Carvedilol: a beta-blocker that also stimulates beta-receptors
β-adrenergic receptor antagonists (β-blockers) are common medications for heart diseases like hypertension and heart failure. One of these β-blockers, carvedilol, has proven particularly effective in the treatment of heart failure, although the mechanisms responsible for this are controversial. Similar to other β-blockers, the primary action of carvedilol is to counter the excessive stimulating effects of endogenous catecholamines (adrenaline and noradrenaline) on β1 and β2 adrenoceptors (βARs). However, it appeared that carvedilol also has the ability to stimulate β2ARs to some extent – the property known as intrinsic sympathomimetic activity (ISA). ISA allows carvedilol to delicately balance the act of blocking and stimulating β-adrenoceptors, which translates into a number of clinical benefits, including improving survival after myocardial infarction. Nevertheless, despite the apparent benefits associated with ISA, the question of how carvedilol exerts its positive signaling effects has puzzled scientists for decades.
A study led by Evi Kostenis resolved this puzzle. This study shows that carvedilol induces all detectable cellular signalling via low intrinsic activation of heterotrimeric G proteins and does not require a contribution from arrestins, as was previously hypothesized. The authors used CRISPR/Cas9-mediated genome editing to engineer cell lines lacking arrestins and/or G proteins, demonstrating that carvedilol exerts its cellular signals by activation of the β2AR-Gs-AC-cAMP signaling axis.
In primary adult cardiomyocytes, carvedilol enhanced cAMP formation through specific activation of endogenous β2AR. Importantly, carvedilol-induced cAMP elevation resulted in speeding up of spontaneous cardiomyocyte beating, as measured by the label-free, impedance-based CardioExcyte 96 platform. In neonatal mouse ventricular myocytes, carvedilol measurably increased the beating frequency. Intriguingly, carvedilol-mediated ERK phosphorylation, the hallmark feature of arrestin-biased signaling, showed an equivalent dependence on Gs, while arrestins were dispensable for eliciting positive ERK signals.
Overall, this study clarifies the molecular mechanisms underlying the intrinsic sympathomimetic activity of carvedilol at β2ARs and could potentially answer the question of why β-blockers with such activity prolong the life of heart failure patients.
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