Associate editor: P. Molenaarβ3-Adrenoceptors in the cardiovascular system: Putative roles in human pathologies
Introduction
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. During the 1980s, the classification of β-adrenoceptors (β-AR) into 2 subtypes (β1 and β2) (Lands et al., 1967) was challenged. Thus, it is now known that 3 different subtypes, β1-, β2- and β3-AR, could at least participate in the regulation of cardiovascular function. β3-AR differs from β1- and β2-AR subtypes by its molecular structure and pharmacological profile. Its stimulation produces specific effects in the cardiovascular system. This review will present an overview of characteristics of β3-AR and reports on the presence and the roles of β3-AR in the cardiovascular system and their potential involvement in different pathologies.
Section snippets
Gene
The gene encoding human β3-AR was cloned in 1989 (Emorine et al., 1989). Since then, the gene has been cloned in rat, mice, bovine, monkey, dog (for review, see Strosberg, 1997), sheep and goat (Forrest & Hickford, 2000). Unlike the genes encoding β1- and β2-AR, the gene encoding β3-AR contains introns. The existence of several exons raises the possibility of alternative splicing and thus of different receptor isoforms with putative distinct pharmacological properties. Among the different
Pharmacology of β3-adrenoceptors
β3-AR are pharmacologically characterized by a set of criteria that include (1) high affinity and potency of selective agonists such as BRL 37344, 5-(2-{[2-(3-chlorophenyl)-2-hydroxyethyl]-amino}propyl)-1,3-benzodioxole-2,2-dicarboxylate (CL 316 243) and (RS)-N-[(25)-7-ethoxycarbonylmethoxy-1,2,3,4-tetrahydronapht-2-yl]-(2)-2-(3-chlorophenyl)-2 hydroethanamide hydrochloride (SR 58611A) (Arch & Kaumann, 1993, Emorine et al., 1994, Strosberg & Pietri-Rouxel, 1996); (2) partial agonistic activity
β3-adrenoceptors in the heart
In the heart, β-AR pathways are the primary means of increasing cardiac performance in response to acute or chronic stress. Until last decade, only β1- and β2-AR were described in the heart with a β1/β2-AR ratio of approximately 80:20 (Bristow et al., 1986). The effects of β1- and β2-AR are well established both in human and other mammals. Their stimulation produces positive chronotropic and inotropic effects. For β1-AR stimulation, the linear Gs-adenylyl cyclase–cAMP–PKA signaling cascade has
β3-adrenoceptors in blood vessels
Over the last 20 years, knowledge of vascular physiology and pharmacology has dramatically changed, mainly because of the recognition of the role of endothelium in vasomotor control. Activation of endothelial receptors induces either vasodilation (Furchgott & Zawadzki, 1980) or vasoconstriction (De Mey & Vanhoutte, 1982). Furthermore, recent work suggests a new perspective of β-AR signaling in the vessels partly in relation with the description of the third β-AR subtype. Stimulation of β-AR
Heart failure
The failing human heart is characterized by a sustained activation of the sympathetic nervous system. The higher catecholamine levels help to maintain cardiac performance over the short-term by increasing contractility and heart rate. At first, the increase of cardiac adrenergic drive is beneficial, but ultimately damaging to the myocardium.
In all models investigated, β3-AR are upregulated in human heart failure (Moniotte et al., 2001) as well as in cardiomyocytes from dog with pacing-induced
Conclusion
The characterization of functional β3-AR in the heart opens new fields of investigations. A lot remains to be done to fully characterize their intracellular signaling pathway(s), in particular the involvement of different ion channels in their cardiac responses as well as their physiological roles in the regulation of the cardiac function in the normal heart. At present time, no hypothesis could explain the discrepancies of β3-adrenergic effects on cardiac contractility observed in vitro and in
Acknowledgments
Chantal Gauthier is supported by the “Institut National de la Santé et de la Recherche Médicale”, the “Fédération Française de Cardiologie”, the “Fondation de France” and the “Fondation Langlois”. Bertrand Rozec was supported by grants from the “Société Française d'Anesthésie et de Réanimation” and the “Fondation de la Recherche Médicale”. We thank Dr. Jacques Noireaud for critical reading. We are grateful to the Departments of Cardiology and the Departments of Cardiovascular Surgery of Laënnec
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Present address: Unit of Pharmacology and Therapeutics, Department of Medicine, University of Louvain Medical School, Brussels, Belgium.