The medical treatment of chronic heart failure has undergone a remarkable transition in the past 10 years. The approach has changed from a short-term hemodynamic/pharmacological paradigm to a more long-term, reparative strategy that aims to favorably alter the biological properties of the failing heart.1 This is dramatically illustrated by the recent success in treating mild-to-moderate chronic heart failure with β-adrenergic blocking agents. This review describes how a treatment that began as a contraindication1 2 3 became an established treatment of chronic heart failure.

The failing human heart is adrenergically activated,4 5 6 which helps to maintain cardiac performance over the short term by increasing contractility and heart rate. In contrast, in the resting state there is no adrenergic support of normally functioning human left ventricles.6 Multiple lines of evidence7 8 9 indicate that it is the increase in cardiac adrenergic drive rather than an increase in circulating norepinephrine that is both initially supportive and then ultimately damaging to the failing human heart.

As shown in Table 1⇓, there are 3 adrenergic receptors (β1, β2, and α1) in human cardiac myocytes coupled to a positive inotropic response and cell growth.10 11 12 β-Adrenergic receptors are coupled via the “stimulatory” G protein Gs to the effector enzyme adenylyl cyclase, which converts the substrate MgATP to cAMP. cAMP is a positively inotropic and chronotropic second messenger and is strongly growth promoting. In nonfailing human left or right ventricles, the β1/β2 ratio is 70 to 80/30 to 20, but in failing human ventricles, 35% to 40% of the total number of β-receptors are β2 because of selective downregulation in the β1 subtype.10 11 α1 Receptors are coupled via a different G protein (G …

β-Adrenergic Receptor Blockade in Chronic Heart Failure

A wide variety of tissues undergo a change of functional state on exposure to noradrenaline or adrenaline. Those molecular constituents of the effector cells of a tissue with which molecules of these catecholamines must first interact in order to produce a change of state — or response — of the tissue, are the so-called adrenoceptors (also commonly called adrenergic receptors). For convenience, we refer to noradrenaline, adrenaline and other agents which produce responses in tissues by interacting with adrenoceptors, as adrenergic agonists. An agent which specifically inhibits a response produced by an adrenergic agonist is referred to as adrenergic blocking agent or adrenergic antagonist.

The Classification of Adrenoceptors (Adrenergic Receptors). An Evaluation from the Standpoint of Receptor Theory

1. The optical isomers of propranolol have been compared for their β-blocking and antiarrhythmic activities.

2. In blocking the positive inotropic and chronotropic responses to isoprenaline, (+)-propranolol had less than one hundredth the potency of (-)-propranolol. At dose levels of (+)-propranolol which attenuated the responses to isoprenaline, there was a significant prolongation of the PR interval of the electrocardiogram.

3. The metabolic responses to isoprenaline in dogs (an increase in circulating glucose, lactate and free fatty acids) were all blocked by (-)-propranolol. (+)-Propranolol had no effect on fatty acid mobilization but significantly reduced the increments in both lactate and glucose.

4. Both isomers of propranolol possessed similar depressant potency on isolated atrial muscle taken from guinea-pigs.

5. The isomers of propranolol exhibited similar local anaesthetic potencies on an isolated frog nerve preparation at a level approximately three times that of procaine. The racemic compound was significantly less potent than either isomer.

6. Both isomers of propranolol were capable of preventing adrenaline-induced cardiac arrhythmias in cats anaesthetized with halothane, but the mean dose of (-)-propranolol was 0.09±0.02 mg/kg whereas that of (+)-propranolol was 4.2±1.2 mg/kg. At the effective dose level of (+)-propranolol there was a significant prolongation of the PR interval of the electrocardiogram. Blockade of arrhythmias with both isomers was surmountable by increasing the dose of adrenaline.

7. Both isomers of propranolol were also capable of reversing ventricular tachycardia caused by ouabain in anaesthetized cats and dogs. The dose of (-)-propranolol was significantly smaller than that of (+)-propranolol in both species but much higher than that required to produce evidence of β-blockade.

8. The implications of these results are discussed.

/pdf/the-biological-properties-of-the-optical-isomers-of-t0olz20fvx.pdf

The biological properties of the optical isomers of propranolol and their effects on cardiac arrhythmias

1β-Adrenoceptor antagonists (‘β-blockers’) are one of the most widely used classes of drugs in cardiovascular medicine (hypertension, ischaemic heart disease and increasingly in heart failure) as well as in the management of anxiety, migraine and glaucoma. Where known, the mode of action in cardiovascular disease is from antagonism of endogenous catecholamine responses in the heart (mainly at β1-adrenoceptors), while the worrisome side effects of bronchospasm result from airway β2-adrenoceptor blockade. The aim of this study was to determine the selectivity of β-antagonists for the human β-adrenoceptor subtypes.
23H-CGP 12177 whole cell-binding studies were undertaken in CHO cell lines stably expressing either the human β1-, β2- or the β3-adrenoceptor in order to determine the affinity of ligands for each receptor subtype in the same cell background.
3In this study, the selectivity of well-known subtype-selective ligands was clearly demonstrated: thus, the selective β1 antagonist CGP 20712A was 501-fold selective over β2 and 4169-fold selective over β3; the β2-selective antagonist ICI 118551 was 550- and 661-fold selective over β1 and β3, respectively, and the selective β3 compound CL 316243 was 10-fold selective over β2 and more than 129-fold selective over β1.
4Those β2-adrenoceptor agonists used clinically for the treatment of asthma and COPD were β2 selective: 29-, 61- and 2818-fold for salbutamol, terbutaline and salmeterol over β1, respectively. There was little difference in the affinity of these ligands between β1 and β3 adrenoceptors.
5The clinically used β-antagonists studied ranged from bisoprolol (14-fold β1-selective) to timolol (26-fold β2-selective). However, the majority showed little selectivity for the β1- over the β2-adrenoceptor, with many actually being more β2-selective.
6This study shows that the β1/β2 selectivity of most clinically used β-blockers is poor in intact cells, and that some compounds that are traditionally classed as ‘β1-selective’ actually have higher affinity for the β2-adrenoceptor. There is therefore considerable potential for developing more selective β-antagonists for clinical use and thereby reducing the side-effect profile of β-blockers.


British Journal of Pharmacology (2005) 144, 317–322. doi:10.1038/sj.bjp.0706048

/pdf/the-selectivity-of-b-adrenoceptor-antagonists-at-the-human-3aip4ilte4.pdf

The selectivity of β-adrenoceptor antagonists at the human β1, β2 and β3 adrenoceptors

/pdf/selective-blockade-of-adrenoceptive-beta-receptors-in-the-3j8nzft1ze.pdf

Selective blockade of adrenoceptive beta receptors in the heart

Much evidence has accumulated to justify the classification of pronethalol (Alderlin; I.C.I.) as a sympathetic β-receptor antagonist described in terms of Ahlquist's (1948) dual-receptor hypothesis. There has now been confirmation in animal experiments of antagonism to adrenergically induced vasodilatation (Ahlquist, 1963; Abboud, Eckstein & Zimmerman, 1963), cardiac stimulation (Meester, Hardman & Barboriak, 1963; Kako, Krayenbuhl, Luthy & Hegglin, 1964; Donald, Kvale & Shepherd, 1964), bronchodilatation (Nagasaka, Schaepdryver & Heymans, 1964), uterine relaxation (Levy & Tozzi, 1963) and gut relaxation after block or loss of α-receptors (Lum & Kermani, 1963). In human pharmacological studies antagonism to catecholamine-induced vasodilatation and cardiac stimulation (Dornhorst & Robinson, 1962; Lowe & Robinson, 1964) has been reported. Reduction of exercise tachycardia in man has been described by Bishop & Segel (1963), Chamberlain & Howard (1964), Harrison, Braunwald, Glick, Mason, Chidsey & Ross (1964) and Schroder & Werko (1964).

The effects of pronethalol in experimental cardiac arrhythmias in dogs and guinea-pigs have been investigated. Antagonism of arrhythmias induced by cardiac glycosides has been reported by Erlij & Mendes (1964), Vaughan-Williams & Sekiya (1963) and Somani, Hardman & Lum (1963). Prevention of arrhythmias induced by adrenaline during anaesthesia with a hydrocarbon has been found by Murray, McKnight & Davis (1963) and by Hess & Hampton (1964). Somani et al. (1963) have shown that pronethalol will block ectopic ventricular tachycardia produced by large doses of adrenaline, and Ehringer & Gogel (1963) claim that it reduces the apical myocardial necrosis produced in rats by large doses of isoprenaline.

This interest in the cardiovascular actions of pronethalol is also shown in various clinical reports. Success in the treatment of some cardiac arrhythmias, including digitalis intoxication, has been reported by Stock & Dale (1963) and Grandjean & Rivier (1963). Encouraging results in the treatment of angina have been found in a multicentre double-blind trial (Alleyne, Dickinson, Dornhorst, Fulton, Green, Hill, Hurst, Laurence, Pilkington, Prichard, Robinson & Rosenheim, 1963) and in a small, placebo-controlled, trial of effort tolerance (Apthorp, Chamberlain & Hayward, 1964). Potential therapeutic value of pronethalol in the management of phaeochromocytoma (Dornhorst & Laurence, 1963) and hypertrophic obstructive cardiomyopathy (Harrison et al., 1964; Cohen, Effat, Goodwin, Oakley & Steiner, 1964) has been described. Effective treatment of ventricular arrhythmias occurring during halothane anaesthesia has been reported by Johnstone (1964) and by Payne & Senfield (1964). These reports confirm the suggestions by Black & Stephenson (1962) that sympathetic β-receptor antagonists might be valuable in the study and treatment of certain cardiac disorders.

The overt toxic effects of pronethalol described by Black & Stephenson (1962) were tremors and convulsions. These signs were correlated with the evidence that the brain concentrations of pronethalol were of the order of 100-times the blood concentration. The acute toxic signs appeared at doses seven- to ten-times greater than those needed for effective β-receptor blockade. While tremors and convulsions have not been described in man, effective doses are often associated with unpleasant subjective side-effects. Mild disorientation, slight inco-ordination, nausea and vomiting have been described (Alleyne et al., 1963). Since the toxic signs in animals are seen with the inactive (+)-isomer as as well as with the active (–)-isomers (Howe, 1963), it has been assumed that the effects of pronethalol on the central nervous system are probably not due to β-receptor blockade. A more serious toxic manifestation was found in mice. Studies showed that pronethalol was a moderately potent carcinogen in this species. Malignant tumours, mainly thymic lymphosarcomata, began to appear after 10 weeks continuous dosing (Paget, 1963; Alcock & Bond, 1964).

This combination of nonspecific central actions and carcinogenic potential in a compound of clinical interest put a premium on finding a less toxic compound. A preliminary communication (Black, Crowther, Shanks, Smith & Dornhorst, 1964) on such a compound has been published; this compound is propranolol (Inderal; LCI.). The relationship of propranolol to pronethalol is shown by the structural formulae:

This paper presents details of the comparative activity of these compounds. Detailed studies of their toxicity by our colleagues have shown that daily treatment of mice with propranolol over a period of 18 months did not produce thymic tumours (Alcock, Baker & Tucker, 1965).

https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1476-5381.1965.tb01782.x

Comparison of some properties of pronethalol and propranolol

https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1476-5381.1967.tb01953.x

The peripheral vascular effects of propranolol and related compounds.

https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1476-5381.1966.tb01911.x

R. G. Shanks

Papers

Selective blockade of adrenoceptive beta receptors in the heart

Comparison of some properties of pronethalol and propranolol

The peripheral vascular effects of propranolol and related compounds.

The effect of propranolol on the cardiovascular responses to isoprenaline, adrenaline and noradrenaline in the anaesthetized dog

Comparison of some properties of pronethalol and propanolol