A new study has shown that the majority of β-adrenoceptor antagonists (beta-blockers) currently in clinical use for hypertension, heart disease and, more recently, heart failure have poor selectivity between adrenoceptor subtypes β1 and β2 in whole-cell assays. The report by Jillian Baker in the British Journal of Pharmacology suggests that the development of existing, more selective, β-adrenoceptor antagonists as beta-blocker drugs should be considered as an alternative to those already in clinical use.

The clinical rationale for using beta-blockers to treat most cardiovascular disorders is to antagonize β1-adrenoceptor signalling to reduce the rate and force of cardiac muscle contraction. However, the beneficial mode of action in heart failure is still not understood. Although highly selective β1-antagonists do exist, most of the beta-blockers available for clinical use also antagonize β2-adrenoceptors, which are expressed at high levels in the airways, causing bronchospasm, a major side-effect of this therapeutic class.

One of the challenges when comparing the subtype-specificity of different β-adrenoceptor antagonists is the method by which the selectivity was originally determined. Initially, drugs were screened for selectivity by observing changes in heart rate or contraction of cardiac muscle (β1-selective) or bronchial smooth muscle (β2-selective) using animal or human tissue. However, these measurements are subject to great variation caused by differences in cellular context and between individuals and species, as well as the effects of underlying disease or of previous medication, such as exposure to β-adrenoceptor drugs. Results obtained by this method therefore more accurately reflect tissue-binding specificity, rather than the receptor-binding specificity of the drug.

The study by Baker measured the binding of a wide range of β-adrenoceptor antagonists to stably expressed β1-, β2- and β3-adrenoceptors in an identical mammalian cell culture environment. Using a competitive binding assay, KD values (the concentration at which half the receptors are bound by the competing ligand) were determined for each drug. The values showed that although there is great variation in the potency of clinically used beta-blockers for all receptor subtypes (from nanomolar to micromolar affinity), they showed little selectivity between β1 and β2 subtypes, and only one drug was found to be selective for the β3-adrenoceptor. Some drugs (for example, metoprolol, bisoprolol and atenolol) thought to be β1-adrenoceptor-selective and currently used to treat cardiovascular disorders are poorly β1-selective, whereas others (for example. carvedilol, sotalol and timolol) actually have higher affinities for the β2-adrenoceptor subtype.

It is becoming clear that the clinical benefit of beta-blockers in heart failure cannot be attributed to receptor affinity alone, and other factors, such as longevity of action at the receptors, must also play a part. Indeed, this study comes at a controversial time for beta-blockers — the paradoxical hypothesis that beta-blockers might actually be beneficial in asthma is now being tested in clinical trials after it was shown that long-term exposure can reduce lung sensitivity in a mouse model of asthma. As more is learnt about the complex pharmacology of adrenoceptors, there is clearly great potential for the development of drugs with greater selectivity and less side-effects for a range of indications.