Relevance of intrinsic sympathomimetic activity for beta blockers

Abstract

Intrinsic sympathomimetic activity (ISA) characterizes a group of β blockers that are able to stimulate β-adrenergic receptors (agonist effect) and to oppose the stimulating effects of catecholamines (antagonist effect) in a competitive way. Partial agonists are ligands that elicit a submaximal response when bound to β receptors at maximal occupancy. In the isolated rat atrium, acebutolol produces a maximal stimulatory effect that is only 17 ± 8% of the maximal effect induced by the full β agonist isoproterenol. The presence of ISA results in less resting bradycardia and less of a reduction in cardiac output than is observed with β blockers without ISA. In the long term, partial β agonists may produce arterial vasodilation and increase arterial compliance, possibly leading to additional beneficial effects in the treatment of hypertension. β blockers with ISA do not have adverse effects on plasma lipoproteins during long-term treatment; in addition, the presence of ISA could counteract the up-regulation of β adrenoceptors often observed with β blockers without ISA. Finally, the presence of ISA has been a conflicting issue for the use of such β blockers in secondary prevention after myocardial infarction. However, the impressive results of the Acebutolol Prevention of Secondary Infarction trial in high-risk patients after myocardial infarction show that acebutolof, a β blocker with moderate partial agonist activity, can be effective in decreasing the postinfarction mortality rate. By exhibiting a strikingly different hemodynamic profile from that of β blockers without ISA, the partial β agonists form an intriguing pharmacologic class of drugs for which prospective clinical trials should be extensively pursued.