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(Circulation Research. 2000;87:1079.)
© 2000 American Heart Association, Inc.

Editorial

The Cellular Actions of ß-Adrenergic Receptor Agonists

Looking Beyond cAMP

Susan F. Steinberg

From the Departments of Pharmacology and Medicine, College of Physicians and Surgeons, Columbia University, New York, NY.

Correspondence to Susan F. Steinberg, MD, Department of Pharmacology, College of Physicians and Surgeons, Columbia University, 630 W 168 St, New York, NY 10032. E-mail sfs1@columbia.edu

Key Words: ß-adrenergic receptors • cAMP • mitogen-activated protein kinases • phosphatidylinositol 3'-kinase • apoptosis

	Introduction

 
General concepts regarding the role of the sympathetic nervous system in the pathogenesis of heart failure (and as a site for therapeutic intervention) have undergone a remarkable transition in the last few years. When ß-adrenergic receptor (ß-AR) blockers were first introduced into clinical practice more than 30 years ago, they were viewed as contraindicated in heart failure. Conventional wisdom held that patients with impaired ventricular function rely on increased sympathetic drive as a mechanism to maintain mechanical performance and would clinically deteriorate if exposed to the negative inotropic actions of ß-AR antagonists. However, clinical practice demonstrated that although positive inotropic agents and vasodilators (agents that directly or indirectly activate neurohormonal pathways) induce short-term hemodynamic improvement, this is offset by long-term adverse effects to accelerate the natural history of heart failure. In contrast, ß-AR–blocking drugs prevent or reverse many of the structural and functional changes that develop during the progression of heart failure and prolong life in experimental animal models.¹

The mechanisms whereby long-term ß-AR activation leads to abnormalities in cardiomyocyte growth, energy use, calcium regulation, and a progressively dysfunctional and mechanically inefficient heart have become an important focus of recent research. The cellular actions of catecholamines generally are attributed to the predominant ß₁-AR subtype that couples to the stimulatory GTP regulatory protein (G_s), activation of adenylyl cyclase (AC), and accumulation of cAMP. Although cardiomyocytes also express pharmacologically distinct ß₂-ARs and these assume increasing importance in heart failure syndromes (where ß₁-ARs are downregulated), the traditional teaching holds . . . [Full Text of this Article]

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