Beta-adrenergic Blocking Activity Research Articles

Synthesis and beta-adrenergic blocking activity of a novel class of aromatic oxime ethers.

A new series of beta-adrenergic blocking amines containing an oximino-propanolic chain linked to an aromatic nucleus was synthesized. Most of the derivatives are characterized by beta2-selectivity. The structure-activity relationship are discussed. One of the compounds, selected for further studies, was more active on the trachea than on the atria of guinea pig, 155 times in vitro and 26 times in vivo. In comparison, butoxamine's beta2-selectivity is 13 in vitro and only 2 in vivo. With a series of 30 acetophenone oxime derivatives, no quantitative structure-activity relationships could be detected.

An approach to peripheral vasodilator-beta-adrenergic blocking agents.

The syntheses of 2-phenyl- and 2-pyridyl-4-trifluoromethylimidazoles having a 3-tert-butylamino-2-hydroxypropoxy moiety attached to the aryl or heteroaryl substituent are described. Structure--activity relationships based on results from an evaluation of these compounds for antihypertensive, vasodilating, and beta-adrenergic blocking activities are discussed.

PHARMACOLOGY OF SCH 11973, N-(2-PHENYLISOPROPYL)-N-p-TOLUENE SULFONYL UREA, A POTENTIAL NEW ANTIANGINAL AGENT

Antianginal drugs were evaluated on the basis of their ability to protect against subepicardial electrogram changes induced by local ventricular ischemia in anesthetized dogs. Sch 11973 [N-(2-phenylisopropyl)-N-p-toluene sulfonyl urea], a potential new antianginal agent, was also effective against local ventricular ischemia with its maximum effect appearing at 1mg/kg, i.v. or i.d. and with a duration of at least 2 hours. Nitroglycerin, at a dose of 0.04 mg/kg given bucally, exerted less protection, lasting on the average less than 15 minutes. Protection by propranolol at 1 mg/kg, i.v., was not better than nitroglycerin, but lasted up to one hour, while dipyridamole was ineffective when given in a dose range of 0.1-10 mg/kg, i.v. Sch 11973 differed from standard antianginal agents which may act via beta-adrenergic blocking activity or alteration of cardiac or circulatory dynamics since no acute pharmacological changes were observed after Sch 11973 was administered.

β‐(5‐Pyrimidinyl)ethanolamines

Abstract2,4‐Diphenyl‐5‐pyrimidinyl methyl ketone (8) and 2‐phenyl‐4‐methyl‐5‐pyrimidinyl phenyl ketone (12) were prepared by condensation of benzamidine with 2‐ethoxymethyl‐1‐phenyl‐1,3‐butanedione (10). Their structures were elucidated by the nmr spectra of their derivative alcohols 13 and 14, respectively. The ketone 8 was converted by way of the bromoketone 15 to 2‐[1‐methylethylamino]‐1‐[2,4‐diphenyl‐5‐pyrimidinyl]ethanol hydrochloride (17) and 2‐amino‐1‐[2,4‐diphenyl‐5‐pyrimidinyl]ethanol hydrochloride (20). Pharmacologic testing indicated that 17 and 20 did not possess either antihypertensive or beta adrenergic blocking activities.

Beta-adrenergic mechanisms in action tremor.

To study the mechanisms by which propranolol suppresses essential tremor, accelerometric recordings were made from four normal subjects and eight patients with that tremor, and small amounts of isoproterenol and propranolol were infused intravenously or into one brachial artery. Intra-arterial isoproterenol increased tremor amplitude selectively in that arm in normal subjects and in patients with essential tremor (range, 1.85 to 3.50 with mean 2.74 times the base-line level). Intra-arterial or intravenous propranolol quickly blocked the enhanced action tremor in both groups. It did not simultaneously affect the underlying essential tremor, whereas long-term oral propranolol therapy did diminish the amplitude of the essential tremor in each patient. Peripheral beta-adrenergic tremorogenic receptors function normally even in patients with essential tremor; their function is not necessary for the production of essential tremor, and the efficacy of chronic propranolol therapy in the suppression of essential tremor is not mediated via its peripheral beta-adrenergic blocking action.

Effects of Beta Blockers on Cardiac Function and Myocardial Oxygen Consumption in the Isolated Supported Heart Preparation of the Dog

Effects of 2 different types of beta blockers, CS-359 and practolol, on mechanical performance and myocardial oxygen consumption (MVO2) in the isovolumic contraction of the isolated, blood-perfused canine heart with a support dog were studied. Two dose levels of the beta blockers were given intravenously to the support dog, one of which was enough to produce a significant beta adrenergic blocking action and other of which was a higher dose to reveal a direct depressant action on the isolated heart. CS-359 in the lower dose produced significant decreases in heart rate (HR), peak ventricular systolic pressure (peak VSP), and peak dp/dt while practolol caused no change in these parameters. The HR of the support dog was significantly decreased to the same degree in the lower dose of respective blocker. In the higher dose CS-359 decreased all parameters more definitely whereas practolol diminished peak VSP and peak dp/dt but did not significantly HR. MVO2 was decreased dose-relatedly by CS-359, but not affected significantly by practolol. From the analysis of relationships of MVO2 to peak VSP and HR in the isolated heart it is concluded that the effective reduction in MVO2 by CS-359 resulted mainly from a reduction in the peak VSP in the lower dose and additional decrease in HR in the higher dose of CS-359.

Cardiovascular effects of a newer antiarrhythmic agent, disopyramide phosphate

The effect on myocardial contractility of a new antiarrhythmic drug, disopyramide phosphate, was investigated and compared with that of quinidine using a Walton-Brodie strain gauge arch. Quinidine and disopyramide phosphate were compared at the same dosage, ranging from 1 to 10 mg. per kilogram of body weight. At 1 mg. per kilogram of body weight, the contractile force was unaffected by quinidine but was depressed 42 per cent by disopyramide phosphate. At higher dose (5 to 10 mg. per kilogram of body weight) the contractile force was depressed 50 to 100 per cent more by disopyramide phosphate than by quinidine. End-diastolic muscle segment length increased 5 per cent with disopyramide phosphate at 1 mg. per kilogram of body weight, whereas no change was observed with quinidine at this dosage. Both drugs widened QRS and P duration and prolonged PR interval to the same degree. Disopyramide appears to have no beta-adrenergic blocking activity, since it did not alter the contractile force or arterial blood pressure responses to isoproterenol, norepinephrine, or tyramine. Coronary blood flow was decreased by both drugs. The cardiac depressant effect of disopyramide phosphate would appear to limit its usefulness, but for the same degree of cardiac depression, disopyramide phosphate exhibited fewer ECG abnormalities and hence could be used as a replacement therapy for quinidine.

Direct action of methoxamine on the isolated heart muscle.

A direct effect of methoxamine on the contractile state of heart muscle was determined by examining its effects on isometric peak force (F), maximum velocity of force development (dF/dt) and time to peak force (TPF) in isolated canine trabeculae. Methoxamine at the concentrations over 5×10-5M caused a concentration-dependent depression of F and dF/dt. TPF was slightly shortened at higher concentrations of methoxamine (over 1×10-4M). These results suggest that methoxamine possesses a direct negative inotropic action which is mainly due to a decrease in the intensity of the active state. An increase in F produced by isoproterenol was antagonized by methoxamine at a concentration about 100 times higher than that of isoproterenol, suggesting a weak beta-adrenergic blocking action of methoxamine. This antagonistic action of methoxamine was seen also in the effects of isoproterenol on dF/dt as well as TPF. The effect of methoxamine on the mechanics of muscle contraction is qualitatively similar to, but quantitatively different from that of other beta-adrenergic blockers.

Beta-adrenergic blocking activity and haemodynamic effects in man of Kö 1313, a new beta-adrenergic antagonist.

The beta-adrenergic blocking activity and haemodynamic effects of o-[2-hydroxy-3-(isopropylamino)-propoxy]-benzonitril (Ko 1313) have been studied in 22 patients. Antagonism of isoproterenol-induced tachycardia was used as a measure of the beta-adrenergic blocking activity. Ko 1313 1.0 mg had its maximum beta-adrenoceptor blocking effect 5–30 min after intravenous injection. Ko 1313 10.0 mg produced maximum betablockade 1–4 h after oral administration. 1.0 mg Ko 1313 injected intravenously had approximately the same beta-adrenergic blocking effect as 1.0 mg propranolol also given intravenously. After intravenous administration Ko 1313 was 3–4 times as potent as the same dose given orally. An intravenous dose of 2.0 mg Ko 1313 reduced the heart rate and produced insignificant fall in cardiac output. Total peripheral resistance was increased by Ko 1313.

Studies on 1-(o-cyclopropylphenoxy)-3-isopropylamino-2-propanol, a new β-adrenergic blocking drug

The beta-adrenergic blocking action, the effects on resting cardiovascular parameters and the anti-arrhythmic properties of 1-(o-cyclopropylphenoxy)-3-isopropylamino-2-propanol hydrochloride (SD 2124-01) were investigated. SD 2124-01 was 6 to 43 times more potent than propranolol in antagonizing the effects of isoproterenol on heart rate, myocardial contractile force, dLVP/dt and diastolic blood pressure. In isolated preparations (guinea pig atria and tracheal chains), it was 7 to 10 times more potent than propranolol. LD 50's of SD 2124-01 and propranolol in mice were not significantly different. At beta-adrenergic blocking doses, SD 2124-01 was devoid of any intrinsic beta sympathomimetic activity and did not depress the resting cardiovascular parameters of chloralose-anesthetized dogs. Simultaneously, SD 2124-01 facilitated ‘auriculoventricular conduction’. At high doses, it reversed ouabain-induced ventricular tachycardia but reversio was then associated with moderate cardiac depression. Thus, SD 2124-01 appears to be, like prinodolol, one of the most potent and least cardiodepressive beta-adrenergic blocking drugs.

Plasma propranolol levels associated with suppression of ventricular ectopic beats.

The plasma propranolol levels associated with the abolition of chronic, stable ventricular ectopic beats have been studied. Racemic propranolol (DL) suppressed the ectopic foci at plasma levels of 40-85 ng/ml in eight patients, but levels of 70-200 ng/ml were unsuccessful in four patients. Dextro-(D) propranolol levels of 180-310 ng/ml were ineffective in four patients who had previously responded at levels of 60-75 ng/ml of racemic propranolol. The significance of the sympathetic nervous system in the genesis of ectopic beats is discussed. It is concluded that propranolol is clinically effective by virtue of its beta-adrenergic blocking activity.

The effects of propranolol on the electrophysiology of the heart.

The effects of propranolol on the electrical behavior of ventricular muscle fibers were investigated in the anesthetized dog by simultaneously recording surface and intracellular electrograms. After administration of propranolol during sinus rhythm, the RR, PQ and QT intervals were significantly prolonged, while the QRS duration remained unchanged. During electrically driven rhythm, propranolol caused a slight but insignificant prolongation of the QT interval. There were no changes in the QRS duration. Significant delay of the interatrial and atrioventricular conduction times was observed. There were no significant changes in the intraventricular conduction time. Propranolol principally affects the sinoatrial node, the atrioventricular node and the conduction time of the atria. Effects of propranolol on the intracellular electrograms from the ventricle were as follows. The duration of the membrane action potential was significantly prolonged. No changes were observed in the amplitudes of the membrane action potential, membrane resting potential and overshoot. The maximum upstroke velocity of the membrane action potential did not change. Propranolol has a quinidine-like action as well as a beta adrenergic blocking action. Both actions contribute to the effectiveness of the drug in the treatment of cardiac arrhythmias.

COMPARISON OF BETA-ADRENERGIC BLOCKING EFFECT OF DCI, METHOXAMINE, PROPRANOLOL, MJ 1999, H 56/28, LB 46 AND I.C.I. 50 172 ON THE CHRONOTROPIC RESPONSE TO ISOPRENALINE

In 1958, Powell and Slater (1) first described that DCI had beta-adrenergic blocking activity even though it included beta-adrenergic stimulations. Such property was found also in methoxamine besides its alpha-adrenergic stimulant activity (2, 3). In the following decade, many beta-adrenergic blocking agents have been synthesized successively (4-8) and one of them, propranolol was first introduced in the clinical medicine. Since Ahlquist classified alpha and beta-adrenergic receptors, it has been well established that positive chronotropic and inotropic effects and vaso and broncho-dilator actions of catecholamines are mediated through an interaction between drug and beta-receptor. However, it is not gotten clear, whether all beta-adrenergic blocking agents would have the same potency to block beta-adrenergic receptor in different organs. In many experiments, the blockade of the positive chronotropic response to catecholamines has been chosen in order to evaluate the potency of beta-adrenergic blocking agents. Excised preparation of atria (3, 9) and also whole animals (5, 7) were used, while drug was added in the bath or given intravenously. James and Nadeau (10) examined the effect of DCI on the sinoatrial pacemaker activity when it was given selectively into the sinus node artery. In this paper we compared the effect of beta-adrenergic blocking activity of DCI (1), methoxamine (2), propranolol (4), MJ 1999 (5), H 56/28 (6), LB 46 (7) and I.C.I. 50 172 (8) selectively administered into the sinus node artery, while isoprenaline was used as an agonist.

A comparison of the antihypertensive action of propranolol and the optical isomers of N-isopropyl-p-nitrophenylethanolamine (INPEA)

In hypertensive patients, the effect of propranolol and of the optical isomers of N-isopropyl-p-nitrophenylethanolamine (INPEA) on blood pressure was studied. Single oral doses of 40 mg propranolol, 700 mg (−)-INPEA and 700 mg (+)-INPEA decreased supine systolic as well as standing systolic and diastolic blood pressure. Single intravenous doses of 75 mg (−)-INPEA and 75 mg (+)-INPEA lowered supine systolic and diastolic blood pressure. The antihypertensive action of the beta adrenergic blocking levorotatory isomer of INPEA and of the dextrorotatory isomer, which is devoid of beta adrenergic blocking activity, did not differ. It is concluded from these results that the antihypertensive action of beta adrenergic blocking agents is not related to their beta receptor blocking effect.

An involvement of St 155 [2-(2,6-dichlorophenylamino)-2-imidazoline hydrochloride, Catapres ®] in cholinergic mechanisms

St 155 causes hypotension and bradycardia, actions which have been reported to result from central suppression of sympathetic outflow. Our objective was to determine if increased vagal activity might contribute to the bradycardia. Using anesthetized dogs with cardiac sympathetic function abolished by adrenergic neurone or beta-blockade, it was found that St 155 caused a bradycardia which was overcome by atropine or bilateral vagotomy. In such dogs the tachycardias or null effects of adrenaline and noradrenaline became bradycardias after St 155, and reverted to pre-St 155 responses after bilateral vagotomy, carotid sinus denervation or atropine. St 155 did not alter responses to peripheral vagal stimulation or have any beta-adrenergic blocking activity. Our data suggests that St 155 may enhance vagal activity such that resting heart rate is lowered and compensatory reflexes initiated by adrenaline and noradrenaline pressor responses may predominate over the positive chronotropic activity of these amine.

ANESTHETIC-DOPAMINE CARDIAC ARRHYTHMIAS AND THEIR PREVENTION BY BETA ADRENERGIC BLOCKADE

The effects of dopamine (1-100 µg/kg) were determined in cats anesthetized with pentobarbital, cyclopropane or halothane. The iv. injection of dopamine increased myocardial contractile force, systolic and diastolic pressure markedly and heart rate slightly. Cardiac arrhythmias were not produced in pentobarbital-anesthetized animals. However, during cyclopropane or halothane inhalation, dopamine produced cardiac arrhythmias or ventricular fibrillation. The arrhythmias could be prevented by the i.v. injection of 0.5 mg/kg of levo H56/28, a beta adrenergic blocking agent, but not by dextro H56/28, which has only [unknown] to [unknown] the beta adrenergic blocking action of the levo isomer. In halothane-anesthetized hypotensive cats, the infusion of 10 µg/kg/min of dopamine for 30 to 60 min increased systolic and diastolic pressure more than 60% without producing cardiac arrhythmias. After weighing the possible beneficial effects of dopamine against the possibility of producing cardiac arrhythmias, it seems reasonable to undertake a cautious study of the value of dopamine in hypotension and shock in patients anesthetized with cyclopropane or halogenated hydrocarbons.

Antiarrhythmic properties of stereoisomers of a beta-adrenergic blocking agent (H56-28).

Cardiac arrhythmias were produced in the cat by inhalation of 1 per cent halopropane, 10 per cent CO2 and 89 per cent O2 and also by injection of epinephrine during inhalation of 1 per cent halopropane and 99 per cent O2. Dextro-H56/28, which has local anesthetic properties but only 1/40th the beta receptor blocking activity of the levo form of H56/28, had a weak, brief antiarhythmic effect on the halopropane-CO2 arrhythmia and did not significantly increase the threshold dose of epinephrine required to produce an arrhythmia during halopropane administration. However, levo-H56/28, when tested against the halopropane- CO2 and halopropane-epinephrine arrhythmias, had a marked, prolonged antiarrhythmic effect which was attributed to its beta-adrenergic blocking action.

Comparative Study of the Beta Adrenergic Blocking Action of INPEA & BNPEA

Comparative Study of the Beta Adrenergic Blocking Action of INPEA & BNPEA

Effects of pronethalol on the cardiovascular actions of catecholamines during blockade by phenoxybenzamine.

British Journal of Pharmacology and ChemotherapyVolume 27, Issue 3 p. 459-467 Free Access EFFECTS OF PRONETHALOL ON THE CARDIOVASCULAR ACTIONS OF CATECHOLAMINES DURING BLOCKADE BY PHENOXYBENZAMINE J. GARRETT, J. GARRETT Department of Pharmacology, Medical Faculty, University of Porto, PortugalSearch for more papers by this authorA. MALAFAYA-BAPTISTA, A. MALAFAYA-BAPTISTA Department of Pharmacology, Medical Faculty, University of Porto, Portugal Since deceased.Search for more papers by this authorW. OSSWALD, W. OSSWALD Department of Pharmacology, Medical Faculty, University of Porto, PortugalSearch for more papers by this author J. GARRETT, J. GARRETT Department of Pharmacology, Medical Faculty, University of Porto, PortugalSearch for more papers by this authorA. MALAFAYA-BAPTISTA, A. MALAFAYA-BAPTISTA Department of Pharmacology, Medical Faculty, University of Porto, Portugal Since deceased.Search for more papers by this authorW. OSSWALD, W. OSSWALD Department of Pharmacology, Medical Faculty, University of Porto, PortugalSearch for more papers by this author First published: September 1966 https://doi.org/10.1111/j.1476-5381.1966.tb01857.xCitations: 5 AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat REFERENCES Black, J. W. & Stephenson, J. S. (1962). Pharmacology of a new adrenergic beta-receptor-blocking compound (Nethalide). Lancet, ii, 311– 314. Eltherington, L. G. & Horita, A. (1960). Interactions of dibenzyline and DCI on the cardiovascular system and nictitating membrane. Fedn Proc., 19, 122. Gokhale, S. D., Gulati, O. D. & Parikh, H. M. (1964). An investigation of the adrenergic blocking action of chlorpromazine. Br. J. Pharmac. Chemother., 23, 508– 520. Gulati, O. D., Gokhale, S. D. & Udwadia, B. P. (1965). Antagonism of adrenergic blockade by pronethalol. Archs int. Pharmacodyn. Thér., 156, 389– 397. Honkomp, L. J. & Buckley, J. P. (1964). Further evidence for beta-receptors in the cat nictitating membrane. Fedn Proc., 23, 125. Karim, S. M. M. (1964). The mechanism of the depressor action of noradrenaline in the cat. Br. J. Pharmac. Chemother., 23, 592– 599. Koch-Weser, J. (1964). Direct and beta adrenergic receptor blocking actions of nethalide on isolated heart muscle. J. Pharmac. exp. Ther., 146, 318– 326. Levy, B. (1964). Alterations of adrenergic responses by N-isopropyl-methoxamine. J. Pharmac. exp. Ther., 146, 129– 138. Levy, B. & Ahlquist, R. P. (1957). Inhibition of the adrenergic depressor response. J. Pharmac. exp. Ther., 121, 414– 420. Moreira, M. G. & Osswald, W. (1965). Pronethalol-induced reversal of adrenergic vasodepression. Nature, Lond., 208, 1006– 1007. Nickerson, M. & Chan, G. C.-M. (1961). Blockade of responses of isolated myocardium to epinephrine. J. Pharmac. exp. Ther., 133, 186– 191. Nickerson, M., Henry, J. W. & Nomaguchi, G. M. (1953). Blockade of responses to epinephrine and norepinephrine by dibenamine congeners. J. Pharmac. exp. Ther., 107, 300– 309. Osswald, W. (1960). Reversal of adrenergic vasodepression. Archs int. Pharmacodyn Thér., 126, 346– 358. Sutherland, J. H. R., Ahlquist, R. P. & Ogden, W. S. (1964). The mechanism of the cardiovascular action of isopropylmethoxamine. Fedn Proc., 23, 124. Tuttle, R. S. (1965). Reciprocal antagonism of dibenzyline and nethalide. Fedn Proc., 24, 712. Waflen, M. J. G. A., Sonneville, P. F., Ariëns, E. J. & Simonis, A. M. (1964). The pharmacology of catecholamines and their derivatives. Part II: An analysis of the actions on blood flow and oxygen exchange in skin and muscle. Arzneim.-Forsch., 14, 11– 19. Wislicki, L. (1964). The effect of pronethalol on rabbit auricles and its interactions with sympathomimetic amines. Archs int. Pharmacodyn. Thér., 152, 69– 78. Citing Literature Volume27, Issue3September 1966Pages 459-467 ReferencesRelatedInformation

THE ANTIARRHYTHMIC ACTIONS OF BETA ADRENERGIC BLOCKING AGENTS

Pronethalol and N-isopropyl- p -nitrophenyl-ethanolamine (INPEA) were found to antagonize the inotropic and chronotropic actions of epinephrine and isoproterenol as well as the vasodilator action of the latter, thus confirming the beta adrenergic blocking actions of the two agents. The two agents also antagonized the cardiac arrihythmias induced by epinephrine but not those produced by coronary artery ligation. The ventricular tachycardia produced by ouabain was suppressed by pronethalol but not by INPEA. A parallelism between beta adrenergic blockade produced by pronethalol and its antiarrhythmic act ion against epinephrine but not against ouabain was observed. The beta adrenergic blocking agents thus appear to inhibit arrlmythmias induced by sympathomimetic amines on the basis of specific adrenergic blockade. On the other hand, pronethalol suppressed the ouabain-induced arrhythmia apparently because of an additional nonspecific ( quinidinelike) action.