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At least 19 recordsLinked to original sources

PubMed2003

Atypical cardiostimulant beta-adrenoceptor in the rat heart: stereoselective antagonism by bupranolol but lack of effect by some bupranolol analogues.

1. Atypical beta-adrenoceptors resistant to propranolol, but blocked by bupranolol, increase contractile force and/or frequency of the heart in humans and rats. We compared the potencies of the enantiomers of bupranolol and examined the possible effects of seven bupranolol analogues including bevantolol (BEV) at this receptor in pithed and vagotomized rats. 2. CGP 12177, an agonist of the atypical beta-adrenoceptor, increased heart rate dose-dependently. Its dose-response curve was shifted to the right by S-(-)-bupranolol 10 micro mol kg(-1) by a factor of 8.4, but not affected by the same dose of R-(+)-bupranolol. 3. Desmethylbupranolol and compounds BK-21, BK-22, BK-23 and BK-25 also increased heart rate dose-dependently. The beta(1)-adrenoceptor antagonist CGP 20712 given in combination with the beta(2)-adrenoceptor antagonist ICI 118,551 (0.1 micro mol kg(-1) each) reduced the positive chronotropic action of the five bupranolol analogues without affecting that of CGP 12177. The potencies of the bupranolol analogues to increase heart rate were correlated (r=0.91, P<0.05) with their affinities for beta(1)-adrenoceptor binding sites in rat brain cortex membranes labelled with [(3)H]CGP 12177 (in the presence of ICI 118,551). 4. BK-26 and BEV, 10 micro mol kg(-1) each, had only minor effects on heart rate by themselves and did not antagonize the effect of CGP 12177. However, at 1 micro mol kg(-1), they antagonized the increase in heart rate elicited by the beta(1)-adrenoceptor agonist prenalterol. 5. In conclusion, bupranolol is a stereoselective antagonist at the atypical cardiostimulant beta-adrenoceptor. The effects of the bupranolol analogues are related to the activation or blockade of beta(1)-adrenoceptors, but not of atypical beta-adrenoceptors.

Adrenergic beta-Antagonists↗

PubMed1980

Evidence that (+)-bupranolol interacts directly with myocardial beta-adrenoceptors. Control of optical purity with differential thermal analysis.

Melting points measured with the capillary method were 150.5 degree C, 150.5 degree C and 224.0 degree C for hydrochlorides of (+)-bupranolol, (-)-bupranolol and (+/-)-bupranolol, respectively. The large difference in melting points of 73.5 degree C prompted us to determine possible contaminations of (+)-bupranolol with traces of (-)-bupranolol using differential scanning calorimetry. We detected as little as 0.001% (-)-bupranolol in a standard mixture of (+)-bupranolol and (-)-bupranolol. A batch of (+)-bupranolol not measurably contaminated with (-)-bupranolol (optically purity greater than 99.999%) was used in pharmacological and biochemical assays. The affinities of (-)-bupranolol and (+)-bupranolol were determined functionally by the blockade of isoprenaline stimulation of spontaneously beating rat right atria and electrically driven kitten papillary muscles; and directly by inhibition of binding of 3H-(-)-propranolol to kitten ventricle membrane particles. In all 3 systems the enantiomeric (-)/(+) affinity ratio was 50--120 for bupranolol. These experiments prove that (+)-bupranolol itself binds to the beta-adrenoceptors of mammalian myocardium.

Animals↗

PubMed1993

Interactions of bupranolol with the polymorphic debrisoquine/sparteine monooxygenase (CYP2D6).

The beta-adrenoceptor blocker bupranolol turned out to be a competitive inhibitor of the polymorphic cytochrome P450 CYP2D6 of which sparteine is a substrate. There was stereo-selectivity of bupranolol involved: (-)-bupranolol was the weakest inhibitor with an apparent Ki value of 1.32 microM, (+)-bupranolol was the most potent with an apparent Ki value of 0.55 microM, while the therapeutically used racemic bupranolol had an intermediate value of 0.88 microM. A 10 min pre-incubation of 5 microM bupranolol with the enzyme preparation prior to the addition of substrate, reduced the inhibition of sparteine metabolism from 52 to about 25%. This suggests that--during these inhibition studies--bupranolol was much more rapidly metabolized than was sparteine, so that the measured Ki values must represent overestimates. The enzyme catalysing bupranolol metabolism was CYP2D6: microsomes from a liver with the genetic enzyme deficiency did not metabolize bupranolol; in microsomes from livers containing the enzyme and 10 microM bupranolol, 5 microM quinidine caused a 72% inhibition of bupranolol metabolism. Although our methods were not sufficiently sensitive to measure the Km of bupranolol directly, it is undoubtedly the beta-adrenoceptor blocker with the highest-known apparent affinity for CYP2D6. High affinity and rapid metabolism are infrequent combinations in enzymology.

Binding, Competitive↗

PubMed1980

[On the inhibition of thrombocyte aggregation by bupranolol / Aggregometric and electron microscopic study in vitro (author's transl)].

The ADP-induced primary aggregation of human thrombocytes in vitro was inhibited by 1.5X10(-4) mol/l (+/-)bupranolol. At this concentration a strong desaggregation was obtained. The stereoisomers of bupranolol did not differ in effectiveness. Fractional addition was just as effective as a single dose. Not beta-receptor blocking but a membrane stabilizing effect is, therefore, the probable mechanism -- as in the case of propranolol. The less lipophilic metabolites hydroxybupranolol and carboxybupranolol were one-fourth and one-fifth as effective, respectively, as bupranolol. 5X10(-4) mol/l ASA (final concentration) showed the same inhibition of primary aggregation as did 1.5X10(-4) mol/l bupranolol but elicited less desaggregation. Doubling this dose of ASA resulted in a weaker inhibition than the subsequent addition of the aforementioned doses of bupranolol and ASA or vice versa, while this combination, in turn, inhibited less than a double dose of bupranolol. 1.5X10(-4) mol/l bupranolol inhibited the formation of pseudopodia by thrombocytes not stimulated with ADP. At 3X10(-4) mol/l this inhibition was drastic but no morphological damage was seen.

Adenosine Diphosphate↗

PubMed1976

Effects of bupranolol, a new beta-blocker, on platelet functions of rabbit and human in vitro.

The effects of bupranolol, a new beta-blocker, on platelet functions were investigated in vitro in rabbits and humans as compared with propranolol, a well-known beta-blocker. At first, the effect of adrenaline on ADP-induced rabbit platelet aggregation was studied because adrenaline alone induces little or no aggregation of rabbit platelets. Enhancement of ADP-induced rabbit platelet aggregation by adrenaline was confirmed, as previously reported by Sinakos and Caen (1967). In addition the degree of the enhancement was proved to be markedly affected by the concentration of ADP and to increase with decreasing concentration of ADP, although the maximum aggregation (percent) was decreased. Bupranolol and propranolol inhibited the (adrenaline-ADP-)induced aggregation of rabbit platelets, bupranolol being approximately 2.4-3.2 times as effective as propranolol. Bupranolol stimulated the disaggregation of platelet aggregates induced by a combination of adrenaline and ADP, but propranolol did not. Platelet adhesion in rabbit was also inhibited by the beta-blockers and bupranolol was more active than propranolol. With human platelets, aggregation induced by adrenaline was inhibited by bupranolol about 2.8-3.3 times as effectively as propranolol. From these findings. We would suggest that bupranolol might be useful for prevention or treatment of thrombosis.

Adenosine Diphosphate↗

PubMed1980

A radioautographic study on the incorporation of 14C-bupranolol (beta-blocking agent) into the rabbit eye.

Localization of instilled 14C-bupranolol was studied in the rabbit eye by means of light microscopic radioautography. After the administration of 50 microliter of 14C-bupranolol into the eyes of two rabbits, both eyes were enucleated at intervals of 15 and 30 min respectively, and radioautographic procedures were carried out on cryostat sections by means of both dry-mounting and wet-mounting methods. Although with the former it was possible to demonstrate many radioautographic silver grains in the specimens, with the latter it was not possible to detect their localization. On the dry-mounting procedure, radioautographic grains were observed mainly in the epithelium of the ciliary body 15 and 30 min after the administration of 14C-bupranolol. The numbers of grains were counted on the 15 and 30 min specimens. They were decreased in the conjunctiva, and cornea 30 min after the administration. On the contrary, they were remarkably increased in the epithelium of the ciliary body. From these results it is concluded that the 14C-bupranolol first penetrates into the epithelium of the conjunctiva and cornea, then moves rapidly to the ciliary body, and that only very small amount of 14C-bupranolol is changed into the insoluble form. Also, these results suggest that bupranolol plays a role in the control of aqueous production in the ciliary processes.

Animals↗

PubMed1999

Effect of bupranolol for BRL37344 and noradrenaline-induced relaxations mediating atypical beta/beta3-adrenoceptor in rat oesophageal muscularis mucosae.

We previously suggested that the existence of atypical beta/beta3-adrenoceptor with pA2-values for bupranolol, a non-selective beta-adrenoceptor antagonist, against BRL37344 and noradrenaline were 5.79 and 5.53 in guinea pig taenia caecum, respectively. We furthermore determined the affinity of bupranolol to subclassify atypical beta/beta3-adrenoceptor in rat oesophageal muscularis mucosae, because it is rich in atypical beta/beta3-adrenoceptor. BRL37344 and noradrenaline produced a concentration-dependent relaxation of rat oesophageal muscularis mucosae. The responses to BRL37344 and noradrenaline were resistant to 3x10(-6) M propranolol, 10(-4) M atenolol, and 10(-4) M butoxamine. However, bupranolol antagonized the responses to BRL37344 and noradrenaline in a concentration-dependent manner. Schild plot analyses of bupranolol against BRL37344 and noradrenaline gave pA2-values of 7.06 and 6.96, respectively. These results suggest that bupranolol can distinguish the difference in affinity between atypical beta/beta3-adrenoceptors in rat oesophageal muscularis mucosae and guinea pig taenia caecum. The difference in behavior of bupranolol confirms the existence of some atypical beta/beta3-adrenoceptors subtypes.

Adrenergic alpha-Agonists↗

PubMed1986

Transdermal delivery of bupranolol: pharmacodynamics and beta-adrenoceptor occupancy.

Bupranolol is a non-selective beta-adrenoceptor antagonist with a Ki-value of 6-15 nmol/l (equivalent to 1.5-4 ng/ml in plasma) at beta 1- (rat salivary gland) and beta 2-adrenoceptors (rat reticulocytes) in receptor binding studies with 3H-CGP 12177 in the presence of human plasma. After oral administration of 200 mg bupranolol to healthy volunteers, the maximal plasma concentration was observed within 1.2 h but it only reached a level close to the Ki-value. Elimination from plasma was rapid (t 1/2 = 2.0 h). Administration of 30 mg bupranolol in a transdermal delivery system (TTS) every 24 h to 6 healthy volunteers for 72 h yielded steady state plasma concentrations 4- to 5-times above the Ki-value as shown by in vitro inhibition of beta-adrenoceptor binding by plasma samples. The pharmacodynamic effect, measured as the reduction in exercise tachycardia, showed a stable inhibitory effect; antagonism of a bolus injection of isoprenaline indicated a 10- to 15-fold right shift of the dose-response curve during the observation period of 72 h. It is concluded that steady-state plasma concentrations and effect of the elsewise rapidly eliminated beta-blocker bupranolol can be achieved by a transdermal delivery system applied each day.

Administration, Cutaneous↗

PubMed1995

Effect of bupranolol on CGP 12177-induced relaxation and cAMP accumulation in the guinea pig taenia caecum.

1. The effect of bupranolol on CGP 12177-induced relaxation and cAMP accumulation in the guinea pig taenia caecum was examined. 2. The relaxant response to CGP 12177 was unaffected by propranolol (approximately 10(-6) M), whereas that to CGP 12177 was antagonized in a concentration-dependent manner by bupranolol; Schild plot of the data revealed the pA2 value of 5.61. 3. CGP 12177 significantly increased cyclic AMP level in this preparation. Bupranolol (10(-4) M) significantly decreased the cyclic AMP level that was elicited by CGP 12177, whereas propranolol (10(-5) M) produced no effect. 4. These results suggest that bupranolol appears to be an efficient beta3-antagonist in the guinea pig taenia caecum and confirm that the response to CGP 12177 is mediated by beta3-adrenoceptors.

Adrenergic beta-Antagonists↗

PubMed2000

Functional identification of beta3-adrenoceptors in the guinea-pig ileum using the non-selective beta-adrenoceptor antagonist (+/-)-bupranolol.

1. To clarify whether there is a species difference or a tissue difference in beta3-adrenoceptors, the beta3-adrenoceptors mediating relaxations to catecholamines ((-)-isoprenaline, (-)-noradrenaline and (-)-adrenaline), a selective beta3-adrenoceptor agonist BRL37344 and a non-conventional partial beta3-adrenoceptor agonist (+/-)-CGP12177A (a potent beta1- and beta2-adrenoceptor antagonist with a partial beta3-adrenoceptor agonist property) were investigated in the guinea-pig ileum. 2. Catecholamines and beta3-adrenoceptor agonists induced concentration-dependent relaxations of pre-contracted strips of the guinea-pig ileum. The rank order for their relaxing potency was (-)-isoprenaline (pD2: 7.60) > BRL37344 (7.05) > (-)-noradrenaline (6.38) > (+/-)-CGP12177A (6.25) > (-)-adrenaline (6.07). 3. In the presence of the non-selective beta1- and beta2-adrenoceptor antagonist (+/-)-propranolol (1 microM), only small rightward shifts of the concentration-response curves (CRCs) to these agonists were observed and the rank order of potency of agonists was BRL37344 (pD2: 7.00) > (+/-)-CGP12177A (6.17) > (-)-isoprenaline (6.01) > (-)-noradrenaline (5.69) > (-)-adrenaline (5.41). 4. In the presence of (+/-)-propranolol (1 microM), the additional presence of (+/-)-bupranolol (3-30 microM), a non-selective beta1-, beta2- and beta3-adrenoceptor antagonist, caused a concentration-dependent rightward shift of the CRCs to catecholamines and beta3-adrenoceptor agonists. Schild plot analyses of (+/-)-bupranolol against these agonists gave pA2 values of 6.02 ((-)-isoprenaline), 6.03 ((-)-noradrenaline), 6.01 ((-)-adrenaline), 6.56 (BRL37344) and 5.74 ((+/-)-CGP12177A), respectively. All Schild plot slopes were not significantly different from unity. The pA2 values of (+/-)-bupranolol obtained for the guinea-pig beta3-adrenoceptors were about one log unit less than the values obtained for the rat beta3-adrenoceptors and about two log units less than the values obtained for dog beta3-adrenoceptors. 5. These results confirm that functional beta3-adrenoceptors are present in the guinea-pig ileum and that the relaxations of these agonists are mainly mediated via beta3-adrenoceptors in this tissue. The differential antagonistic potency of (+/-)-bupranolol may suggest that there is a species difference between the three species (guinea-pig, dog and rat) in their beta3-adrenoceptors.

Adipocytes↗

PubMed1980

[Long-term treatment of angle-closure glaucoma with bupranolol eye drops (author's transl)].

In this study we report on the effect of Bupranolol eye drops on 10 patients who, prior to treatment, experienced decompensation of their glaucoma in spite of the use of miotics or who were not given biotics treatment because of their occupation or because of severe subjective complaints. Treatment with Bupranolol is given for six months and results in clear reduction of intraocular pressure in all patients, so that satisfactory control can be achieved with Bupranolol eye drops either alone or in combination with a miotic agent. As a rule, Bupranolol is tolerated well by all patients.

Adult↗

PubMed2004

Role of alpha-adrenergic receptors in the effect of the beta-adrenergic receptor ligands, CGP 12177, bupranolol, and SR 59230A, on the contraction of rat intrapulmonary artery.

This study investigates the effect of the aryloxypropanolamines 4-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-1,3-dihydro-2H-benzimidazol-2-one (CGP 12177), bupranolol, and 3-(2-ethylphenoxy)-1[(1S)-1,2,3,4-tetrahydronaphth-1-ylamino]-(2S)-2-propanol oxalate (SR 59230A) [commonly used as beta(3)- and/or atypical beta-adrenergic receptors (beta-AR) ligands] on the contractile function of rat intralobar pulmonary artery. Affinities of beta-AR ligands for alpha(1)-adrenergic receptors (alpha(1)-AR) were also evaluated using [(3)H]prazosin binding competition experiments performed in rat cortical membranes. In intralobar pulmonary artery, CGP 12177 did not modify the basal tone, but antagonized the contraction induced by the alpha(1)-AR agonist phenylephrine (PHE). In arteries precontracted with PHE, CGP 12177 elicited relaxation, whereas in those precontracted with prostaglandin F(2alpha) (PGF(2alpha)), it further enhanced contraction. CGP 12177 induced an increase in intracellular calcium concentration in pressurized arteries loaded with Fura PE-3 and precontracted with PGF(2alpha). In PGF(2alpha) precontracted arteries, phentolamine (an alpha-AR antagonist) and phenoxybenzamine (an irreversible alpha-AR antagonist) antagonized the contractile responses to PHE and CGP 12177. Both responses were also decreased by bupranolol and SR 59230A. Specific [(3)H]prazosin binding was displaced by CGP 12177, bupranolol, and SR 59230A with pK(i) values of 5.2, 5.7, and 6.6, respectively. In contrast, (+/-)-(R*,R*)-[4-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]phenoxy]acetic acid sodium (BRL 37344) and disodium 5-[(2R)-2-([(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino)propyl]-1,3-benzodioxole-2,2-dicarboxylate (CL 316243) (nonaryloxypropanolamines beta(3)-AR agonists) displayed very low affinity for [(3)H]prazosin binding sites (pK(i) values below 4). These data suggest that CGP 12177 exhibits partial agonist properties for alpha(1)-AR in rat pulmonary artery. They also show that bupranolol and SR 59230A exert an alpha(1)-AR antagonist effect. As a consequence, these aryloxypropanolamine compounds should be used with caution when investigating the role of beta(3)- and atypical beta-AR in the regulation of vascular tone.

Adrenergic alpha-Antagonists↗

PubMed1979

[Lowering of intraocular pressure by aqueous solution of bupranolol in chronic uncomplicated glaucoma simplex (author's transl)].

In two previous studies the effects of topically applied 1% and 0.2% solutions of bupranolol on intraocular pressure were investigated in 21 and respectively 20 eyes with chronic uncomplicated open-angle glaucoma.--As early as 30 minutes after both solutions a very significant pressure drop, without concomittant pupillary reaction, was recorded. The 1% bupranolol solution was less well tolerated and caused some ocular irritation. The present study was therefore initiated in order to find out whether a 0.2% solution of bupranolol would yield significantly different results in comparison with the former.--Statistical evaluation, based on variance analysis linked with multiple t-tests, showed a barely significant difference between the pressure-lowering effects of the 1% and 0.2% solutions after one hour, whereas after 2 hours the difference became clearly significant in favour of the 0.2% solution. Furthermore, the 0.2% solution clearly showed a tendency to prolonged duration of effect, beyond the two-hour observation time. It therefore seems justified to supplement the present findings by long-term studies aimed at assessing optimal concentrations of the drug on the one hand, and its long-acting properties on the other. In this way, bupranolol is likely to gain recognition as an antiglaucomatous agent.

Aged↗

PubMed1977

[Effect of the beta-adrenergic blocking agent bupranolol on the plasma renin activity in normotensive rats].

The effects of the beta-adrenergic blocking agent 3-tert.-butyl-amino-1-(6'-chloro-3'-methylphenoxy)-propan-2-ol hydrochloride (bupranolol; KL 255; Betadrenol) on the plasma renin activity (PRA) of normotensive rats were studied in comparison to propranolol. Bupranolol (10--100 microgram/kg) reduced basal PRA and inhibited the isoproterenol as well as dihydralazine induced increase of PRA in a dose dependent fashion. Bupranolol exhibited an effect 2--4 times stronger than that of propranolol. The PRA inhibiting effects of bupranolol seem to be linked to its beta-receptor blocking properties.

Adrenergic beta-Antagonists↗

PubMed1987

[Effect of bupranolol on hypoxic respiratory stimulation in healthy probands].

To determine whether hypoxic ventilatory response results, in part, from concomitant systemic sympathoadrenal stimulation, we studied ventilation in 20 healthy subjects before and after administration of a beta-blocking agent. A single oral dose of 100 mg bupranolol (vs placebo) significantly lowered minute ventilation from 9.4 +/- 0.7 to 8.3 +/- 0.2 l/min (mean +/- SEM) during normoxia, and from 10.8 +/- 0.8 to 8.9 +/- 0.2 l/min, when 11% O2 was inhaled. In our study, there were marked oscillations of ventilation on changing from room air to hypoxic breathing and back. They were ascribed to the preceding sampling of specimens for blood gas analysis. However, bupranolol had no influence on these transients. Bupranolol also had only slight cardiocirculatory effects during normoxia and did not prevent significant T-wave flattening, increase in heart rate, and fall in diastolic blood pressure during hypoxia. However, it did block the hypoxic increase in systolic blood pressure. From our results we suggest that (1) in spontaneously breathing conscious subjects, hypoxia-induced hyperventilation is also due to hypoxic sympathoadrenal activity and individual mental state, and (2) these influences do not affect all aspects of the cardiocirculatory response.

Adult↗

PubMed1980

[Long-term treatment of open-angle glaucoma with bupranolol eye drops (author's transl)].

In this study we examined the effect of Bupranolol eye drops on 10 patients with open-angle glaucoma. Treatment extended over six months. Bupranolol eye drops lowered intraocular pressure by about 15% over a prolonged period. Some patients needed treatment in combination with miotics. Visual acuity and visual fields remained constant. As a rule, Bupranolol was tolerated well by the patients

Adult↗

PubMed1992

Betablocking drugs in essential hypertension: transdermal bupranolol compared with oral metoprolol.

In the present study the antihypertensive efficacy and tolerability of transdermal bupranolol (30 mg once-daily) was compared with oral metoprolol (100 mg once-daily). Blood pressure measurements were performed in the office, at home, and with ambulatory 24-h blood pressure devices. Systemic and local side-effects, as well as compliance and acceptance, were evaluated every two weeks. The treatment period lasted eight weeks. The results showed a significant decrease in blood pressure under the bupranolol transdermal therapeutic system in the office, at home, and with 24-h blood pressure measurements day- (08h00-20h00) and night-time (20h00-08h00). Under oral metoprolol there was a significant blood pressure decrease in the office, at home, and in the mean daytime values of the 24-h blood pressure measurements. The night-time values, however, demonstrated only a slight decrease in blood pressure, being significant only for diastolic values. Systemic side-effects were comparable in both groups. 69% of the patients had local side-effects at the patch side (erythema, papulous exanthema, pruritus). Six patients dropped out because of localized urticarial exanthema (five patients treated with transdermal bupranolol, one patient treated with oral metoprolol). In comparison to the oral form, twice as many patients had admitted to have been non-compliant with the patches (13 versus 7 patients). At the end of the study, 24 out of 32 patients preferred to be treated with capsules.

Administration, Cutaneous↗

PubMed1989

Assessment of beta-blocking activity of low-dose bupranolol.

In the present study an investigation was made on the pharmacodynamic effect of the beta-blocking agent bupranolol in the low-dose range. Bupranolol is usually given in doses of 100 mg twice daily in the treatment of hypertension, however the dose range between 20 and 100 mg was studied using graded isoproterenol injections in healthy volunteers. A significant beta-1-blocking activity was observed for the 20 mg dose already. This effect was reduced after a treatment of 10 days. The effect increased with the higher doses, there might be a linear correlation between the logarithm of the dose and the reduction of the tachycardia after the isoproterenol injections in the low-dose range. It was concluded that using the safe and sensitive isoproterenol injection method, the clinical effect of very low doses of bupranolol may be demonstrated. The low dose might be useful to reduce the reflex tachycardia seen in the treatment of hypertension with vasodilating drugs.

Adrenergic beta-Antagonists↗