β-Adrenergic Pathways in Nonfailing and Failing Human Ventricular Myocardium

β-Adrenergic pathways in the human ventricular myocardium mediate the powerful positive inotropic effects of released neurotransmitters (norepinephrine) and circulating hormones (epinephrine) and the response to therapeutically administered,β-agonists. Two genetically and pharmacologically distinct receptors, β₁, and β₂, mediate the contractile effects of catecholamines in a similar manner. The biologic signal produced by the occupancy of, β-adrenergic receptors by catecholamine agonists is transduced, amplified, and regulated by a family of guanine nucleotide-binding proteins (G proteins), which serve both stimulatory and inhibitory functions. Although the major biochemical effector of, β-adrenergic receptors is the enzyme adenylate cyclase, recent data in myocardial cells indicate that the receptors may be G protein-coupled directly to ion channels that regulate inotropic and electrophysiological effects. In human ventricular myocardium, heart failure produces changes in the β-adrenergic receptor pathways that have the collective effect of reducing the degree of inotropic stimulation that may be produced by a given amount of β-agonist. These changes include downregulation of β₁-adrenergic receptors, uncoupling of β₂-adrenergic receptors, and an increase in the functional activity of the inhibitory G protein. These effects in turn are probably caused by exposure to increased amounts of neurotransmitter resulting from a complex series of changes in the cardiac sympathetic nervous system. Finally, the components of the β-receptor-G protein system may be both acutely and chronically modulated by certain kinds of pharmacological therapy. These observations underscore the importance of the adrenergic nervous system in heart failure, and they create the potential for the development of new interventional strategies designed to alter the natural history of heart muscle disease and heart failure.