β‐Adrenoceptor Blockers as Agonists: Coupling of β 2 ‐Adrenoceptors to Multiple G‐Proteins in the Failing Human Heart

Beta blockers have been shown in clinical trials to improve cardiac function and reduce mortality of heart failure patients. However, these agents require careful titration since they can produce an initial decrease in cardiac output. The authors have recently shown that β blockers, including some used clinically, can directly depress contraction of myocardium from the failing (but not nonfailing) human heart. This occurs on single ventricular myocytes and is therefore completely independent of any inhibition of endogenous catecholamines. The effect appears to be mediated primarily by the β 2 ‐adrenoceptor (AR) and is dependent on the inhibitory guanine nucleotide binding protein, Gi. Using a transgenic mouse model, as well as adenoviral vectors to overexpress Gi or the human β 2 AR in adult myocytes of various species, the authors demonstrate that agents that are blockers for βAR/Gs coupling can be agonists at a β 2 AR/Gi‐coupled form of the receptor. The negative effect of β blockers could contribute to the initial cardiodepression that is observed when introducing these agents in heart failure patients. However, in the long term, β 2 AR/Gi coupling may enhance the ability of β blockers to protect and improve the function of the failing heart.