(Hypertension. 1997;29:715-722.)
© 1997 American Heart Association, Inc.
Articles |
The Cardiac ß-Adrenoceptor–Mediated Signaling Pathway and Its Alterations in Hypertensive Heart Disease
Scienze Mediche, Universita degli Studi di Brescia (Italy) (M.C.), and Klinik III fur Innere Medizin der Universitat zu Koln (Germany) (M.B.).
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Abstract |
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 Top Abstract IntroductionGeneral Architecture of the...Regulation of the...Alterations of the Cardiac...Postreceptor Events in...Development of Hypertensive...Conclusions and PerspectivesReferences |
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Hypertension-induced cardiac hypertrophy is a predictor of the development of cardiac failure. It is unknown which cellular markers contribute to the progression from compensated hypertrophy to failure. In heart failure, several signal transduction defects leading to adenylate cyclase desensitization have been demonstrated, such as ß-adrenoceptor downregulation, increase of inhibitory G protein expression, and uncoupling of ß-adrenergic receptors, presumably by an increase of receptor kinase activity. In hypertensive heart disease, most studies have been performed in rat models of hypertension. As in heart failure, heterologous adenylyl cyclase desensitization occurs. The mechanisms are often different between the heterogeneous models for acquired and genetic hypertension, but Gi protein alterations and ß-adrenoceptor downregulation have been observed frequently. The underlying mechanism for desensitization is most likely a sympathetic activation in established hypertension rather than genetic alterations of signal transduction proteins. The data available suggest that ß-adrenergic desensitization could represent a mechanism that contributes to the progression from hypertrophy to failure. The key question remains whether those hypertensive patients who develop heart failure are more prone to ß-adrenergic desensitization or whether early intervention to reduce sympathetic activity is more effective in preventing or delaying the transition from compensated hypertrophy to overt failure.
Key Words: hypertrophy • sympathetic nervous system • receptors, adrenergic, beta • G proteins • heart failure
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Introduction |
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TopAbstractIntroductionGeneral Architecture of the...Regulation of the...Alterations of the Cardiac...Postreceptor Events in...Development of Hypertensive...Conclusions and PerspectivesReferences |
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In physiological conditions, the stimulation of myocardial ß-ARs by catecholamines represents a key step in the adaptation of cardiac output to an increase of peripheral demand for oxygen and substrates. On the other hand, increased sympathetic nervous system activity, increased peripheral response to adrenergic stimulation, or both have been considered as important factors in the pathogenesis of arterial hypertension. In this context, cardiac ß-adrenergic mechanisms can be affected in two different ways: (1) An increased cardiac adrenergic activity may contribute to the cardiovascular pattern that seems to be present in the initial phase of several hypertensive conditions as well as to the development of cardiac structural alterations (left ventricular hypertrophy); (2) alternatively, cardiac ß-adrenergic mechanisms may be secondarily altered in hypertension as a compensatory response that aims to (partially) offset the effects of primary changes. This review describes first the general biochemical organization and regulation of the cardiac ß-AR–mediated signaling pathway, as recently elucidated by the relevant contribution of molecular biology. Second, it focuses on the alterations observed in experimental and, whenever possible, human hypertension. This review will not deal with the possible alterations of the effector adenylyl cyclase and its isoforms, with signal transduction pathways of G proteins to effectors other than adenylyl cyclase (eg, ionic channels), or with
-ARs, which are coupled to phospholipase C. |
General Architecture of the ß-AR–Activated Pathway |
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TopAbstractIntroductionGeneral Architecture of the...Regulation of the...Alterations of the Cardiac...Postreceptor Events in...Development of Hypertensive...Conclusions and PerspectivesReferences |
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The ß-AR is the first element in the signal transduction chain mediating adrenergic stimulation of the heart. All known subtypes of ß-ARs (ß1, ß2, and ß3) are glycoproteins with extracellular amino termini, seven hydrophobic transmembrane domains, and intracellular carboxy termini (Fig 1
) (see Reference 1 for details). While specific amino acid residues in the hydrophobic membrane spanning regions appear to be essential for ligand binding with catecholamines, the third intracellular hydrophilic loop and the amino-terminal portion of the cytoplasmic carboxyl terminus of the receptor are involved in coupling to the second element of the signal transduction cascade, namely, a heterotrimeric (ß
) G protein. The G protein coupled with a ß-AR always represents a Gs subunit, which confers substrate specificity and interacts in a stimulatory way with the third element of the cascade, adenylyl cyclase (see Reference 2 for details). In addition to this "classic" coupling, Gs may also be able to directly modulate cardiac L-type calcium channels and sodium channels.3 Fig 2 is a schematic representation of the biochemical signaling system that mediates the effects of adrenergic stimulation through stimulation of ß-ARs.
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Adenylyl cyclase is a membrane-bound enzyme that catalyzes the synthesis of cAMP from ATP, which in turn activates the cAMP-dependent protein kinase (PKA). In its inactive form, this enzyme consists of two catalytic and two regulatory subunits; the binding of two cAMP molecules to each regulatory subunit promotes the release and activation of the catalytic subunits. Among the several protein targets of PKA-mediated phosphorylation in cardiac cells, voltage-dependent L-type calcium channels play a key role. They are activated by PKA-induced phosphorylation, with subsequent larger Ca2+ influx during each action potential, which accounts for an increased Ca2+-induced Ca2+ release from the sarcoplasmic reticulum and finally produces the positive inotropic effect of ß-adrenergic stimulation.
Besides the effects of ß-adrenergic stimulation on contractility, some effects of ß-adrenergic agonists on the induction of hypertrophy and growth processes have been described.4 Although no effects of ß-adrenergic stimulation on protein synthesis of freshly isolated cardiomyocytes have been observed, hypertrophic responses can be elicited by cultivation of cardiomyocytes in low concentrations of isoproterenol or in the presence of fetal calf serum.5 Interestingly, cocultivations of noncardiomyocytes (smooth muscle cells and fibroblasts) with cardiomyocytes or supplementation with growth factors is necessary to evoke the ß-AR–mediated growth effects in cardiomyocytes. With respect to the ß-AR subtype involved, it is interesting that ß2-ARs are most likely the mediators of the growth response in the heart. The growth response following activation of ß2-ARs has been observed to depend on transforming growth factor-ß released from cardiomyocytes into the medium.6
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Regulation of the ß-AR–Activated Pathway |
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TopAbstractIntroductionGeneral Architecture of the...Regulation of the...Alterations of the Cardiac...Postreceptor Events in...Development of Hypertensive...Conclusions and PerspectivesReferences |
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The expression and functional status of the proteins participating in the ß-adrenergic signaling system involve complex regulatory mechanisms.
Gene Regulation of ß-ARs
At the receptor level, both the number of ß-ARs and their ability to interact with the G protein are affected through transcriptional, posttranscriptional, and posttranslational mechanisms. Most of our knowledge of the regulation of ß-AR gene expression is derived from studies on the ß2-AR subtype.1 The 5' flanking region of this receptor contains several regulatory domains, including a CRE. This sequence is recognized and stimulated by a 43-kD phosphoprotein, called CRE binding protein (CREB), which is at least partly under the control of PKA-dependent phosphorylation processes. Thus, it appears that agonist binding to the receptor with consecutive activation of the cAMP-phosphorylation cascade may enhance the transcription of the receptor itself via a cAMP-PKA-CREB–modulated pathway. This is the mechanism most likely involved in the transient increase of steady-state ß2-AR mRNA levels observed in the early phase after exposure to ß-agonists.7 However, after prolonged exposure to agonists, the level of steady-state ß2-AR mRNA is decreased, and there is evidence that this downregulation is mediated by a shortening of ß2-AR mRNA half-life.8 It is not clear whether an inhibitor of CRE, such as the described CRE modulator (CREM),9 may contribute to the agonist-induced downregulation of ß2-ARs by modulating gene transcription.
Phosphorylation of ß-ARs
The posttranslational regulation of ß-ARs is mainly mediated by processes of receptor phosphorylation. Both, ß1- and ß2-ARs contain phosphorylation sites in their putative intracytoplasmic domains, which are recognized by two different kinases: PKA and ß-ARK (Fig 3).10 PKA produces a relatively slow (t½, 3.5 minutes) phosphorylation of the ß-AR, which impairs the ability of the receptor to activate Gs.11 This occurs at rather low agonist concentrations and also after stimulation of other receptors coupled to adenylyl cyclase (heterologous desensitization). ß-ARK phosphorylates only the agonist-occupied receptor (homologous desensitization) by a rapid process (t½, 20 seconds) that triggers the binding of the cytosolic protein ß-arrestin to the receptor and results in uncoupling of the ß-AR from Gs (see References 10 and 11 for further details). Fig 3 shows a schematic representation of the mechanisms of ß-AR desensitization by phosphorylation processes.10
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Regulation by G Proteins
Another critical site in the regulation of the ß-AR–mediated signaling pathway is at the level of G proteins. In fact, the interaction between the stimulatory and inhibitory pathways, which exert opposite effects on adenylyl cyclase activity, may consequently modulate cAMP production and PKA activity. Treatment of rats with catecholamines has been reported to desensitize adenylyl cyclase by a downregulation of ß-ARs and an increase of Gi, whereas Gs was unchanged.12 These observations suggest that excessive ß-AR stimulation of the heart could also be relevant in this receptor-independent adenylyl cyclase regulation. The cAMP-dependent increase of Gi is apparently due to an activation of transcription, as shown by Muller et al12 in nuclear run-on assays. In this respect, it is noteworthy that the promoter region of the Gi gene, which is the predominant Gi subtype in the human heart, possesses a consensus sequence of CRE as well as a binding domain for activator protein-2, (AP-2) which is a transcription-promoting factor at least partly regulated by cAMP.13 14 Interestingly, heterologous adenylyl cyclase desensitization could not be induced by epinephrine in S49 cyc- and S49 kin- mouse lymphoma cells, genetically lacking Gs and PKA, respectively.15 Thus, a cAMP-dependent phosphorylation of CREB may be involved in the transcriptional effects of cAMP by activating the promoter region of Gi.
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Alterations of the Cardiac ß-AR–Activated Pathway in Hypertensive Heart Disease |
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TopAbstractIntroductionGeneral Architecture of the...Regulation of the...Alterations of the Cardiac...Postreceptor Events in...Development of Hypertensive...Conclusions and PerspectivesReferences |
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Cardiac Sympathetic Activity
There is now compelling evidence that the activity of the sympathetic nervous system is increased in a substantial fraction of individuals with essential hypertension, and this generalized pattern appears to be present also in the heart. In fact, an increased cardiac norepinephrine spillover to plasma has been reported in essential hypertensive patients compared with normotensive subjects.16 This finding may be considered as indirect evidence of increased cardiac sympathetic outflow in hypertensive individuals, because differences in blood flow or neuronal norepinephrine reuptake were excluded. Similarly, evidence of increased cardiac norepinephrine turnover has been observed in animal models of hypertension.17 The validity of catecholamine measurement in assessing "overall" sympathetic activity has been debated: circulating norepinephrine does not necessarily reflect the amount of neurotransmitter released in the synaptic cleft18 ; on the other hand, relatively small changes of circulating epinephrine may influence norepinephrine release through a prejunctional ß2-AR–mediated pathway19 that has been demonstrated also in the human heart.20 In addition, the pattern of sympathetic discharge can be quite heterogeneous in different organs. However, different approaches suggest that the generalized pattern of increased sympathetic activity may be present also in the heart. This finding may be considered as indirect evidence of increased cardiac sympathetic outflow in hypertensive individuals because differences in blood flow or neuronal norepinephrine turnover have been observed in animal models of hypertension.17
Cardiac ß-AR–Mediated Responses
Despite some methodological limitations, the chronotropic response to the exogenous agonist isoproterenol can be considered as an easily accessible method for exploration of cardiac ß1-adrenergic responsiveness in humans. With this approach, a decreased chronotropic response with increasing blood pressure has been observed in hypertensive individuals (for review, see Reference 21).
Cardiac ß-ARs
No direct data on cardiac ß-ARs are available in human hypertension. There is evidence that human lymphocyte ß2-ARs, as evaluated by radioligand binding techniques, are somehow correlated with the density of the same receptor subtype in human heart.22 On the other hand, a large number of studies have investigated possible alterations of cardiac ß-ARs in animal models of genetic or experimental hypertension. The relevance of these data for human hypertension is conditional on the assumption that the functional characteristics, regulatory mechanism, and pathophysiological changes of ß-ARs produced by the hypertensive state are similar in the experimental models and in humans. Although the proportion of ß1 to ß2 cardiac ARs is higher in rats than in humans, no definite evidence of functional diversities between the two species has emerged.
An experimental model closely resembling the features of human essential hypertension is the SHR, which presents a polygenic determination of hypertension. Recently, a transgenic rat has been developed [TG(mREN2)27] that expresses the mouse renin gene in several tissues and is characterized by fulminant hypertension with cardiac hypertrophy.23 Finally, several models have been investigated in rats with experimentally induced hypertension caused by renal artery banding, with (one-kidney, one clip) or without (two-kidney, one clip) one-sided nephrectomy, aortic banding, reduced renal mass, corticosteroid (deoxycorticosterone acetate) and salt feeding, or salt loading in Dahl rats.
The quantitative aspects of ß-AR expression have been mostly conducted by evaluation of the density (Bmax) and affinity (Kd) of ß-ARs with the radioligand binding technique.22 More recently, a few studies have also examined cardiac ß-AR gene expression, as evaluated by steady-state mRNA levels in cardiac tissue. Overall, the results are quite heterogeneous and not suitable for a "meta-analytical" approach. Several sources of variability may contribute to this controversial picture. First, there is an obvious heterogeneity related to differences among the various experimental models, but also within the same model of hypertension the findings are often controversial. For example, in the SHR, which is the model most extensively investigated, the number of cardiac ß-ARs appears to be reduced compared with the number in controls in most studies, but it has also been reported to be unchanged and even increased in some other studies (for review, see References 22 and 24).
Kurtz et al25 pointed out that SHR provided by different suppliers exhibit a remarkable genetic variability, and this heterogeneity is present also in Wistar-Kyoto controls. Moreover, by using an analysis of DNA "fingerprint" patterns generated with six multilocus probes, they showed that the SHR obtained from one of the major suppliers is genetically quite different from its normotensive Wistar-Kyoto control, because the two strains share only approximately 50% of their DNA fingerprint bands in common. Similarly, the inbred Dahl salt-sensitive rat (SS/Jr strain) and Dahl salt-resistant rat (SR/Jr strain) share only approximately 80% of their DNA fingerprint bands in common. Another potential source of heterogeneity among studies performed in the same experimental model is related to different time points of sampling during the development of hypertension. For example, an increase of ß1-AR density26 or mRNA levels27 has been observed in young, prehypertensive SHR compared with Wistar-Kyoto controls but not in older SHR after a significant blood pressure rise. Considering the potential sources of variability among the different studies and the impossibility of analyzing most of them retrospectively, the near impossibility of drawing any firm conclusions becomes evident. However, if a trend should be identified in these studies, this would be toward a reduction of ß-AR number, in particular, of the ß1-subtype, at least in the more severe forms of both genetic and acquired hypertension.
No consistent change in the affinity of cardiac ß-ARs for ligand, as expressed by the Kd of the radioligand binding studies, can be identified. The development of molecular biological techniques, such as directed mutagenesis, has initiated the investigation of structure-function relationships of ß-ARs. In a recent study,28 a conservative substitution of the C-terminal portion of the third intracellular loop of the ß2-AR (residues 266 through 272) determined a constitutive, agonist-independent activation of adenylyl cyclase. This phenomenon has been observed with 2-ARs29 and raises the question of whether AR mutants may account for different patterns of ß-AR–mediated cardiac (and extracardiac) stimulation. The only study available thus far investigating the possible association between a polymorphism of the ß1-AR gene and hypertension has given negative results,30 but a systematic search for the detection of ß-AR gene mutants has so far not been undertaken.
Transgenic animal technology may also be advantageous in exploring the relationships among ß-ARs, cardiac function, and hypertension. A recent study31 reported that transgenic mice with cardiac-specific overexpression of the ß2-AR showed an increase in basal myocardial adenylyl cyclase activity, heart rate, atrial contractility, and left ventricular function in vivo. On the other hand, arterial pressure was not different in transgenic animals and controls in basal conditions and was even decreased in transgenic mice after infusion of isoproterenol.
G Protein–Coupled Receptor Kinases
Desensitization mechanisms can occur as a rapid loss of receptor function, despite the fact that these receptors are still present in the membrane. As pointed out, these phenomena involve phosphorylation of receptors by the second messenger–dependent protein kinases such as PKA or protein kinase C and a family of specific G protein–coupled receptor kinases (GRKs). The subtypes of the latter family, which are abundantly expressed in the heart, are GRK-2 (ß-ARK1), GRK-3 (ß-ARK2), and GRK-5. ß-ARK1 and ß-ARK2 require free ß-subunits for activation and targeting of the kinases from the cytosol to the membranes.11 In the failing human heart, ß-ARK1 has been shown to be increased, as judged from studies on enzyme activity and steady-state mRNA levels.32 Studies in models of hypertensive animals have not been performed. These studies would provide us with further clues on the mechanism of ß-adrenergic dysfunction in hypertensive heart disease. Recently, transgenic mice were developed with cardiac-specific overexpression of the bovine ß-ARK1 and the peptide inhibitor of ß-ARK1. The peptide inhibitor corresponds to the C-terminus (last 191 amino acids) of ß-ARK1 and competes for G protein ß-subunit binding to the enzyme, which is involved in the activation step of ß-ARK1.33 ß-ARK1 overexpression led to a reduction in G protein–coupled ß-ARs, which are in the high-affinity state for agonist binding. These alterations coincided with a depressed adenylyl cyclase activity in cardiac membranes. Cardiac overexpression of the ß-ARK1 inhibitor peptide resulted in an increased contractility and enhanced chronotropic effects of isoproterenol. These reports demonstrate that these components are powerful regulators of ß-adrenergic function in vivo and could easily play a pathophysiologically important role in cardiac hypertrophy and failure.
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Postreceptor Events in Hypertensive Heart Disease |
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TopAbstractIntroductionGeneral Architecture of the...Regulation of the...Alterations of the Cardiac...Postreceptor Events in...Development of Hypertensive...Conclusions and PerspectivesReferences |
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After prolonged exposure to high concentrations of catecholamines, heterologous desensitization of adenylyl cyclase occurs. Since in pathological conditions such as heart failure a heterologous desensitization of adenylyl cyclase due to postreceptor events occurs in response to a strong adrenergic activation, the question is whether these alterations also play a role in the stage of hypertensive cardiac hypertrophy. Because of the fact that vital myocardium from individuals with hypertension is not available, experiments on alterations of sympathetic neuroeffector mechanisms have to be performed in animal models for hypertensive cardiac hypertrophy. The classic model is the SHR, with a polygenetic determination of hypertension.25 Recently, the monogeneic TG(mREN2)27 rat was developed, which expresses the mouse renin gene in several tissues and is characterized by fulminant hypertension with cardiac hypertrophy.23 Finally, several models have been investigated in rats with experimentally induced hypertension due to renal artery banding and one-sided nephrectomy (one-kidney, one clip), reduced renal mass, and corticosteroid feeding (deoxycorticosterone acetate) or salt loading in Dahl rats. Interestingly, most of the models mentioned exhibit a desensitization of adenylyl cyclase (for review, see References 24 and 34). Isoproterenol-stimulated adenylyl cyclase activity is depressed in SHR24 35 36 37 ; one-kidney, one clip rats35 ; deoxycorticosterone acetate hypertensive rats, and, salt-sensitive Dahl rats; and TG(mREN2)27 rats.24 35 36 37 Fig 4
shows adenylyl cyclase after stimulation with the nonhydrolyzable guanine nucleotide guanylyl imidodiphosphate [Gpp(NH)p]. The guanine nucleotide derivative was used to study heterologous desensitization of adenylyl cyclase and to characterize postreceptor events in hypertensive cardiac hypertrophy. The depression of the stimulatory Gpp(NH)p effect on adenylyl cyclase activity in all studied models provided evidence for an additional defect beyond ß-AR downregulation. Since the catalytic subunit of adenylyl cyclase and Gs protein were reported to be unchanged in some studies,24 the possibility remains that an increased amount or function of Gi could represent an important mechanism of heterologous adenylyl cyclase desensitization.
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Fig 5 summarizes the immunodetectable amount of Gi in models of acquired hypertension as well as in SHR and TG(mREN2)27 rats (from References 35 through 37). All models exhibited increased steady-state levels of Gi proteins. These findings provide evidence that the increase of Gi and desensitization of adenylyl cyclase are common features of cardiac hypertrophy in polygenic, monogenic, and acquired types of hypertension. In this respect, it is interesting that unlike in human heart failure, ß-ARs are unchanged in several models although adenylyl cyclase is strongly desensitized.34 However, one must clearly differentiate between the abundance and activity of Gi proteins. Because inhibition of Gi by pertussis toxin treatment of cardiac membranes has been reported to restore adenylyl cyclase activity in hypertensive cardiac hypertrophy,37 the observations reported strongly argue in favor of a functionally relevant role of Gi proteins in hypertensive heart disease. The studies available on myocardial G protein expression are summarized elsewhere.24 34
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Development of Hypertensive Heart Disease and Cardiac ß-Adrenergic Dysfunction |
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TopAbstractIntroductionGeneral Architecture of the...Regulation of the...Alterations of the Cardiac...Postreceptor Events in...Development of Hypertensive...Conclusions and PerspectivesReferences |
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According to the data of the Framingham study, chronic pressure overload is the most common cause of heart failure.38 After an increase of pressure load imposed on the myocardium by hypertension, cardiac hypertrophy occurs. Hypertrophy is regarded as an adaptational process to reduce wall stress39 but is also suggested to precede the development of chronic heart failure.40 When and why the hypertrophic heart begins to fail are unknown. Recently, the hypothesis has been put forward that desensitization of adenylyl cyclase in hypertension could contribute to contractile dysfunction and the development of heart failure. Several reports favor this suggestion. Increases in the activity of the sympathetic nervous system have been implicated in the pathophysiology of hypertension.41 In SHR, an increase in norepinephrine concentrations has been observed in the heart and vessels.27 42 These findings as well as those discussed above provide evidence that sympathetic activation could represent one early alteration in hypertension that could be important for the development of heart failure. Thus, sympathetic activation is frequently observed in hypertensive states. As a consequence, ß-adrenergic desensitization appears to represent one key alteration besides others in the development of cardiac hypertrophy. The mechanism of desensitization of ß-adrenergic responses is not identical in all models of hypertension. Downregulation of ß-ARs and an increase of Gi protein
-subunits are the cellular events that underlie ß-adrenergic desensitization. These mechanisms can occur as isolated events or act in concert to reduce myocardial cAMP formation in hypertensive cardiac hypertrophy. Since in prehypertensive SHR neither a downregulation of ß-ARs nor an increase of Gi proteins27 has been observed, it is likely that ß-adrenergic desensitization is a consequence of high blood pressure or sympathetic activation in cardiac hypertrophy rather than an alteration preexisting before the development of the hypertensive syndrome. In this respect, it is interesting that in SHR treated with subhypotensive doses of angiotensin-converting enzyme inhibitors43 44 45 or Ca2+ antagonists,43 44 the sympathetic activation as judged from circulating and cardiac norepinephrine45 or neuropeptide Y43 concentrations, the increase of Gi,44 45 and adenylyl cyclase desensitization43 44 were completely reversed, whereas cardiac hypertrophy was unaffected.43 45 It should be pointed out that all cellular alterations have been investigated in animal models of acquired and genetic hypertension. The future experimental goals should focus on the characterization of these defects in the human myocardium. At present, these data are not available because of the lack of human tissue available from hypertensive patients. Only one investigation reported an increase of myocardial Gi concentrations46 in hypertrophied human myocardium from hypertensive patients. Unfortunately, receptor studies and the determination of adenylyl cyclase were not possible in these postmortem specimens. The future goals in this field are clearly to study ß-adrenergic responsiveness in patients with hypertension and cardiac hypertrophy and to investigate the ß-adrenergic signal transduction defects that are very likely to occur.
Myocardial hypertrophy following chronic pressure overload of the heart has been regarded as one common cause of heart failure.38 Consistently, animals with chronic myocardial pressure overload due to hypertension, eg, SHR47 or Dahl salt-sensitive hypertensive rats,48 will develop heart failure. In the failing human heart, ß-AR downregulation and an increase of Gi proteins are well established (for review, see References 49 and 50). These alterations lead to a blunted response to catecholamines and other cAMP-dependent positive inotropic agents (for review, see Reference 50). The cellular alterations are quite similar to those observed in the hypertrophied hearts of hypertensive rats. From these data it is tempting to suggest that ß-adrenergic subsensitivity could contribute to the development of contractile dysfunction already in the stage of hypertrophy. Thus, ß-adrenergic subsensitivity could be one candidate of factors that could be involved in the pathogenesis and progression of compensated cardiac hypertrophy to heart failure following long-standing pressure overload of the myocardium.
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Conclusions and Perspectives |
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TopAbstractIntroductionGeneral Architecture of the...Regulation of the...Alterations of the Cardiac...Postreceptor Events in...Development of Hypertensive...Conclusions and PerspectivesReferences |
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During recent years, desensitization of ß-adrenergic effects has been identified in compensated hypertrophied heart in hypertension and heart failure. Since the desensitization process is always accompanied by activation of the sympathetic nervous system, these phenomena are most likely consequences rather than causes of pressure overload–induced hypertrophy and sympathetic activation. However, the ß-adrenergic desensitization could in the long run contribute to the progression from compensated cardiac hypertrophy to heart failure. The key question, whether those individuals who develop heart failure are more prone to developing ß-adrenergic desensitization when hypertensive heart disease develops, presently remains open. This key topic will have to be the subject of future studies, which could provide clues to the question of whether all patients respond similarly to ß-AR antagonist treatment or whether differential responses to individual regimens exist in different groups of patients. When these issues are resolved, one would have to decide whether, besides their blood pressure–lowering effects, ß-AR antagonists would be useful in preventing ß-adrenergic desensitization and heart failure. This is a particularly interesting perspective because these antiadrenergic agents recently have been demonstrated to be useful in the treatment of overt heart failure,51 and an increased sympathetic activation has been recognized as a predictor of poor prognosis.52
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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M.C. is supported by grants from the Ministro della Universita della Ricerca Scientifica e Tecnologica. M.B. is supported by the Deutsche Forschungsgemeinschaft (Heisenberg and Gerhard Hess-programs). We thank Andreas Schwarz for expert assistance. We are grateful to Dr Georg Nickenig and Dr Petra Schnabel for critical discussion.
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Footnotes |
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Reprint requests to Michael Bohm, Klinik III fur Innere Medizin der Universitat zu Koln, Joseph-Stelzmann Straße 9, 50924 Koln, FRG.
Received May 13, 1996;
first decision June 3, 1996;
first decision September 25, 1996;
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TopAbstractIntroductionGeneral Architecture of the...Regulation of the...Alterations of the Cardiac...Postreceptor Events in...Development of Hypertensive...Conclusions and PerspectivesReferences |
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