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As β3‐adrenoceptors were first demonstrated to be expressed in adipose tissue they have received much attention for their metabolic effects in obesity and diabetes. After the existence of this subtype had been suggested to be present in the heart, studies focused on its role in cardiac function. While the presence and functional role of β3‐adrenoceptors in the heart has not uniformly been detected, there is a broad consensus that they become up‐regulated in pathological conditions associated with increased sympathetic activity such as heart failure and diabetes. When detected, the β3‐adrenceptor has been demonstrated to mediate negative inotropic effects in an inhibitory G protein‐dependent manner through the NO–cGMP–PKG signalling pathway. Whether these negative inotropic effects provide protection from the adverse effects induced by overstimulation of β1/β2‐adrenoceptors or in themselves are potentially harmful is controversial, but ongoing clinical studies in patients with congestive heart failure are testing the hypothesis that β3‐adrenceptor agonism has a beneficial effect. Linked Articles This article is part of a themed section on Adrenoceptors—New Roles for Old Players. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.14/issuetoc

The second year of the COVID-19 pandemic had no adverse effect on the number of new drug approvals by the US Food and Drug Administration (FDA). Quite the contrary, with a total of 50 new drugs, 2021 belongs to the most successful FDA years. We assign these new drugs to one of three levels of innovation: (1) first drug against a condition (“first-in-indication”), (2) first drug using a novel molecular mechanism (“first-in-class”), and (3) “next-in-class”, i.e., a drug using an already exploited molecular mechanism. We identify 21 first-in-class, 28 next-in-class, and only one first-in-indication drugs. By treatment area, the largest group is once again cancer drugs, many of which target specific genetic alterations. Every second drug approved in 2021 targets an orphan disease, half of them being cancers. Small molecules continue to dominate new drug approvals, followed by antibodies and non-antibody biopharmaceuticals. In 2021, the FDA continued to approve drugs without strong evidence of clinical effects, best exemplified by the aducanumab controversy.

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Ozakca I, Arioglu-Inan E, Esfahani H, Altan VM, Balligand JL, Kayki-Mutlu G, Ozcelikay AT. Nebivolol prevents desensitization of ␤-adrenoceptor signaling and induction of cardiac hypertrophy in response to isoprenaline beyond ␤ 1-adrenoceptor blockage. Am J Physiol Heart Circ Physiol 304: H1267-H1276, 2013. First published March 1, 2013; doi:10.1152/ajpheart.00352.2012.-The importance of chronic stimulation of ␤-adrenoceptors in the development of cardiac dysfunction is the rationale for the use of ␤-blockers in the treatment of heart failure. Nebivolol is a third-generation ␤-blocker, which has further properties including stimulation of endothelial nitric oxide synthase and/or ␤3-adrenoceptors. The aim of this study was to investigate whether nebivolol has additional effects on ␤-adrenoceptor-mediated functional responses along with morphologic and molecular determinants of cardiac hypertrophy compared with those of metoprolol, a selective ␤ 1-adrenoceptor blocker. Rats infused by isoprenaline (100 g·kg Ϫ1 ·day Ϫ1 , 14 days) were randomized into three groups according to the treatment with metoprolol (30 mg·kg Ϫ1 ·day Ϫ1 ), nebivolol (10 mg·kg Ϫ1 ·day Ϫ1 ), or placebo for 13 days starting on day 1 after implantation of minipump. Both metoprolol and nebivolol caused a similar reduction on heart rate. Nebivolol mediated a significant improvement on cardiac mass, coronary flow, mRNA expression levels of sarcoplasmic reticulum Ca 2ϩ ATPase (SERCA2a) and atrial natriuretic peptide and phospholamban (PLN)/ SERCA2a and phospho-PLN/PLN ratio compared with metoprolol and placebo. Nebivolol prevented the detrimental effects of isoprenaline infusion on isoprenaline (68% of control at 30 M), BRL37344 (63% of control at 0.1 M), and forskolin (64% of control at 1 M) responses compared with metoprolol (isoprenaline, 34% of control; BRL37344, no response; forskolin, 26% of control) and placebo (isoprenaline, 33% of control; BRL37344, 28% of control; forskolin, 12% of control). Both ␤-blockers improved the changes in mRNA expressions of ␤ 1-and ␤3-adrenoceptors. Our results suggest that nebivolol partially protects the responsiveness of ␤-adrenoceptor signaling and the development of cardiac hypertrophy independent of its ␤1-adrenoceptor blocking effect. nebivolol; inotropy; adrenergic stimulation; ␤-adrenoceptors PLASMA CATECHOLAMINE LEVELS play a pivotal role in the shortand long-term regulation of cardiac function. In acute term, as seen in the fight-or-flight response, the activation of sympathetic drive induces positive effects on inotropy, chronotropy, and lusitropy, which are mediated especially by cardiac ␤ 1 -adrenoceptors. However, sustained activation of ␤-adrenoceptors by circulating catecholamines can cause detrimental effects on cardiac muscle. This phenomenon can be observed in the progress of the heart failure; in the early stages of the pathology, the increase of the plasma catecholamines compensates the dysfunction of the cardiac muscle, but in the long term the sympathetic overactivation contributes to dysfu...