension in patients with cirrhosis.

BACKGROUND/AIMS: Effective protection from the risk of variceal bleeding is achieved when the hepatic venous pressure gradient is reduced to 12 mmHg or at least by 20% of baseline values. Such a marked decrease is rarely achieved with propranolol, and new agents or combinations of them are now being explored. The present randomized study investigated whether chronic treatment with the combination of propranolol plus molsidomine, a preferential venous dialator that reduces hepatic venous pressure gradient and does not cause pharmacological tolerance, achieves greater reduction in hepatic venous pressure gradient than propranolol alone. METHODS: A hemodynamic study was performed in 34 patients with cirrhosis with portal hypertension in baseline conditions and after 3 months of chronic oral treatment with propranolol alone (n = 19) or propranolol plus molsidomine (n = 15). RESULTS: Propranolol produced a significant reduction in hepatic venous pressure gradient (-16%, p < 0.01). Propranolol plus molsidomine also caused a slight but significant decrease in hepatic venous pressure gradient (-9%, p < 0.05). Hepatic blood flow and the hepatic and intrinsic clearance of indocyanine green were significantly reduced by propranolol. The combined administration of propranolol+molsidomine significantly reduced hepatic blood flow but not hepatic and intrinsic clearance of indocyanine green. Both treatment groups produced similar reduction in azygos blood flow, heart rate and cardiac output. However, contrary to propranolol alone, propranolol plus molsidomine did not increase cardiopulmonary pressures. CONCLUSIONS: The current study shows that although the combined administration of propranolol plus molsidomine prevents some of the adverse effects of propranolol on liver function and cardiopulmonary pressures, it does not achieve a greater reduction in hepatic venous pressure gradient than propranolol alone and therefore, does not support the use of this combined therapy for the pharmacological treatment of portal hypertension.

Adult↗

PubMed1989

Comparative study of the effect of nifedipine versus diltiazem on exercise performance, serum propranolol levels, and ST-segment abnormalities in patients with chronic stable angina taking propranolol.

Twelve patients (10 men and 2 women), mean age 60.6 years (range 50 to 75), with stable angina pectoris were administered propranolol until beta blockade was evident. Treadmill exercise testing was performed, 24-hour ambulatory electrocardiograms were recorded, and serum propranolol levels were assessed at 1 and 2 hours after dosing with propranolol alone, and after 2 weeks of combined therapy with either nifedipine, 10 or 20 mg, or diltiazem, 60 or 120 mg, administered every 8 hours. Patients were assigned to treatment regimens in randomized, double-blind, crossover fashion. At the time of exercise testing, maximal exercise time, time to angina, peak exercise heart rate and systolic blood pressure and time to 1 mm of ST-segment depression were measured. The rate-pressure product was also calculated. Maximal exercise time increased from 708 +/- 140 seconds with propranolol alone to 795 +/- 156 seconds after combined propranolol-nifedipine therapy (p less than 0.05), and to 790 +/- 107 seconds (p less than 0.05) after propranolol-diltiazem therapy. Time to onset of angina increased from 472 +/- 191 seconds with propranolol alone to 564 +/- 123 seconds (p = NS) after propranolol-nifedipine treatment and to 607 +/- 197 seconds (p less than 0.05) after propranolol-diltiazem treatment. Peak exercise heart rate remained unchanged with propranolol-nifedipine therapy (103 +/- 16 beats/min vs 104 +/- 17 with propranolol alone). However, with propranolol-diltiazem therapy, peak exercise heart rate significantly decreased to 95 +/- 14 beats/min (p less than 0.05); peak systolic blood pressure and rate-pressure products were comparable on all treatment regimens.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗

PubMed1990

Differences in stereoselective disposition of propranolol do not explain sensitivity differences between white and Chinese subjects: correlation between the clearance of (-)- and (+)-propranolol.

We have previously demonstrated that Chinese subjects are more sensitive than white subjects to beta-blockade produced by propranolol. To determine if this difference was because a greater proportion of the total propranolol was the more active (-)-isomer of propranolol in the Chinese subjects than in the white subjects, the relative pharmacokinetics of (+)- and (-)-isomers of propranolol after administration of a single, 80 mg oral dose of racemic propranolol was studied in 10 Chinese male and in 9 white male healthy subjects. The plasma concentrations of both (+)- and (-)-propranolol were lower in Chinese than in white subjects, resulting in significantly lower peak plasma concentrations and areas under the concentration-time curve (AUC) in Chinese subjects, the half-life of elimination did not differ significantly between Chinese and white subjects or between the two isomers. The concentrations of the active (-)-propranolol were higher in both groups of subjects because of the lower clearance of the (-)-propranolol compared with the (+)-propranolol. An excellent correlation between the clearance of (+)- and (-)-propranolol was seen in the same individual. The ratio of AUC of (-)- and (+)-propranolol did not differ between Chinese subjects (0.64 +/- 0.03) and white subjects (0.71 +/- 0.09). The data suggest that the proportion of the two isomers found in Chinese and white subjects did not differ, and therefore differences in stereoselective disposition of propranolol cannot explain the increased sensitivity seen in Chinese individuals.

Adult↗

PubMed2005

Stereoselective urinary excretion of S-(-)- and R-(+)-propranolol glucuronide following oral administration of RS-propranolol in Chinese Han subjects.

AIM: To study the stereoselectivity of phase II glucuronidation metabolism of side-chain propranolol in Chinese Han population. METHODS: Sixteen adult Chinese Han volunteers with an average age of 20 years were given a single oral dose of 20 mg racemic propranolol. Human urine at indicated time after administration was collected and S-(-)-propranolol glucuronide and R-(+)-propranolol glucuronide were determined simultaneously by using RP-HPLC. RESULTS: The mean values of k were 0.19+/-0.04 h(-1) and 0.28+/-0.06 h(-1), of t(1/2) 3.56+/-0.73 h and 2.45+/-0.50 h, of T(max) 2.21+/-0.45 and 1.75+/-0.33 h, and of Xu(0-24) 5.65+/-0.98 and 2.95+/-0.62 micromoL for S-(-)- and R-(+)-propranolol glucuronide, respectively. The cumulative excretion percentages in urine of doses were 14.7+/-2.46% and 7.68+/-1.60% for S-(-)- and R-(+)-propranolol glucuronide, respectively. The results showed the elimination rate constant k of S-(-)-propranolol glucuronide was less than that of R-(+)-propranolol glucuronide; and the elimination half-life (t(1/2)), T(max) and the cumulative excretion amount(Xu(0-24)) of R-(+)-propranolol glucuronide were significantly less than that of S-(-)-propranolol glucuronide. CONCLUSION: The propranolol glucuronidation of the side-chain undergoes stereoselective excretion in Chinese Han population after an oral administration of racemic propranolol.

Administration, Oral↗

PubMed1975

Brain concentration of propranolol in relation to hypotensive effect in the rabbit with observations on brain propranolol levels in man.

Intracerebroventricular (ICV) injection of propranolol in the dog, cat and rabbit produces a significant fall in arterial pressure. In the following experiments, regional brain propranolol concentrations and changes in mean arterial pressure (MAP) have been measured in the rabbit after central and peripheral administration of the drug and the results compared to human brain/plasma levels. In the conscious rabbit, ICV injection of l-propranolol (500 mug) produced a prolonged fall in MAP, maximal at 105 minutes (16.8 plus or minus 5.9 mm Hg below base line). The regional brain propranolol concentrations after ICV injection of 14C-dl-propranolol (530 mug) were determined and the levels compared to those achieved following i.v. infusion of the unlabeled drug (1.0 and 2.0 mg/kg/hr). The propranolol concentrations in the hypothalamus, medulla pons and midbrain after i.v. infusion were similar to the propranolol content in these areas at 60 and 120 minutes after ICV injection. Intravenous infusion of propranolol also resulted in significant falls in MAP between 60 and 120 minutes. In control studies, infusions of d-propranolol (1.0, 2.0 and 4.0 mg/kg/hr), which is virtually devoid of beta adrenoceptor blocking activity, produced only slight reductions in MAP. Postmortem studies in patients treated with prolonged i.v. infusions of d-propranolol as part of the treatment of paraquat poisoning indicate that the brain/plasma concentration of propranolol in man is similar to that observed in the rabbit. Propranolol is therefore highly concentrated in human brain tissue and comparable brain levels in the rabbit result in a hypotensive response.

Adult↗

PubMed1978

The contribution of propranolol metabolites to the fluorometric assay of propranolol in human plasma.

1. Studies were undertaken to determine the fluorescent properties of several propranolol metabolites under the conditions of the fluorometric propranolol assay. Of the metabolites studied, propranolol glycol and N-desisopropylpropranolol had significant molar fluorescent coefficients relative to propranolol (72 and 79% respectively). N-desisopropylpropranolol was extracted with the same efficiency as propranolol (greater than 90%) wheras the glycol metabolite had only 34% extraction efficiency. Addition of each metabolite to samples of human plasma containing propranolol produced the predicted increase in fluorescent intensity. 2. Gas chromatographic analysis of plasma collected from 22 hypertensive patients chronically receiving oral propranolol revealed low concentrations of propranolol glycol and N-desisopropylpropranolol relative to propranolol. The results of these studies indicate that fluorescent metabolites of propranolol are not present in sufficient concentration to significantly interfere with the fluorometric assay of propranolol.

Chromatography, Gas↗

PubMed1990

Quinidine reduces clearance of (+)-propranolol more than (-)-propranolol through marked reduction in 4-hydroxylation.

Because both quinidine and propranolol bind to the cytochrome P-450 responsible for the oxidation of debrisoquin, six healthy male subjects were studied to determine whether an interaction occurred between the two drugs and the pharmacodynamic consequences of that interaction. The coadministration of quinidine resulted in a doubling of the area under the plasma concentration-time curve of (+/-)-propranolol (530 +/- 99 versus 1051 +/- 138 ng.hr/ml; p less than 0.05) and a reduction in the clearance of (+/-)-propranolol from 3087 +/- 648 to 1378 +/- 173 ml/min (p less than 0.05). The metabolism of propranolol by the 4-hydroxylation pathway was almost abolished by quinidine, resulting in a fall in the partial metabolic clearance by this pathway from 678 +/- 246 to 56 +/- 11 ml/min (p less than 0.05). Quinidine differentially affected the metabolism of (+)-propranolol and (-)-propranolol, resulting in an increase of 176.6% +/- 45.5% and 100.4% +/- 25.5% in the area under the plasma concentration-time curve of (+)-propranolol and (-)-propranolol, respectively (p less than 0.05). The pharmacokinetic changes were associated with pharmacodynamic effects. The combination of propranolol and quinidine resulted in increased beta-blockade measured by reduction in exercise heart rate and prolongation of the QTc and PR intervals. We conclude that quinidine stereoselectively inhibits the metabolism of propranolol through inhibition of the debrisoquin isozyme. The increased concentration of propranolol produced by quinidine results in increased beta-blockade.

Adult↗

PubMed2000

Propranolol stimulates histone phosphorylation by a putative PK-C in partially purified homogenate of rat testicular interstitial cells. A possible mechanism for increased testosterone secretion by propranolol.

The beta-adrenoceptor blocker propranolol stimulated testosterone secretion by rat testicular interstitial cells (Leydig cell-enriched preparation) in vitro at concentrations ranging from 10(-5) M to 10(-4) M. Treatment of these cells with H7 (20 microM), an inhibitor of protein kinase C, reduced the stimulatory effect of L-propranolol on testosterone secretion by about 5-fold. At concentrations ranging from 31.25 microM to 1000 microM, L-propranolol reduced [3H]phorbol 12,13-dibutyrate binding (IC50 = 75 microM) to rat testicular interstitial cells. At similar concentrations, L-propranolol displaced the binding of [3H]phorbol 12,13-dibutyrate to the homogenate of these cells by only 5%. These findings suggest that the effect of L-propranolol on [3H]phorbol 12,13-dibutyrate binding could be indirect, possibly by increasing the concentration of a chemical mediator interacting with the regulatory domain of protein kinase C. At even lower concentrations (10(-9) M to 10(-7) M), propranolol added directly to the reaction mixture with protein kinase C partially purified from rat testicular interstitial cells increases the phosphorylation of histone. This phosphorylation was comparable to that obtained with (25 microg/ml) phosphatidylserine. The D- and L-stereoisomers of propranolol were equally active. A complete reversal of this propranolol effect on histone phosphorylation was achieved with (20 microM) H-7. In the absence of Ca2+, propranolol was not able to phosphorylate the histone. Taken together, these results suggest that protein kinase C could be the putative kinase involved in this reaction and that its activation by propranolol may be due to interaction of the drug with the regulatory domain of the enzyme at a site differing from the site of interaction with phorbol 12,13-dibutyrate. The ability of propranolol to activate the putative protein kinase C could be related to its stimulatory effect on testosterone secretion by Leydig cells.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗

PubMed1983

Chemical aspects of propranolol metabolism. Synthesis and identification of 3-(4-hydroxy-1-naphthoxy)propane-1,2-diol as a metabolite of propranolol in the dog, in man and in the rat liver 9000g supernatant fraction.

4-Hydroxypropranolol glycol (2), a suspected metabolite of propranolol was synthesized from 4-allyloxy-1-naphthaldehyde (4). Osmium tetroxide oxidation of 4 afforded a glycol (5) and subsequent Baeyer-Villiger rearrangement afforded 2. Its presence as a biliary metabolite in a dog maintained on a constant infusion of pseudoracemic propranolol (made up of equal molar 2S-propranolol-3',3'-d2 and 2R-propranolol-d0) into the portal vein was confirmed based on GC-MS data of the TFA and TMS derivatives of the standard and biliary metabolites. Greater amounts of 2 arose from 2R-propranolol than from 2S-propranolol (1.5:1). Similarly, 2 was formed as a urinary metabolite in one subject maintained on oral propranolol, 80 mg every 6 hours. Compound 2 was also formed when propranolol and propranolol glycol were incubated in the presence of the rat liver 9000g supernatant fraction. In addition to 2, an isomeric ring-hydroxylated propranolol glycol, perhaps 7-hydroxypropranolol glycol, was formed when propranolol glycol was the substrate.

Aged↗

PubMed1981

Systemic and forearm haemodynamic and metabolic effects of racemic propranolol or D-propranolol in healthy subjects.

1. The immediate haemodynamic and metabolic effects of intravenous administration of DL-propranolol and D-propranolol were studied in healthy male subjects at rest and during dynamic forearm exercise. The dose of DL-propranolol and of D-propranolol was 0.1 and 1.0 mg/kg body weight respectively. 2. DL-Propranolol reduced heart rate significantly at rest, during forearm exercise and post-exercise, whereas D-propranolol had a lesser effect on heart rate which was significant only at the end of the exercise period. Arterial blood pressure and forearm blood flow were unchanged after either drug. 3. Both drugs reduced the release of lactate from the exercising forearm. Forearm exchange of oxygen, glucose, free fatty acids and triglycerides remained unchanged. 4. The arterial blood glucose concentration increased after D-propranolol, but was unchanged after DL-propranolol. The arterial serum free fatty acid concentration decreased after DL-propranolol, but was not changed after D-propranolol. Arterial concentrations of lactate and triglycerides were not influenced by the drugs. 5. The chronotropic response to beta-adrenoceptor blockade appears to be stereoselective, suggesting specific blockade of beta-adrenoceptors. Metabolic responses to beta-adrenoceptor blockade are difficult to explain in terms of the known adrenoceptor system and may be due to non-specific actions of beta-adrenoceptor antagonists. An exception is inhibition of lipolysis, which is probably mediated via beta-adrenoceptors.

Adult↗