Search

It remains unknown whether β-blockers are useful and safe in acute myocardial infarction (MI). Owing to its pharmacological profile and vasodilating action, nebivolol (N) is useful in MI. The aim of the present study was to assess in rat whether early nebivolol treatment could be beneficial in MI. It remains unknown whether β-blockers are useful and safe in acute MI. On day (D) 0, male Sprague-Dawley rats underwent left coronary artery ligation (MI) or simple thoracotomy (SHAM). On D1 and D2, the rats were treated with either nebivolol (5 mg.kg -1 .day -1 , MI-N and Sham-N) or vehicle (V, MI-V and Sham-V). On D3, heart rate, left ventricle (LV) intrinsic contractility (PESmid) and arterial elastance were measured. Cardiac and aortic β-Adrenoceptor (AR) subtype mRNA were quantified using real time quantitative RT-qPCR. Catecholamine response was assessed on isolated heart and aortic rings with isoproterenol. PESmid was decreased in MI without worsening the decrease nebivolol. In LV, β 1 - and β 3 -AR mRNA were respectively decreased and increased in all MI. β 3 -AR mRNA increase was partly limited by nebivolol. Ex vivo, basal contractility was less decreased in MI-N than in MI-V. Isoproterenol response was only altered in MI-V. In MI aorta, Nebi prevented β 2 - and β 3 -AR mRNA increases. In addition, Acetylcholine-induced relaxation was lowered in MI-V but preserved with nebivolol. We demonstrated an early modulation of cardiovascular β 3 -AR transcription early MI. Despite its putative negative inotropic properties, nebivolol did not worsen cardiac function in basal conditions and preserved LV catecholamine response., (© 2020 John Wiley & Sons Australia, Ltd.)

Catecholamines play a key role in the regulation of cardiovascular function, classically through ß(1/2)-adrenoreceptors (AR) activation. After ß(3)-AR cloning in the late 1980s, convincing evidence for ß(3)-AR expression and function in cardiovascular tissues recently initiated a reexamination of their involvement in the pathophysiology of cardiovascular diseases. Their upregulation in diseased cardiovascular tissues and resistance to desensitization suggest they may be attractive therapeutic targets. They may substitute for inoperant ß(1/2)-AR to mediate vasodilation in diabetic or atherosclerotic vessels. In cardiac ventricle, their contractile effects are functionally antipathetic to those of ß(1/2)-AR; in normal heart, ß(3)-ARs may mediate a moderate negative inotropic effect, but in heart failure, it may protect against adverse effects of excessive catecholamine stimulation by action on excitation-contraction coupling, electrophysiology, or remodelling. Thus, prospective studies in animals and patients at different stages of heart failure should lead to identify the best therapeutic window to use ß(3)-AR agonists and/or antagonists.

To date, three β-adrenoceptor (β-AR) subtypes have been identified, but only β(1)-ARs and β(2)-ARs have been characterized in human lungs. Moreover, β(2)-ARs physically interact with the cystic fibrosis transmembrane conductance regulator (CFTR) through the Na(+)/H(+) Exchanger Regulatory Factor 1 (NHERF1) protein. β(3)-ARs, which stimulate CFTR activity in transfected cells, have not been identified in human lungs. This study aimed (1) to characterize the presence of β-AR subtypes, especially β(3)-AR, in human bronchi, and (2) to compare their expression as well as that of NHERF1 in non-cystic fibrosis (CF) versus advanced CF lung samples. In human non-CF bronchi, β(1)-AR, β(2)-AR, β(3)-AR, and NHERF1 transcripts and proteins were expressed mainly in bronchial epithelial cells. Those results were strengthened by the native expression of β(1)-AR, β(2)-AR, and β(3)-AR in a human epithelial cell line, 16HBE14o(-). All β-AR subtypes stimulated CFTR activity. In CF bronchi, we demonstrated β(1)-AR and β(3)-AR overexpression, and NHERF1 and β(2)-AR underexpression. The origin of this protein remodeling (involving the physical or functional absence of CFTR, infection, inflammation, or high adrenergic tone) deserves further investigation. These results evidence for the first time, to the best of our knowledge, the presence of β(3)-ARs in human bronchi, and suggest their usefulness as a putative new pharmacologic target in lung diseases where fluid homeostasis is altered. Furthermore, NHERF1 may be a new therapeutic target in patients with CF, to facilitate the trafficking of mutated CFTR to plasma membrane.

Objective: To analyze the implication of the beta3-adrenoceptor (beta3-AR) pathway in human septic myocardium and a murine model of sepsis, a condition associated with myocardial depression., Methods and Results: beta3-AR and eNOS protein abundance were increased (332+/-66.4% and 218+/-39.3; P<0.05) in hearts from septic patients. The effect of BRL37344, a beta3-AR-preferential agonist, was analyzed by videomicroscopy on the contractility of neonatal mouse ventricular myocytes (NMVM) incubated with conditioned medium from LPS-stimulated cultured macrophages (Mc-LPS+ medium). Stimulation of untreated NMVM with BRL37344 dose-dependently decreased the amplitude of contractile shortening (P<0.05). This response was abolished by L-NAME (NOS inhibitor). Incubation in Mc-LPS+ medium potentiated the depressing effect of BRL37344 (P<0.05) as well as of SR58611A (P<0.05) in wild-type myocytes. Importantly, the contractile depression was abrogated in cardiomyocytes from beta3-AR KO mice., Conclusions: beta3-AR are upregulated during sepsis in the human myocardium and by cytokines in murine cardiomyocytes, where they mediate an increased negative inotropic response to beta3 agonists. Activation of the beta3-AR pathway by catecholamines may contribute to the myocardial dysfunction in sepsis.

The sympathetic system is central in the understanding of numerous physiological and physiopathological phenomena. During the last decade, the characterization of a new beta-adrenoceptor subtype, beta(3), in addition to beta(1) and beta(2)-adrenoceptor in the cardiovascular system has changed the view of the roles of the sympathetic system. In heart, beta(3)-adrenoceptor stimulation produce an opposite effect to that induced by beta(1) and beta(2)-adrenoceptors suggesting that in normal heart, the negative inotropic effect induced by the beta(3)-adrenergic stimulation might play a role of a "safety-valve" during intense adrenergic stimulation. In vessels, all beta-adrenoceptors subtypes, beta(1), beta(2) and beta(3), mediate a vasodilation. As beta(3)-adrenoceptors are activated at higher concentrations of catecholamines than beta(1) and beta(2)-adrenoceptors, they could play the roll of a receptor reserve. beta(3)-adrenoceptors are overexpressed in heart failure and hypertension and could constitute a new therapeutic target. In addition, the efficiency of some beta-blockers such as nebivolol could result from an action on beta(3)-adrenoceptors.

The sympathetic nervous system is central for the neurohumoral regulation of the cardiovascular system and is largely involved in many cardiovascular diseases affecting millions of people around the world. It is classically admitted that beta-adrenoceptors (beta-AR) of the beta1 and beta2 subtypes mediate the effects of catecholamines on the force of contraction of cardiac muscle, and on the relaxation of vascular smooth muscle. However, the molecular characterization in 1989 of a third beta-AR subtype, beta3, and later its identification in human heart has changed the classically admitted paradigm on the regulation of heart function by the beta-adrenergic system. In blood vessels, beta3-AR, like beta1 and beta2, produced a relaxation. But at the present time, the physiological role of beta3-AR is not clearly identified. Thus, the purpose of this review is to summarize the pharmacological and molecular evidence supporting the functional roles of beta3-AR in cardiovascular tissues of various species, including humans. In addition, this review discusses the potential role of beta3-AR in several cardiovascular diseases and emphasizes their putative involvement as new therapeutic targets.

Objectives: The aim of the present study was to analyze whether beta3-adrenoceptors (beta3-ARs) were effectively present and functional in the human internal mammary artery (IMA)., Background: The beta1- and beta2-adrenoceptors classically mediate the relaxant effects of catecholamines in the vessels. In vitro and in vivo studies performed in various animal species described vasodilating effects due to activation of a third beta-ARs subtype (beta3)., Methods: Reverse transcription-polymerase chain reaction analysis, Western blot experiments, and pharmacological studies were carried out in human IMA samples harvested from 27 patients undergoing coronary bypass surgery., Results: The beta3-ARs messenger ribonucleic acid and protein were detected in intact IMA, but were absent in endothelium-free samples. This finding was confirmed by immunohistochemical experiments. In organ baths, a beta3-AR agonist, SR 58611A, induced an endothelium-dependent relaxation of phenylephrine-precontracted IMA rings. This vasodilation was not modified by beta1/beta2-AR antagonists, but was greatly altered in the presence of L-748,337, a selective human beta3-AR antagonist. Moreover, the inhibition of nitric oxide (NO) synthases abolished the beta3-adrenergic vasodilation, suggesting the involvement of a NO-signaling pathway., Conclusions: Those results demonstrated the presence of beta3-ARs in the endothelial layer of human IMA. The present work highlights the role of beta3-ARs in vasomotor control of IMA and opens new fields of investigation in coronary bypass graft management, heart failure, and hypertension.

Knowledge of the sympathetic system is a basic element in the understanding of numerous physiological and physiopathological phenomena. In the two last decades, new pharmacological, biochemical and molecular tools have changed our approach to the roles of beta-adrenoceptors in the cardiovascular system. In the heart, the positive inotropic effect of predominant beta 1-adrenoceptor stimulation is classically recognised. Several studies reveal a significant physiological relevance of the beta 2-adrenoceptor which could activate different signalling pathways in addition to that of cAMP. Moreover, the detection of a third beta-adrenoceptor subtype, beta 3, in human heart, responsible for a negative inotropic effect through a NO signalling pathway, has changed the classically admitted paradigm on the regulation of heart function by the beta-adrenergic system. The identification of atypical beta-adrenoceptors, based on pharmacological tools, led to the discovery of "putative" beta 4-adrenoceptors, which constituted a low affinity state of the beta 1-adrenoceptors. In vessels, all beta-adrenoceptors subtypes, beta 1, beta 2 and beta 3, mediated a vasodilation, but the signalling pathway involved in this effect was variable according to their localization (endothelial or smooth muscle cells), the species and the vascular bed. beta-adrenoceptors are involved in several cardiovascular disease and could constitute a determinant therapeutic target. The efficiency of some beta-blockers used in the treatment of heart failure could result from action on beta 3-adrenoceptors. Moreover, a mutation of the beta-adrenoceptor subtype suggested a role in hypertension and diabetes mellitus.