b-Adrenergic Receptor Signaling: An Acute Compensatory Adjustment—Inappropriate for the Chronic Stress of Heart Failure? Insights from Gsa Overexpression and Other Genetically Engineered Animal Models

Under normal physiological conditions, the heart must be able to increase its output 5-fold to supply the required blood flow to the coronary circulation and skeletal muscles during severe stress. This is normally met by '5-fold increases in myocardial contractility, '3-fold increases in heart rate, and additional increases in stroke volume.1 This increased load requires a commensurate increase in myocardial blood flow, because oxygen extraction across the heart is nearly complete, even under normal conditions. Accordingly, the design of the cardiovascular system evolved to conserve myocardial metabolic demand, and consequently coronary blood flow, at rest, but with considerable reserve that can be called on rapidly in times of stress. There is a host of compensatory adjustments, including changes in metabolic substrates and kinetics, as well as oxygen-carrying capacity, that may be recruited in response to stress. However, none is more important than the autonomic nervous system in general, and the sympathetic arm in particular, in terms of providing large, rapid changes in cardiac function. When this compensatory mechanism is unavailable, eg, after treatment with propranolol, the 3-fold increases in heart rate and 5-fold increases in myocardial contractility in response to exercise cannot be achieved.1 In this connection, it is recognized that heart failure is a state characterized by enhanced sympathetic tone, but when the failing myocardium is challenged by b-adrenergic stimulation in vivo or in vitro, the most frequent result is b-adrenergic downregulation or desensitization.2–5 An impairment of cardiac function leads to autocrine, paracrine, and neurohormonal adjustments, including a strong sympathetic component (Figure 1); under acute conditions, these reflex adjustments are beneficial, as noted above. However, when the sympathetic nervous system is chronically and tonically stimulated, as occurs in the pathogenesis of heart failure, desensitization mechanisms are called into play, such that the effects of sympathetic stimulation are muted.2–5 These mechanisms include decreased b-adrenergic receptor density, decreased adenylyl cyclase activity, and uncoupling the b-adrenergic receptor from Gs, in conjunction with an increase in b-adrenergic receptor kinase (bARK) activity, as well as an increase in the content of the inhibitory GTPbinding protein, Gi.2–5 If one of the consequences of chronic stress is the generation or development of desensitization, then one might argue that the desensitization response is appropriate. However, there is no consensus regarding this point, and indeed, this aspect of cardiovascular pathophysiology and therapy has been controversial for the past half century. Diametrically opposing camps have emerged, one supporting a role for b-adrenergic supplementation in heart failure6–8 and the other suggesting that further inhibition of b-adrenergic signaling and enhancing desensitization is palliative.9–12 In fact, a b-adrenergic receptor agonist, dobutamine, is still frequently administered acutely to patients with cardiac failure, because it may provide short-term benefit. However, a recent study suggested that patients receiving intravenous dobutamine have an increased risk of death.13 This is the crucial point that must be kept in mind: the differences between the initial salutary action of sympathomimetic amines and the effects of chronically and tonically stimulating this pathway. There have been several approaches to resolving this controversy related to whether chronic sympathetic stimulation or inhibition is better in heart failure therapy. Most recently, a variety of genetic approaches have been used, in which key components of the b-adrenergic receptor signaling pathway have either been overexpressed or diminished in mice.6,7,14–17 One goal of this review is to summarize the results from these experiments and, importantly, to point out again, as noted above, the critical differences between the consequences of acute and chronic b-adrenergic receptor stimulation. One unifying feature for all of these models is that in young animals, enhancement of b-adrenergic receptor signaling,