Beta-adrenergic Blocking Activity Research Articles

Effects of chlorpromazine on the disposition and beta-adrenergic blocking activity of propranolol in the dog.

The effects of chlorpromazine (100 mg p.o., 2 hr before propranolol) on the disposition and beta-adrenergic blocking actions of both intravenous (6 mg) and oral (40 mg) propranolol were studied in the dog. Chlorpromazine pretreatment significantly reduced (69%) the oral clearance of propranolol, resulting in significant increases in propranolol bioavailability (159%), and in the total beta-adrenergic blocking activity (111%) after the oral dose. The increase in the total beta-adrenergic blocking activity of oral propranolol after chlorpromazine pretreatment was mostly due to an increased contribution from the parent compound; the apparent activity from active propranolol metabolites was not affected by chlorpromazine. Chlorpromazine pretreatment had no significant influence on the systemic clearance, elimination half-life, apparent volume of distribution, and plasma binding of propranolol, or on the apparent hepatic blood flow. After intravenous propranolol, chlorpromazine pretreatment had no effect on either the total amount of beta-adrenergic blocking activity or the amount of activity attributable to active metabolites. The decreased oral propranolol clearance by chlorpromazine was seen as a shift to the left in the propranolol dose vs. AUC relationship, eliminating the apparent nonlinear kinetic behavior of oral propranolol, and reducing the apparent oral threshold dose. Chlorpromazine's major, if not only, effect on propranolol disposition was to reduce the presystemic elimination of propranolol, possibly through inhibition of its metabolism via a pathway other than ring oxidation.

Effect of early propranolol treatment in an animal model of congestive cardiomyopathy: I Mortality and Ca2+ transport in sarcoplasmic reticulum.

Young turkeys inbred for congestive cardiomyopathy were treated with propranolol prior to the development of cardiac enlargement. One-day-old inbred and commercial turkeys received propranolol, 2 mg X kg-1 X day-1 for 1 month. Propranolol treated inbred birds showed a significantly reduced mortality from 5 to 15 days of age when compared with untreated inbred birds. However, by 28 days of age, cumulative mortality in the treated inbred birds was equal to that in the untreated inbred birds, 29 and 32%, respectively. Propranolol-treated and untreated commercial birds have a 28-day cumulative mortality of 5%. Ca2+ transport in isolated cardiac sarcoplasmic reticulum was studied at 10 and 28 days of age. At 10 days of age Ca2+ uptake and Ca2+ binding in propranolol-treated birds was reduced to 56% and 83%, respectively, of values in untreated inbred birds. By 28 days of age Ca2+ uptake and Ca2+ binding in treated and untreated inbred birds were similar. Ca2+-stimulated ATPase activity was significantly elevated in treated inbred birds compared with age-matched untreated inbred birds at 10 and 28 days of age. Ca2+ transport in isolated cardiac SR from propranolol-treated commercial control birds was not significantly different from the values in untreated commercial birds at 10 or 28 days of age. Improvement in early mortality may be due to the prevention of arrhythmias. Propranolol alters Ca2+ transport in isolated cardiac SR from inbred birds by uncoupling Ca2+-stimulated ATPase. Whether this is due to a direct effect of propranolol on the SR membrane or occurs from its beta-adrenergic blocking action is unclear.

Synthesis and beta-adrenergic blocking activity of 2-(N-substituted amino)-1,2,3,4-tetrahydronaphthalen-1-ol derivatives.

In a search for a new structural type of β-adrenergic antagonist. a series of trans-2-(N-substituted amino)-1, 2, 3, 4-tetrahydronaphthalen-1-ol derivatives (3-36) was synthesized in several steps from 3, 4-dihydro-1 (2H)-naphthalenone (37) having a variety of substituents at the 5-, 6-, 7-and 8-positions. Compounds 3-36 were tested in vitro for β-adrenergic activity. Among them, 2-benzhydrylamino-6-chloro-1, 2, 3, 4-tetrahydronaphthalen-1-ol (28c) was found to show a fairly potent β-adrenergic blocking activity.

Treatment of hypertension associated with head injury.

Arterial hypertension that occurs after severe head injury is characterized by elevation of systolic blood pressure, tachycardia, increased cardiac output, normal or decreased peripheral vascular resistance, and increased circulating catecholamines. The effects of two drugs used in the management of hypertension, propranolol and hydralazine, on these indices of cardiovascular function were examined in six head-injured patients. Both drugs effectively normalized blood pressure. However, hydralazine increased heart rate by 30%, cardiac index by 49%, left cardiac work by 21%, and pulmonary venous admixture by 53%, and was responsible for an increase in intracranial pressure or decreased compliance in two patients. Hydralazine produced no consistent change in arterial catecholamines. In contrast, propranolol decreased heart rate by 21%, cardiac index by 26%, left cardiac work by 35%, pulmonary venous admixture by 15%, and oxygen consumption by 18%. Propranolol decreased arterial epinephrine levels by 48% and norepinephrine levels by 28%. Propranolol appears to be a useful antihypertensive drug in the hyperdynamic head-injured patient because it normalizes blood pressure and the underlying hemodynamic abnormalities both by its beta-adrenergic blocking action and by decreasing circulating levels of catecholamines.

Haemodynamic effects of the optical isomers of beta-receptor blocking agents.

All beta-adrenergic blocking agents possess an asymmetric carbon atom in the side chain. Therefore there are two optical isomers. Pharmacological studies have clearly shown that the beta-adrenergic blocking action is almost exclusively due to the levorotatory isomer. Both, the levorotatory and the dextrorotatory isomer of some beta receptor blocking agents possess membrane stabilizing activity. Studies in patients with hypertension and in patients with coronary artery disease revealed that the beneficial effect of adrenergic beta receptor blocking drugs in these disease states is due to their beta adrenergic activity and not to the membrane stabilizing action.

Electrophysiological and cyclic AMP responses to beta-adrenergic receptor stimulation and catecholamine levels in cat and rabbit sympathetic ganglion

The effects of beta 1- and beta 2-selective and nonselective adrenergic agonists and antagonists were studied in the cat and rabbit superior cervical ganglion (SCG) in situ and in vitro. In experiments on the cat SCG in situ beta-adrenergic agonists induced an increase in positive afterpotential (PAP) of compound ganglionic action potential evoked by preganglionic stimulation in the following order of potency: isoprenaline (ISO) > salbutamol ⪢ tazolol. Beta-adrenergic antagonists inhibited the ISO response in the following order of potency: propranolol > exaprolol ⪢ H 35/25. Practolol did not exhibit beta-adrenergic blocking action; on the contrary, in higher doses it enhanced the response to ISO. In higher doses all beta-adrenergic antagonists tested depressed ganglionic transmission in an approximately similar range of doses. In experiments in vitro, using sucrose-gap technique, ISO induced depolarization of the cat SCG and this effect was inhibited in a dose-dependent manner by propranolol. Beta-adrenergic agonists did not induce depolarization of the rabbit SCG in experiments in situ and in vitro. The level of noradrenaline and dopamine in the cat and rabbit SCG did not differ significantly. Low level of adrenaline was found in the cat SCG; however, no adrenaline was detected in the rabbit SCG. No statistically significant change of cyclic AMP content was observed in the cat and rabbit SCG or in the incubation medium under conditions similar to those in which ISO induced depolarization of the cat SCG. It is concluded that the beta-adrenergic receptors present in the cat SCG resemble the beta 2-subtype and that the presence of an electrophysiological response to beta-adrenergic agonists appears to be species-dependent. The depolarization of the cat SCG due to beta-adrenergic receptor stimulation is not coupled with cyclic AMP increase.

Propranolol in the ischaemic, reperfused, working rat heart: Association between beta-adrenergic blocking activity and protective effect

Propranolol in the ischaemic, reperfused, working rat heart: Association between beta-adrenergic blocking activity and protective effect

Beta-Adrenergic blocking agents. alpha- and gamma-methyl(aryloxy)propanolamines.

A series of gamma-methyl- (5) and alpha-methyl(aryloxy)propanolamines (6) were synthesized and evaluated for beta-adrenergic blocking action. The binding constant (KD) was determined for compounds 5a-j on cultured C6-2B astrocytoma cells. Compounds 5a-j and 6a-e were evaluated for beta 1-antagonist action on guinea pig atria and beta 2-antagonist action on guinea pig tracheal strips. Several gamma-methyl(aryloxy)propanolamines showed affinity for beta receptors and a possible preference for beta 2 receptors.

Salicylamide derivatives related to medroxalol with alpha- and beta-adrenergic antagonist and antihypertension activity.

Analogues of medroxalol (1) were prepared in which the carboxamide function, the phenolic hydroxy group, and the aralkylamine side chain were modified. N-alkyl-substituted amide analogues of 1 showed diminishing beta-blocking activity with increasing steric bulk of the alkyl group. This allowed the conclusion that deactivation of the phenolic hydroxy group of 1 by the carbonyl group of the amide function is responsible for the beta-adrenergic antagonistic properties of 1. This conclusion was strengthened by the finding that the phenolic O-methyl analogue 5-[2-[[3-(1,3-benzodioxol-5-yl)-1-methylpropyl]amino]-1hydroxyethyl]-2-methoxybenzamide (13) was found to have enhanced beta-adrenergic blocking activity. The finding that 13 also had decreased alpha-blocking activity compared to 1 indicated that the phenolic hydroxy group of 1 enhances alpha-adrenergic antagonism. The finding that 1 and 13 showed such a large difference in relative alpha- to beta-blocking potency while exhibiting approximately equal antihypertensive activity in spontaneously hypertensive rats was surprising. In indicated that pharmacologic properties other than alpha- and beta-adrenergic blockade may contribute to the antihypertensive activity of medroxalol. One of the analogues in which the aralkylamine side chain of 1 was replaced by a fragment of a known alpha-adrenergic receptor blocker, 2-hydroxy-5-[1-hydroxy-2-[4-(2-methylphenyl)-1-piperazinyl]ethyl]benzamide (22), showed an interesting pharmacologic profile of potential therapeutic usefulness.

Hemodynamic effects of newer antiarrhythmic drugs

The aim of antiarrhythmic drug therapy is to terminate or suppress specific arrhythmias and improve cardiovascular function. Short-term studies of the new Class I drugs encainide, mexilitine, and tocainide have demonstrated only minor falls in cardiac index with modest rises in mean aortic pressure. In contrast, disopyramide has been shown to depress myocardial function in both animals and patient studies. Heart failure may be precipitated by therapy with disopyramide and electromechanical dissociation has been reported. Class II agents with beta-adrenergic blocking actions all produce a degree of myocardial depression. Atenolol resembles propranolol in patients with coronary artery disease in its hemodynamic effects, whereas acebutolol is less of a depressant, resembling practolol. The Class III agent amiodarone has only a mild depressant effect associated with a reduction in afterload and an increase in coronary blood flow. The Class IV agent verapamil, which is a calcium channel blocker, has potent myocardial depressant actions and causes peripheral vasodilatation. Hypotension, heart failure, and shock have been precipitated particularly in patients receiving beta-blocking drugs concurrently. While all the new antiarrhythmic drugs currently studied will cause some degree of hemodynamic depression in an appropriately high concentration, present investigations suggest that particular caution needs to be taken when disopyramide, aprindine, atenolol, and verapamil are administered either acutely by the intravenous route or chronically by the oral route.

Urinary metabolites of timolol from humans and laboratory animals. Syntheses and beta-adrenergic blocking activities.

Syntheses are reported for three metabolites (2-4) of timolol (1) formed by oxidative metabolism of the morpholine ring. GLC-MS comparisons are presented which establish that the two metabolites whose structures were previously in question are identical with their synthetic counterparts 2 and 3. In 2, metabolic oxidation of the 4-morpholinyl group of 1 had occurred at the carbon next to oxygen to give the 2-hydroxy-4-morpholinyl moiety, whereas in 3, the morpholine of 1 has been oxidized one step further and then ring opened to produce the N-(2-hydroxyethyl)glycine substituent. Biological testing of synthetic samples of the three major metabolites from human urine (3, 4, and 6) indicated that only 4, in which the morpholine moiety has been degraded to a 2-hydroxyethylamino group, had significant beta-adrenergic blocking activity (one-seventh that of timolol in anesthetized dogs).

A radioreceptor assay for propranolol and 4-hydroxypropranolol.

A radioreceptor assay for the measurement of propranolol and 4-hydroxypropranolol levels in plasma is described. Maximum sensitivity for propranolol was 1.2 +/- 0.15 ng/ml and for 4-hydroxypropranolol 4.2 +/- 0.4 ng/ml. Interassay and intra-assay variations for both were under 10%. Modifications in the radioreceptor assay permitted the measurements of total beta-adrenergic blocking activity and the separate contributions of parent drug and metabolite. When 4-hydroxypropranolol was stabilized, a composite level of total beta-adrenergic blocking activity in plasma was obtained. When the 4-hydroxy metabolite was oxidized, only the stable parent drug was detected. The difference in values between measurements made under these conditions was equivalent to the amount of 4-hydroxypropranolol in the sample. The radioreceptor assay was also used to measure the amount of free propranolol and 4-hydroxypropranolol. Under identical experimental conditions, more 4-hydroxypropranolol than propranolol circulated in the free form. These observations establish the feasibility of adapting the radioreceptor assay for propranolol to the measurement of total beta-adrenergic blocking activity and its components in plasma as well as to the measurement of free drug and metabolite levels.

Mechanism of renin inhibition by beta adrenergic blocking agents. Effects of dl-, d-, l-propranolol and pindolol on renin release.

In order to reveal the mechanism of renin inhibition by beta adrenergic blocking agents, the effects of dl-, d-, l-propranolol and pindolol on renin release were studied. This was done by injecting them intraperitoneally or by using an in vitro system of rat kidney slices. In the in vivo study, dl-, d-, and l-propranolol inhibited plasma renin activity and renal renin content significantly in normal rats. Furthermore, in the in vitro study, the basal levels of renin in the media and that in the kidney were significantly inhibited by these agents. Pindolol also inhibited renin release, but its effects were significantly less than those of other agents. The finding that d-propranolol which has little beta adrenergic blocking action inhibited renin release, and that the effects of pindolol which displays strong beta adrenergic blocking action but little membrane stabilizing action, were less than those of other agents, may suggest that the inhibitory effects of beta adrenergic blocking agents on renin release are dependent mainly on the membrane stabilizing action rather than the beta adrenergic blocking action.

Ocular Hypotensive Action of Labetalol

Labetalol has a unique and profound effect on the IOP of rabbits, in contrast to pure beta-adrenergic blockers which have little or no effect in this animal. Its action cannot be satisfactorily explained by simple alpha and beta-adrenergic blocking activity. In the concentrations used, it failed to block the action of a beta-adrenergic agonist (isoproterenol), the action of an alpha-adrenegic agonist (norepinephrine), and its own hypotensive action was neither blocked nor potentiated by the alpha-adrenergic blocker phenoxybenzamine. However, the beta blocker, timolol, did reduce the action of labetalol. These observations and the reduced response to labetalol after cervical sympathectomy, suggest that labetalol's ocular hypotensive effect may occur through some mechanism other than alpha or beta blockade.

EFFECTS OF ALPHA- AND BETA-ADRENERGIC BLOCKERS ON BINDING OF THYROTROPHIN TO FAT CELL MEMBRANE

Alpha- (phentolamine) and beta-adrenergic blocking agents (propranolol) and quinidine similarly enhance the specific binding of TSH to the guinea pig fat cell membranes over the concentration range of 2 X 10(-4) to 4 X 10(-3) M, increasing the binding affinity of TSH to the membranes. The percentage bound increased from 8% in the absence of agents to 32% (phentolamine), 29% (propranolol) and 24% (quinidine), respectively in the presence of these agents (1.5 X 10(-3) M). Each minimal detectable quantity of TSH was approximately 10 microU per tube in the presence of these agents (10(-3) M) as compared to 100 microU per tube in their absence. Both phentolamine and propranolol appeared to enhance the TSH binding to fat cell membranes through membrane-active, non-specific effects besides their alpha- and beta-adrenergic blocking activities.

Synthesis and preliminary biological studies of 4- and 5-[2-hydroxy-3-(isopropylamino)propoxy]benzimidazoles: selective beta2 adrenergic blocking agents.

Benzimidazoles carrying the 2-hydroxy-3-(isopropylamino)propoxy side chain at either the C-4 or C-5 ring positions were synthesized and investigated for beta-adrenergic blocking activity. Both compounds demonstrated beta2 selectivity when evaluated in guinea pig atrial and tracheal preparations. The C-4 isomer was 17 times more selective toward tracheal tissue, and its overall potency was roughly comparable to that of propranolol. beta2 selectivity of the C-5 isomer was minimal, with a potency about one-hundredth that of propranolol.

Effect of oral labetalol on plasma catecholamines, renin and aldosterone in patients with severe arterial hypertension.

Arterial blood pressure and plasma catecholamines, renin activity and aldosterone concentration in 12 patients with severe essential hypertension were studied before and after combined alpha- and beta-adrenergic receptor blockage induced by oral labetalol treatment for 2 months. Furosemide in a fixed dose was employed as a basic antihypertensive agent throughout the study. Blood pressure was adequately controlled in only 6 patients. Mean body weight increased by 1.8 kg and there was a rise in body weight which was inversely correlated with the fall in standing mean blood pressure. The mean plasma noradrenaline concentration decreased from 0.30 to 0.20 ng/ml, whereas plasma adrenaline did not change significantly. Plasma renin activity and aldosterone concentration varied greatly, but the mean values did not change significantly. Change in body weight was correlated inversely with changes in plasma noradrenaline and renin. The results suggest that labetalol, through its combined alpha- and beta-adrenergic receptor blocking action, induces a rise in body weight, probably due to sodium and fluid retention, which partly counterbalances the antihypertensive effect of labetalol, and partly modifies both renin and sympathetic nervous activity.

The anticonvulsant effects of propranolol and β-adrenergic blockade

The anticonvulsant activity of racemic and (+)-propranolol was studied in rats. Neither drug changed the current to produce a minimal seizure in 50% of animals. Both drugs were effective in the maximal electroshock seizure test, the (+) isomer being more potent than the racemic form. Since the (+) isomer is practically devoid of beta-adrenergic blocking activity, the anticonvulsant effects of propranolol do not result from beta-adrenergic blockade.

Nondepressant beta-adrenergic blocking agents. 1. Substituted 3-amino-1-(5,6,7,8-tetrahydro-1-naphthoxy)-2-propanols.

A series of 3-amino-1-(5,6,7,8-tetrahydronaphthoxy)-2-propanols was synthesized and investigated for beta-adrenergic blocking activity and direct myocardial depressant action. The cis- and trans-diols 12--15 were found to retain the beta-blocking potency of propranolol but to lack its myocardial depressant action. Compound 15 (nadolol) is currently undergoing extensive clinical evaluation as a potential antianginal, antiarrhythmic, and antihypertensive agent.

Effects of Kö 1366 on the hemodynamics of the normotensive and hypertensive elderly subjects.

The hemodynamic effects of a new adrenergic beta-receptor blocking agent, Kö 1366 were investigated in normotensive and hypertensive elderly subjects. This study, in its important part, was carried out to clarify whether the intrinsic sympathomimetic activity of Kö 1366 modified the hemodynamic changes due to beta-adrenergic blocking action or not. Hemodynamic changes elicited by intravenously administered Kö 1366 (0.05 mg/Kg) were correlated with age, cardiac index, and electrocardiographic findings, respectively. With reference to age in normotensive subjects, Kö 1366 caused no significant differences in rate of changes of various hemodynamic items between 3 age groups. Normotensive elderly subjects were divided into 3 groups according to cardic index. Cardiac index decreased greatly in high cardiac index group, slightly in normal cardiac index group, whereas it increased greatly in low cardiac index group. Stroke volume index showed the same tendency as cardiac index. Hypertensive elderly subjects were, also divided into 2 groups according to cardiac index. Again, cardiac index decreased in higher cardiac index group, while it increased in lower cardiac index group, though a statistical evaluation showed only a tendency of significant difference between 2 groups. In the next, hypertensive elderly subjects were divided into 2 groups according to electrocardiographic findings of left ventricular hypertrophy. Cardiac index decreased in the subjects without electrocardiographic changes, while it increased in the subjects with electrocardiographic changes. Stroke volume index of both groups increased: a greater increase in the subjects with electrocardiographic changes and a tendency of significant difference between 2 groups was recognized. These results suggested that Kö 1366 exhibited the intrinsic symathomimetic activity on the inotropism in the hearts with depressed contractile function of both normotensive and hypertensive subjects, thereby canceling the negative chronotropic action of this agent. This could be a more advantageous point of Kö 1366 in the treatment of elderly subjects with cardiac diseases than other agents without the intrinsic sympathomimetic activity.