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PubMedDate not supplied

[Bepridil, a functional antagonist of beta1-adrenergic stimulation. Dissociated effects on cardiostimulation and lipolysis. (author's transl)].

1. Methods - In order to verify that the antagonism of isoprenaline by bepridil was not exclusive to cardiac receptors, anesthetized dogs were subjected to a double isoprenaline stimulation (two 15 minute perfusions at a rate of 1 microgram . kg-1 . min . -1 separated by a 75 minute interval). Bepridil at 5 mg . kg-1 was injected intravenously 45 minutes before the second isoprenaline stimulation, and compared to propranolol (1 mg . kg-1), practolol (5 mg . kg-1) and perhexiline (2.5 mg . kg-1). In addition, bepridil (1 mg . kg-1 . min . -1) and perhexiline (0.5 mg . kg-1 . min-1) were also perfused intravenously, simultaneously with the second isoprenaline stimulation. Classical cardiovascular parameters (heart rate, left dP/dt max., arterial pressure, coronary artery flow) together with plasma free fatty acid levels (FFA) were monitored at intervals of 5 minutes throughout the study. 2. Results - The two isoprenaline stimulations caused non-statistically different increases in the various parameters. All the cardiovascular effects of isoprenaline were inhibited by propranolol, except for the increase in coronary flow. Likewise, the increased plasma FFA level fell by 82.7 +/- 4.2% (p = 0.003). The tachycardia and elevated left dP/dt max. were antagonised by practolol, which the increased FFA levels fell by 64.3 +/- 4.8% (p less than 0.01). The other parameters were not altered. No signficant effect was observed with perhexiline. Rapid I.V. infection of bepridil only decreased the isoprenaline. induced tachycardia (from 74 +/- 15.6 syst. Min.-1 to 57.3 +/- 12.7 syst. min.-1). Perfusion of bepridil considerably limited the tachycardia, while moderately reducing the increased contractility later on. However, it had no effect on FFA levels or the other cardiovascular parameters. 3. Discussion and conclusions - The results obtained with propranolol and practolol are consistent with the competitive B-blocking activity of both compounds. The lack of effect noted in this instance with perhexiline may be explained by the recent hypothesis whereby this compound acts on the presynaptic nerve endings of the cardiac pacemaker system and depresses the release of endogenous noradrenaline while unable to antagonise exogenous adrenergic stimulation. The dissociated effects of bepridil with regard to cardiac and lipolytic stimulation by isoprenaline, strongly suggest functional antagonism by both compounds at cardiac level alone. This antagonism is explained by the depressant effects of bepridil on Ca2+/Na+ slow inward currents, as shown previously in myocardial preparations.

Adrenergic beta-Antagonists↗
PubMed1983

Effect of beta-adrenergic blockers on isolated coronary arterial strip and tracheal smooth muscle of pig.

Isolated coronary arterial strip and tracheal smooth muscle of pig, containing predominantly beta 1- and beta 2-adrenoceptors respectively, have been used for estimating the comparative potency of nine beta-adrenergic blocking agents. The order of potency of the antagonists on the isolated coronary arterial strip was propranolol greater than alprenolol greater than H 64/52 greater than H 64/55 greater than practolol greater than H 87/07 greater than atenolol greater than metoprolol greater than H 35/25, whilst the order of potency on the pig tracheal smooth muscle was alprenolol greater than propranolol greater than H 35/25 greater than H 87/07 greater than H 64/55 greater than H 64/52 greater than metoprolol greater than practolol greater than atenolol. Propranolol and alprenolol were almost equipotent in both the preparations and hence were nonspecific. Although practolol, metoprolol, H 64/55 and H 87/07 were beta 1-selective, their selectivity ratio was comparatively smaller than that of atenolol and H 64/52. The study indicates that H 64/52 and atenolol are the most specific beta-adrenergic blocking agents on isolated coronary arterial strip of pig and that their beta 1/beta 2-ratios are 126 and 120 respectively. H 64/52 like atenolol may be of therapeutic value in cardiovascular disorders.

Adrenergic beta-Antagonists↗
PubMed1981

Peyronie's disease and systemic lupus erythematosus syndrome associated with metoprolol administration: a case report.

Peyronie's disease (induratio penis plastica) and a syndrome resembling systemic lupus erythematosus (S.L.E.) contemporaneously developed in a 50-year-old man six months after initiation of treatment with metoprolol. In view of the improvement in symptoms and signs on withdrawal of metoprolol, it seems likely that the drug was responsible for both these conditions. Peyronie's disease has been observed in relation to treatment with other adrenergic blocking agents, including practolol, and the S.L.E. syndrome is thought to be a possible untoward effect of practolol therapy. The relationship between practolol and sclerosing conditions elsewhere in the body is well recognized and an immunological basis for the fibrosis has been suggested. Similarly, the possibility is raised that Peyronie's disease may be in this case a particular expression of the auto immune disorder induced by metoprolol administration.

Humans↗
PubMed1981

Penetration of five beta-adrenergic antagonists into the rabbit eye after ocular instillation.

Aqueous humor and serum levels of five beta-adrenergic blockers were measured using gas chromatographic techniques following ocular instillation of 1% solutions to rabbits. Octanol/buffer partition ratios were also determined. No apparent relationship was found between the peak levels of the agents in aqueous humor and their octanol/buffer partition ratios. However, peak aqueous humor levels of timolol (461 ng/100 mg) and practolol (919 ng/100 mg), whose partition ratios were less than unity, occurred somewhat later (1 h) than the peaks of propranolol (859 ng/100 mg at 30 min), oxprenolol (1,771 ng/100 mg at 30 min) or alprenolol (1,004 ng/100 mg at 10 min) whose partition ratios exceeded unity. Peak levels in serum of timolol (8.0 ng/100 microliter), propranolol (4.2 ng/100 microliter), oxprenolol (11.5 ng/100 microliter), and alprenolol (4.5 ng/100 microliter) were achieved within 10 min and reduced to less than 15% within 4 h. Peak serum levels of practolol (9.9 ng/100 microliter) occurred somewhat later (2 h) and remained high (41%) 6 h later.

Administration, Topical↗
PubMed1977

Pharmacological evidence in vitro and in vivo for functional beta1 receptors in the cerebral circulation.

Blood flow in the caudate nucleus was measured by the thermoclearance technique in non-anesthetized rabbits, accompanied by recording of electrocorticogram, systemic blood pressure, and Pao2 and Paco2 (mass spectrometry). Isoprenaline increased caudate nucleus blood flow and reduced systemic blood pressure. The beta2-receptor agonist, terbutaline, on the other hand, had only peripheral effects. The caudate nucleus flow response was selectively blocked by the beta1-receptor antagonist, practolol, whereas propranolol inhibited all effects of both agonists. Isoprenaline dilated isolated pieces of the tributary artery (middle cerebral) tested in cats, the effect being inhibited not only by propranolol but also by practolol. The results offer further evidence for the view that the beta-receptors in the cerebral vascular bed are of the beta1-type.

Animals↗
PubMed1976

[Specific and non-specific effects of beta-adreno-receptor blocking drugs in man (author's transl)].

The effect of tyramine infusion or exercise on catecholamine concentration and dopamine-beta-hydroxylase activity in plasma of normal volunteers has been studied. Whereas the increase in plasma catecholamine concentrations by tyramine infusion was not changed 90 min after oral application of a single dose of beta-adrenoceptor blocking drugs (penbutolol, practolol, I.C.I. 66082), the increase in blood pressure was diminished. However, the increase in plasma catecholamine, concentration, i.e. the adrenergic response to exercise was significantly enhanced during beta-adrenoceptor blockade. On the other hand, dopamine-beta-hydroxylase activity was not further increased during beta-adrenoceptor blockade. - The non-specific membrane activity of the beta-adrenoceptor blocking drugs wass assessed by the degree of inhibition of serotonin uptake by human platelets in vitro. Their order of potency, according to IC 50 values estimated from the dose response curves was: propranolol less than penbutolol less than practolol less than I.C.I. 66082. The inhibitory activity of these drugs in vivo was also studied by measuring serotonin uptake by platelets isolated 90 min after oral administration. Due to the high dose only propranolol showed a marked membrane activity.

Adrenergic beta-Antagonists↗
PubMed1985

Potentiation by calcium channel blockade of hypoxic myocardial depression in the neonate.

The objectives of this study were to examine the independent and combined effects of beta blockade (practolol) and calcium channel blockade (verapamil) on cardiac responses to hypoxia in the neonate. Lambs were anaesthetized with pentobarbital (20 mg/kg) and were prepared for measurements of left ventricular (LV) performance under controlled hemodynamic conditions. Force generation was assessed from curves relating LV systolic pressure (SP) to end-diastolic pressure (LVEDP) over a broad range of afterloading. Velocity was determined from simultaneous measurements of LV dP/dtmax. Values obtained at LVEDP 10 cm H2O were used to compare interventions. Practolol (P) caused no significant reduction in SP10, but dP/dt10 fell from 51 to 37 (X 10(2] mm Hg/sec (p less than 0.05). Verapamil (V), 2 micrograms/min/kg, reduced measures of contractility (p less than 0.01). Doubling the dose of V further reduced SP10 to 79% of control. Hypoxemia (PaO2, 32 torr) increased SP10 from 172 to 192 mm Hg, and dP/dt10 from 51 to 85 (X 10(2] mm Hg/s (p less than 0.001). After P, the same degree of hypoxia elicited no changes in LV function. During infusion of V (4 micrograms/min/kg), hypoxia reduced SP10 from 138 to 122 mm Hg (p less than 0.01) and dP/dt10 from 29 to 24 (X 10(2] mm Hg/sec (p less than 0.05). It is concluded that in the absence of adrenergic support, hypoxia significantly depresses both force and velocity parameters of contractility in hearts with calcium channel blockade.

Animals↗
PubMed1980

Comparison of five beta-adrenoreceptor antagonists with different ancillary properties during sustained twice daily therapy in angina pectoris.

The effects of five beta-adrenoreceptor blocking agents and placebo during twice daily sustained therapy were compared in 23 patients with stable, exertional angina pectoris. The study was double blind in design, and each drug was prescribed for a period of one month in a random fashion. The number of anginal attacks and consumption of glyceryl trinitrate tablets during the one month period were significantly reduced by a similar degree during therapy with all five beta blocking drugs in comparison to the placebo (P less than 0.01). Exercise tolerance, when assessed 12 hours after a previous dose had been given and 1 hour after the morning dose was given, also improved by a similar degree with all five drugs in comparison to the placebo (P less than 0.01). The increase in exercise duration was associated with a significant reduction in the S-T segment depression, heart rate, systolic blood pressure, and the product of heart rate and systolic blood pressure, with each of the five drugs--effects markedly different from those obtained with the placebo (P less than 0.01). These data show that noncardioselective (propranolol and oxprenolol) and cardioselective (practolol, metoprolol and tolamolol) agents, as well as drugs with intrinsic sympathomimetic activity (oxprenolol and practolol), were equally effective antianginal agents during sustained therapy. Furthermore, twice daily therapy with any of these drugs was effective in the management of patients with angina pectoris.

Adrenergic beta-Antagonists↗
PubMed1981

Characteristics of the beta 1-and beta 2-adrenergic-sensitive adenylate cyclases in glial cell primary cultures and their comparison with beta 2-adrenergic-sensitive adenylate cyclase of meningeal cells.

The agonist specificity pattern of the beta-adrenergic adenylate cyclase in glial primary cultures was not typical of either beta 1- or beta 2-adrenergic receptors. The dose-response curves for adrenaline did not correspond to simple mass action kinetics and their computer analysis suggests the presence of both beta 1- and beta 2-adrenergic-sensitive adenylate cyclase (58 plus or minus 17% and 42 plus or minus 17% respectively). Similar properties of beta 1- and beta 2-adrenergic-sensitive adenylate cyclases were found by computer analysis of the dose-response curves for isoprenaline in the presence of a constant concentration of practolol (a selective beta 1 antagonist) (55 plus or minus 10% and 45 plus or minus 10% of beta 1- and beta 2-sensitive adenylate cyclase respectively). The curves for displacement of [3H]dihydroalprenolol by practolol confirm these results. For purpose of comparison, the beta-adrenergic receptors of meningeal cells in cultures were subjected to similar analysis. The results clearly showed that these cells exclusively contained beta 2-adrenergic receptors.

Adenylyl Cyclases↗
PubMed1976

Analysis of cardiac chronotropic responses to some autonomic blocking agents in conscious trained dogs.

The changes of heart rate in response to i.v. administration of methylatropine (0.5 mg/kg) and/or propranolol (2 mg/Kg) or practolol (2.5 mg/Kg) were studied in conscious trained dogs. Cholinergic blockade alone or combined blockade of sympathetic and parasympathetic effector systems resulted in cardiac acceleration. Conversely, beta-adrenoceptor antagonism with either propranolol or practolol reduced heart rate. The data were analysed by means of a new method, whereby the heart (HRN) of the dog is considered to be the product of the intrinsic heart rate (HR0) and 3 further factors: HRN-HR0 times S times V times W (Multiplicative model). 2 of these factors represent the tonic sympathetic (S) and parasympathetic (V) influences, whereas the third (W) represents the sympathetic-parasympathetic interaction. This type of analysis reveals that W was approximately 1, i.e., the sympathetic-parasympathetic interaction did not play any significant role in determining the heart rate of conscious resting dogs (HRN = HRO-S-V-W = HRO-S-V). The change of heart rate due to the action of parasympathetic system (-53% of the intrinsic heart rate) was more important than the change caused by the action of the sympathetic system (26% of the intrinsic heart rate).

Animals↗
PubMed1976

Analysis of cardiac chronotropic responses to diazepam and bromazepam in conscious trained dogs.

In conscious trained dogs, administration of bromazepam (0.3 mg/kg p.o.) or diazepam (0.3 and 1.0 mg/kg p.o.) had no influence on heart rate. A higher dose (10 mg/kg p.o.) of two benzodiazepines elicited a positive chronotropic effect which was rapid in onset and of long duration. The beta-adrenoceptor blocking agent practolol (2.5 mg/kg i.v.) did not revert heart rate after the benzodiazepines to the same level as in controls, indicating that the tachycardia was not produced by an increase in sympathetic outflow to the heart. For diazepam, a sympathetic--parasympathetic interaction cannot be excluded. However, diazepam and bromazepam significantly reduced the tachycardia which is normally observed after administration of methylatropine (0.5 mg/kg i.v.) alone or in combination with practolol. In anaesthetized dogs, bromazepam failed to modify the heart rate responses to electrical stimulation of cardiac vagal or sympathetic nerves, excluding an action on this compound on ganglionic transmission and cardiac cholinoceptors and adrenoceptors. It is concluded that high doses of diazepam and bromazepam influence the heart rate of conscious dogs in a biphasic way. Firstly, they cause a central reduction of vagal tone to the heart resulting in tachycardia. Secondly, the two drugs decrease the cardiac pacemaker rate directly. Since the overall effect is tachycardia, the central action is more pronounced.

Administration, Oral↗
PubMed1976

On the mechanism of the coronary dilator effect of serotonin in the dog.

In experiments designed to determine the nature of the coronary dilator effect of serotonin the influence of intracoronary administration of the amine on coronary perfusion pressure, heart rate and ventricular contractile force was assessed in anesthetized open-chest dogs in which the left coronary artery was perfused with blood at a constant rate. Serotonin elicited dose-related decreases in coronary perfusion pressure and increases in contractile force, and lowered heart rate slightly. The dilator response was antagonized by methysergide, slightly potentiated by practolol and unaffected by reserpine. The inotropic effect was partially antagonized by methysergide and completely blocked by practolol and reserpine. It is concluded that serotonin induces coronary dilatation by direct stimulation of specific receptors that this effect is independent of the cardiac stimulation produced by the amine, and the latter response is mediated through beta1-adrenoceptors activated by released norepinephrine.

Animals↗
PubMed1976

Frequency dependence of the alpha-adrenoceptor-mediated positive inotropic effect in guinea pig heart.

Evidence for the role of alpha-adrenoceptors in the production of a positive inotropic effect has been obtained chiefly in heart preparations stimulated at a low rate (1 or 1.4 Hz). However, our previous results suggested that the alpha-receptor-mediated positive inotropic effect could be frequency dependent. In the present study cumulative concentration-inotropic effect curves were obtained in guinea pig ventricle strips treated with adrenaline and stimulated at 1 and at 2.5 Hz. Phentolamine (3 X 10(-6) M) and practolol (10(-6) M) were employed as antagonists. Phentolamine antagonized the effect of low concentrations of adrenaline (10(-9)-10(-8) M) in preparations driven at 1 Hz, but did not modify the curve of the agonist at the higher stimulation rate. In preparations driven at 1 Hz, practolol antagonized the effect of adrenaline at concentration above 3 X 10(-8) M without affecting the curve at lower concentrations, the beta-blocker competitively anatagonized the effect of the agonist at 2.5 Hz. It was concluded that a shortening of the interval between beats abolishes the alpha-mediated positive inotropic effect.

Animals↗
PubMed1977

Effects of several 'membrane stabilizing' agents on frog neuromuscular junction.

The effect of several "membrane stabilizing" agents was examined on spontaneously occurring frog miniature end-plate potentials (MEPPs). No consistent parallel was observed between the ability of agents to act as "membrane stabilizers" and their ability to alter MEPP frequency, Vinblastine, chlorpromazine and haloperidol increased MEPP frequency; the concentration of haloperidol which increased MEPP frequency consistently reduced the magnitude of the muscle resting membrane potential. Strychnine, methoxyflurane and practolol decreased MEPP frequency. Similarly, there was no consistent pattern of drug effects on the mean quantal content m of the end-plate potential. Chlorpromazine did not change m, and it is known that vinblastine does not influence m. Strychnine, methoxyflurane, haloperidol and practolol brought about a decline in m.

Animals↗
PubMed1988

Demonstration of beta 1-adrenoceptor mediating relaxation of porcine coronary artery by radioligand binding and pharmacological methods.

beta-adrenoceptors in the porcine coronary artery were characterized by a radioligand binding assay using (-)-[3H]dihydroalprenolol (DHA) and also by measuring the relaxant response of isolated coronary artery to norepinephrine. Specific (-)-[3H]DHA binding in the porcine coronary artery was saturable, reversible and of high affinity (Kd = 1.6 nM) with a maximal number of binding sites of 63 fmol/mg protein, and it showed a pharmacological specificity as well as stereoselectivity which characterized beta-adrenoceptors. The Hofstee analysis of inhibition of (-)-[3H]DHA binding by atenolol, practolol and ICI 118551 has shown that the averaged concentration of beta 1 and beta 2-adrenoceptors in this tissue was 68% and 32% respectively. The relaxant response of isolated coronary artery to norepinephrine was competitively antagonized by (-)propranolol, (+)propranolol, atenolol, practolol and ICI 118551. The pA2 values of these adrenoceptor antagonists were significantly correlated with the Ki values for beta 1 but not beta 2-adrenoceptors determined by the (-)-[3H]DHA binding assay. Thus, the present study demonstrates that the relaxant response of porcine coronary artery to norepinephrine is predominantly mediated through the stimulation of beta 1-adrenoceptors on vascular smooth muscles.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1977

Catecholamine-sensitive adenylate cyclase of human fat cell ghosts: a comparative study using different beta-adrenergic agents.

Some of the effects of beta-adrenergic agonists and antagonists on the adenylate cyclase system of human fat cell ghosts were studied. Isoproterenol, by causing about a fourfold increase of enzyme activity, was more potent than epinephrine and norepinephrine (about 2.5--3.0-fold stimulation). The beta2-adrenergic agonists salbutamol, terbutalin, and fenoterol were considerably less effective than the naturally occurring catecholamines. The stimulatory actions of isoproterenol and beta2-adrenergic agonists were competitively inhibited by the beta-blocking agent propranolol. Isoproterenol stimulation was also inhibited by the selective beta1-adrenergic antagonist practolol. This compound, however, was less potent than propranolol. The results are suggestive for an adenylate cyclase system in human fat cell ghosts coupled to beta1-adrenergic receptor sites. These receptors differ from the cardiac beta receptors with respect to practolol affinity.

Adenylyl Cyclases↗
PubMed1992

On the relationship between the inhibition of thrombin stimulated aggregation and thromboxane formation in isolated platelets treated with beta-adrenoceptor blocking drugs.

Thromboxane B2 (TXB2) formation in isolated, thrombin-stimulated rat platelets was time dependent and appeared after 5 s of incubation. Beta-adrenoceptor blocking (BAB) drugs inhibited thrombin-stimulated TXB2 formation in the following rank order of potency: metipranolol approximately alprenolol approximately propranolol > oxprenolol > practolol. Atenolol was ineffective in inhibiting TXB2 production in stimulated platelets. The inhibition of thrombin-stimulated TXB2 formation by BAB drugs correlated with their inhibitory effect on thrombin-stimulated platelet aggregation, arachidonic acid liberation from membrane phospholipids and with their membrane fluidization. The higher was the liposolubility of the beta-adrenoceptor blocking drugs investigated, the higher was their inhibition of stimulated TXB2 formation. Hydrophilic, selective atenolol and practolol revealed slight or no inhibitory effect on stimulated thromboxane production.

Adrenergic beta-Antagonists↗
PubMed1981

Beta-adrenergic influence on cardiac dynamics during shock-avoidance in dogs.

The role of beta-adrenergic receptors in the mediation of the cardiodynamic effects of a shock-avoidance task was evaluated in conscious dogs with the cardioselective beta-adrenergic antagonist practolol. The animals were chronically instrumented for the measurement of peak rate of change of left ventricular pressure (LV dP/dt), heart rate (HR), cardiac output (CO), systolic (SPB) and diastolic (DBP) blood pressure and total peripheral resistance (TPR), and were each subjected to brief bouts of shock-avoidance with and without practolol pretreatment (2-4 mg/kg). Shock-avoidance evoked reliable increases of LV dP/dt, HR, CO, SBP and DBP, and decreases of TPR. Beta-adrenergic blockade virtually eliminated LV dP/dt increases, attenuated HR and CO increase as well as the vasodilatation, diminished SBP increases in certain animals but did not affect DBP increases. Stable interindividual differences in the magnitude of LV dP/dt and HR increases during shock-avoidance were demonstrated; these differences were abolished by beta blockade. These findings indicate that a beta-adrenergic mechanism accounted for most of the rise of LV dP/dt during avoidance but contributed proportionally less to the elevations of HR and CO. Inter-individual differences in myocardial reactivity were however completely ascribable to beta-adrenergic factors.

Animals↗