β-Adrenergic Receptor Mechanisms in Heart Failure

Summary

In order to explain the attenuated responses of failing hearts to catecholamines, several investigators have attempted to examine the status of β -adrenoceptors by using different experimental models of heart failure as well as in myocardial tissue from patients with heart failure. Conflicting results from different laboratories appear to be due to the stage and type of heart failure. Congestive heart failure due to myocardial infarction in rats exhibited a decrease in the density of β -adrenergic receptors in failing left ventricles, whereas no changes were observed in the hypertrophied right ventricle; these data suggest that the reduced number of β -adrenergic receptors commonly seen in the failing hearts is not due to cardiac hypertrophy per se. Although elevated levels of plasma catecholamines in heart failure are usually considered to result in desensitization of β -adrenoceptors in failing hearts, other different mechanisms, incluing some of local nature, cannot be excluded.

The sympathetic nervous system plays an important role in the regulation of heart function; its influences are mediated by the release of norepinephrine and subsequent activation of primarily β -adrenergic receptors and of α- adrenergic receptors to a lesser extent [1,2]. Although the presence of both β ₁- and β ₂-adrenoceptors has been demonstrated in the heart, their exact contribution in eliciting functional and metabolic changes is poorly under- stood. The β -adrenergic receptors are coupled with adenylyl cyclase through guanine nucleotide binding proteins (G proteins); these receptors initiate the production of cyclic AMP and regulate diverse metabolic and functional events [3]. Thus, in view of the critical role of β -adrenergic receptors, G proteins, and the adenylyl cyclase system in modifying cardiac contractility, any change in the components of this system under pathologic conditions can be seen to impair the signal transduction mechanism in the myocardium. In this regard it should be noted that the depressed inotropic response of the myocardium to adrenergic stimulation has been demonstrated in both clinical heart failure as well as in different experimental models of heart failure [3–5].

Several investigators have also reported a wide variety of alterations in various components of the β -adrenergic receptors, G proteins, and adenylyl cyclase system in heart dysfunction. For example, an increase in β -adrenergic receptor density and an increase in cyclic AMP formation due to catecholamines were reported in myocardial ischemia due to coronary ligation in dogs [6,7]. Although other investigators also observed an increase in the β -receptor density in the ischemic myocardium from dogs and calves, the activities of adenylyl cyclase in the presence or absence of different stimulants as well as Gs protein were depressed [8,9]. On the other hand, no changes in the density of β -receptors and basal adenylyl cyclase activity, but a depression in isoproterenol stimulated adenylyl cyclase activity, were observed in ischemic or hypoxic dog hearts [10,11].

Conflicting results showing either an increase [12] or no change [13] in β -adrenergic receptor density have been reported in hamster cardiomyopathy. However, adenylyl cyclase activities in the presence of different stimulants as well as the levels of Gs protein were found to be depressed in cardiomyopathic hamster hearts [12], whereas the basal enzyme activity was normal [13] and the level of Gi protein was increased [14]. Although β -receptor density did not decrease, adenylyl cyclase activities due to β -receptors and Gs protein were increased in Adriamycin (doxorubicin)-induced cardiomyopathy in rabbits [15]. On the other hand, no alterations in β -adrenergic receptor density, G proteins, or adenylyl cyclase activities were seen in Adriamycininduced cardiomyopathy in rats [16]. Depressions in β -adrenergic receptors and adenylyl cyclase activities in the absence or presence of various stimulants were noted in catecholamine-induced cardiomyopathy in rats [17]. Monocrotaline-induced right heart cardiomyopathy in rats showed depressions in β ₁-receptor density and adenylyl cyclase activities in the presence of isoproterenol and a nonhydrolyzable guanine nucleotide analogue [Gpp(NH)p] without any changes in the absence or presence of NaF and forskolin or β ₂- receptor stimulation. Upon detailed analysis of these results, it is evident that different components of β -adrenergic receptors, G proteins, and the adenylyl cyclase system are either unchanged, upregulated, or downregulated in failing myocardium. Such a discrepancy in results seems to depend upon the type and stage of heart disease as well as the type of membrane preparations employed for investigation. However, none of these studies have attempted to examine the sequence of changes in these components of the adrenergic mechanisms at different stages of heart failure in any experimental model. Although most of the work in this field has also been carried out on myocardial tissues from patients with heart disease, it should be recognized that all these patients were on different cardiac drugs, and thus the results are difficult to interpret in terms of pathophysiologic changes in heart failure.

In addition to defects in the adrenergic mechanisms, it should be pointed out that several biochemical changes have been described to explain the pathophysiology of contractile dysfunction in heart failure, but no precise cause and effect relationship has been determined. The defective mitochondrial ATP production as a mechanism for reduced contractile force in failing hearts was ruled out by observations when heart failure was found to occur in the presence of normal myocardial perfusion and oxygen availability [18,19]. From studies involving the measurement of oxidative phosphorylation activity and the high-energy phosphate content in the failing heart, it became apparent that changes in mitochondrial function are not related to the development of heart failure because the contractility of these hearts was impaired before the occurrence of any defect in mitochondrial function [20,21].

Alterations in myocardial energy utilization have also been postulated to play a role in the development of heart failure because the efficiency of the heart, manifested as the ratio of work performed to oxygen utilized, is depressed in chronic myocardial failure. The possibility of a defect in the conversion of metabolic energy to contractile work has been implied to indicate that myosin heavy chains are differentially expressed and are associated with altered myofibrillar ATPase activity in heart failure [22,23]. However, it has been suggested that this remodeling of the contractile apparatus may increase the efficiency of the myocardium and thus may represent a beneficial alteration, rather than a cause leading to the development of heart failure [24].

Recent advances in research involving Ca²⁺ movements in the heart have been valuable for the formulation of new concepts with respect to the physiologic and pathologic aspects of Ca²⁺ metabolism in the myocardium. It is now well established that Ca²⁺ plays an important role in the excitationcontraction cycle of the cardiac cell, and it has been suggested that abnormalities in intracellular Ca²⁺ metabolism may be the basis of depressed contractility in heart failure. Specifically, both intracellular Ca²⁺ over load and intracellular Ca²⁺ deficiency have been considered to be responsible for defective myocardial contractility, as these events are known to initiate the disruption of energy-generating processes as well as abnormal activation of the contractile machinery [25]. The sarcoplasmic reticulum is responsible for sequestration of Ca²⁺ to allow relaxation, storage of Ca²⁺ during relaxation, and release of Ca²⁺ to initiate contraction.

On the other hand, the sarcolemma plays an important role in the generation and maintenance of transmembrane gradients of Na⁺, K⁺, and Ca²⁺, which are essential for cardiac cell excitability. The sarcolemmal membrane bound cation channels, cation exchange systems, and ATPase pumps contribute to the regulation of membrane potential and the cardiac excitationcontraction coupling process. Rapid Ca²⁺ influx is achieved through opening of the voltage-sensitive Ca²⁺ channels in the sarcolemmal membrane. Both cardiac sarcolemma and sarcoplasmic reticular membranes are known to participate in the beat-to-beat regulation of the myoplasmic Ca²⁺ level [26,27]; a great deal of research has been focused on abnormal sarcoplasmic reticular function in failing myocardium, and some work has been carried out to identify sarcolemmal defects in heart failure. In view of these observations, it is important to keep in mind the role of Ca²⁺-related defects at the level of sarcolemma, sarcoplasmic reticulum, mitochondria, and myofibrils while interpreting changes in adrenergic mechanisms in failing hearts in terms of their functional significance.

It is now well known that the positive inotropic action of catecholamines is primarily mediated by their interaction with β -adrenergic receptors in the cardiac cell surface [28]. The β -adrenergic receptors are thought to be linked to the muscle contraction through cyclic AMP-mediated activation of protein kinase A and subsequent phosphorylation reactions that lead to an increase in Ca²⁺ influx [29]. Since the activation and inhibition of β -adrenergic receptors by endogenous catecholamines and β -adrenergic receptor blocking drugs, respectively, have obvious and important clinical relevance to a wide range of humans diseases, such as congestive heart failure, ischemic heart disease, and hypertension, it is of critical importance to understand how chronic activation of receptors by elevated concentrations of plasma catecholamines that occur in heart failure can regulate various commponents and interactions of the hormone-sensitive adenylyl cyclase system [30,31]. However, for the purpose of this chapter the discussion is limited to the role of β -adrenergic receptors in healthy and failing hearts.