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

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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...

β3-adrenoceptors mediate negative inotropic effect in contrast to classical β1- and β2-adrenoceptors. Cardiac β3-adrenoceptors are upregulated in experimental diabetes. Thus, cardiodepressant effect mediated by β3-adrenoceptors has been proposed to contribute to the impaired cardiac function in this pathology. In our study, we investigated the influence of streptozotocin-diabetes on cardiac contractility to β3-adrenoceptors stimulation by using Langendorff-perfused rat hearts. BRL 37344, a selective β3-adrenoceptor agonist, induced dose-dependent decreases in left ventricular developed pressure (LVDP) in hearts from control rats. BRL 37344 also dose-dependently decreased +dP/dt and -dP/dt values. Effects of BRL 37344 were abolished by SR 59230, but not altered by nadolol pre-treatment. On the other hand, these effects of BRL 37344 were all significantly increased in hearts from diabetic rats. We also observed that diabetes significantly increased the mRNA levels encoding cardiac β3-adrenoceptors. In addition, Giα2 mRNA expressions were found to be increased in the cardiac tissue of diabetic rats as well. The effect of BRL 37344 on cardiac contractility was normalized upon treatment of diabetic rats with insulin. These data demonstrate an increased effect of β3-adrenoceptor stimulation on hemodynamic function of the heart in accordance with an increased mRNA levels encoding cardiac β3-adrenoceptors in 8-week diabetic rats.

Hypertrophy and dysfunction of the urinary bladder are consistently observed in animal models of type 1 and less consistently in those of type 2 diabetes. We have tested the effects of mild hyperglycemia (n = 10 per group) in a randomized, blinded study and, in a blinded pilot study, of type 2 diabetes (n = 6 per group) and its treatment with dapagliflozin (1 mg/kg per day) on weight, contraction, and relaxation of the rat bladder. Based on a combination of high-fat diet and a low dose of streptozotocin, animals in the main study reached a mean peak blood glucose level of about 300 mg/dl, which declined to 205 mg/dl at study end. This was associated with a small, if any, increase in bladder weight. In a pooled analysis of all animals of the main and the pilot study, we detected a correlation of moderate strength between blood glucose and bladder weight ( r 2 = 0.2013; P = 0.0003 for Pearson correlation coefficient). Neither the main nor the pilot study found evidence for an altered contractility (responses to carbachol or KCl) or relaxation (responses to isoprenaline, fenoterol, CL 316,243, or forskolin). Treatment with dapagliflozin in the absence of hyperglycemia increased diuresis in the main study by 43% relative to control and increased bladder weight by 15% in the pooled groups of both studies ( post hoc analysis). We conclude that mild hyperglycemia has no major effects on bladder hypertrophy or function.