How carvedilol does not activate β2-adrenoceptors

The introduction of β-adrenergic receptor blockers, “β-blockers”, as a treatment for heart failure decades ago was a major advance in cardiovascular medicine 1 , 2 , 3 , 4 . Moreover, it has been clear for a number of years that some β-blockers with “intrinsic sympathomimetic activity” (ISA) due to weak partial agonist activity mediated through G protein stimulation did not share this salutary effect 5 , 6 . Yet, a recent paper by Benkel et al. 7 , “How carvedilol activates β 2 -adrenoceptors”, using engineered cells that lack either G proteins or arrestins, proposes that carvedilol, a widely used and effective β-blocker for heart failure, signals through β 2 AR-mediated G protein activation. Here, we explain why we believe the conclusions put forward by Benkel et al. are incorrect and certainly cannot be extended to clinical implications and should not guide decisions in the clinic.