β3-Adrenoceptors in the cardiovascular system: Putative roles in human pathologies

doi:10.1016/j.pharmthera.2005.12.002

Pharmacology & Therapeutics

Volume 111, Issue 3, September 2006, Pages 652-673

https://doi.org/10.1016/j.pharmthera.2005.12.002 Get rights and content

Abstract

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 β-adrenoceptors (β-AR) of the β₁ and β₂ 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 β-AR subtype, β₃, and later its identification in human heart has changed the classically admitted paradigm on the regulation of heart function by the β-adrenergic system. In blood vessels, β₃-AR, like β₁ and β₂, produced a relaxation. But at the present time, the physiological role of β₃-AR is not clearly identified. Thus, the purpose of this review is to summarize the pharmacological and molecular evidence supporting the functional roles of β₃-AR in cardiovascular tissues of various species, including humans. In addition, this review discusses the potential role of β₃-AR in several cardiovascular diseases and emphasizes their putative involvement as new therapeutic targets.

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 G_s-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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¹: Present address: Unit of Pharmacology and Therapeutics, Department of Medicine, University of Louvain Medical School, Brussels, Belgium.

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Associate editor: P. Molenaarβ3-Adrenoceptors in the cardiovascular system: Putative roles in human pathologies

Abstract

Introduction

Section snippets

Gene

Pharmacology of β3-adrenoceptors

β3-adrenoceptors in the heart

β3-adrenoceptors in blood vessels

Heart failure

Conclusion

Acknowledgments

Trends Endocrinol Metab

Eur J Pharmacol

Eur J Pharmacol

Eur J Pharmacol

Cell Signal

Gen Pharmacol

Am J Obstet Gynecol

Eur J Pharmacol

Trends Pharmacol Sci

Ann Thorac Surg

Trends Pharmacol Sci

J Thorac Cardiovasc Surg

J Biol Chem

J Biol Chem

Ann Thorac Surg

Mol Cell Endocrinol

Atypical beta-adrenoceptor on brown adipocytes as target for anti-obesity drugs

Nature

Beta 3 and atypical beta-adrenoceptors

Med Res Rev

Beta 3-adrenoceptors and the regulation of metabolism in adipose tissues

Biochem Soc Trans

Beta3-adrenergic receptor gene polymorphism is not associated with hypertension in NIDDM patients without nephropathy

Horm Metab Res

In situ assessment of the role of the beta 1-, beta 2- and beta 3-adrenoceptors in the control of lipolysis and nutritive blood flow in human subcutaneous adipose tissue

Br J Pharmacol

cGMP inhibition of heart phosphodiesterase: is it clinically relevant?

J Clin Invest

Beta 3-adrenergic activation of adenylyl cyclase in mouse white adipocytes: modulation by GTP and effect of obesity

J Cell Biochem

Beta-3 adrenoceptor-mediated increase in cutaneous blood flow in the dog

J Pharmacol Exp Ther

A trial of the beta-blocker bucindolol in patients with advanced chronic heart failure

N Engl J Med

In vitro inhibition of intestinal motility by phenylethanolaminotetralines: evidence of atypical beta-adrenoceptors in rat colon

Br J Pharmacol

Structural and conformational features determining selective signal transduction in the beta 3-adrenergic receptor

Mol Pharmacol

Nitric oxide synthase expression and role during cardiomyogenesis

Cardiovasc Res

Mesenteric small artery changes after vasoconstrictor infusion in young rats

J Cardiovasc Pharmacol

Acute depression of myocardial beta-adrenergic receptor signaling during cardiopulmonary bypass: impairment of the adenylyl cyclase moiety. Duke Heart Center Perioperative Desensitization Group

Anesthesiology

Vascular beta-adrenoceptor-mediated responses in hypertension and ageing in rats

J Auton Pharmacol

Beta3-adrenergic regulation of an ion channel in the heart-inhibition of the slow delayed rectifier potassium current I(Ks) in guinea pig ventricular myocytes

Cardiovasc Res

Evidence against beta 3-adrenoceptors or low affinity state of beta 1-adrenoceptors mediating relaxation in rat isolated aorta

Br J Pharmacol

Direct demonstration of beta(1)- and evidence against beta(2)- and beta(3)-adrenoceptors, in smooth muscle cells of rat small mesenteric arteries

Br J Pharmacol

Beta 1- and beta 2-adrenergic-receptor subpopulations in nonfailing and failing human ventricular myocardium: coupling of both receptor subtypes to muscle contraction and selective beta 1-receptor down-regulation in heart failure

Circ Res

Redox modulation of L-type calcium channels in ferret ventricular myocytes. Dual mechanism regulation by nitric oxide and S-nitrosothiols

J Gen Physiol

Potent and selective human beta(3)-adrenergic receptor antagonists

J Pharmacol Exp Ther

The internal mammary artery malperfusion syndrome: incidence, treatment and angiographic verification

Eur J Cardiothorac Surg

Reactivity of aorta and mesenteric microvessels to drugs in spontaneously hypertensive rats: role of the endothelium

J Hypertens

The tissue distribution of the human beta3-adrenoceptor studied using a monoclonal antibody: direct evidence of the beta3-adrenoceptor in human adipose tissue, atrium and skeletal muscle

Int J Obes Relat Metab Disord

Are beta-blockers effective in elderly patients who undergo coronary revascularization after acute myocardial infarction?

Arch Intern Med

Upregulation of functional beta(3)-adrenergic receptor in the failing canine myocardium

Circ Res

Differential distribution of beta-adrenergic receptor subtypes in blood vessels of knockout mice lacking beta(1)- or beta(2)-adrenergic receptors

Associate editor: P. Molenaar
β₃-Adrenoceptors in the cardiovascular system: Putative roles in human pathologies

Pharmacology of β₃-adrenoceptors

β₃-adrenoceptors in the heart

β₃-adrenoceptors in blood vessels