This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Castellano, M. Articles by Bohm, M. Search for Related Content PubMed PubMed Citation Articles by Castellano, M. Articles by Bohm, M.

(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

Maurizio Castellano; Michael Bohm

Scienze Mediche, Universita degli Studi di Brescia (Italy) (M.C.), and Klinik III fur Innere Medizin der Universitat zu Koln (Germany) (M.B.).

	Abstract

Top Abstract Introduction General Architecture of the... Regulation of the... Alterations of the Cardiac... Postreceptor Events in... Development of Hypertensive... Conclusions and Perspectives References

 
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 G_i 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

	Introduction

Top Abstract Introduction General Architecture of the... Regulation of the... Alterations of the Cardiac... Postreceptor Events in... Development of Hypertensive... Conclusions and Perspectives References

 
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

Top Abstract Introduction General Architecture of the... Regulation of the... Alterations of the Cardiac... Postreceptor Events in... Development of Hypertensive... Conclusions and Perspectives References

 
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 G_s 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, G_s 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.

View larger version (61K): [in this window] [in a new window]   Figure 1. Structural organization of the ß2-AR. Serine and threonine phosphorylation sites that are covalently modified by the ß-ARK and cAMP-dependent protein kinase (PKA) are indicated as well as amino acids involved in ligand binding, G protein coupling, or desensitization.

View larger version (23K): [in this window] [in a new window]   Figure 2. Schematic representation of receptor and G-protein–regulated adenylyl cyclase in the cardiomyocyte. Norepinephrine is released from sympathetic nerve terminals into the synaptic cleft. The catecholamine stimulates cardiac ß-ARs (selectivity ß1:ß2, approximately 30:1). The action of norepinephrine is (predominantly) terminated by reuptake into presynaptic stores. ß-ARs (ß1- and ß2-subtypes) couple to the adenylyl cyclase through stimulatory G proteins, while m-cholinoceptors (m-Ch) and type 1 adenosine (A1) receptors mediate adenylyl cyclase inhibition and antiadrenergic effects. G proteins are heterotrimeric complexes (sß, iß), the -subunits of which are subject to cholera toxin–catalyzed (s, approximately 45 to 52 kD) or pertussis toxin–catalyzed (i, approximately 40 to 42 kD) ADP ribosylation. The catalyst forms cAMP from ATP, which in turn activates cAMP-dependent protein kinase (PkA).

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

	Regulation of the ß-AR–Activated Pathway

Top Abstract Introduction General Architecture of the... Regulation of the... Alterations of the Cardiac... Postreceptor Events in... Development of Hypertensive... Conclusions and Perspectives References

 
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 (t_½, 3.5 minutes) phosphorylation of the ß-AR, which impairs the ability of the receptor to activate G_s.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 (t_½, 20 seconds) that triggers the binding of the cytosolic protein ß-arrestin to the receptor and results in uncoupling of the ß-AR from G_s (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

View larger version (29K): [in this window] [in a new window]   Figure 3. Mechanisms of ß-adrenergic desensitization involving phosphorylation of receptors. For a detailed description, see text. Modified from Hausdorff et al.10

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 G_i, whereas G_s 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 G_i 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 G_i gene, which is the predominant G_i 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 G_s 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 G_i.

	Alterations of the Cardiac ß-AR–Activated Pathway in Hypertensive Heart Disease

Top Abstract Introduction General Architecture of the... Regulation of the... Alterations of the Cardiac... Postreceptor Events in... Development of Hypertensive... Conclusions and Perspectives References

 
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 (B_max) and affinity (K_d) 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 K_d 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.

	Postreceptor Events in Hypertensive Heart Disease

Top Abstract Introduction General Architecture of the... Regulation of the... Alterations of the Cardiac... Postreceptor Events in... Development of Hypertensive... Conclusions and Perspectives References

 
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 SHR^{24 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 G_s protein were reported to be unchanged in some studies,²⁴ the possibility remains that an increased amount or function of G_i could represent an important mechanism of heterologous adenylyl cyclase desensitization.

View larger version (40K): [in this window] [in a new window]   Figure 4. Guanylyl imidodiphosphate [Gpp(NH)p]–stimulated adenylyl cyclase in left ventricular myocardial membranes from control (Ctr) and hypertensive rats. Different forms of hypertension were investigated. The polygenic form of hypertension was studied in SHR. Monogenic hypertension was studied in transgenic rats harboring the mouse renin gene in several tissues [TG(mREN2)27]. As acquired forms, one-kidney, one clip rats (1K-1C), deoxycorticosterone acetate–treated rats (DOCA), and rats with reduced renal mass (RRM) were studied and compared with respective controls. Note that in each model a depressed guanine nucleotide–dependent adenylyl cyclase was observed. Data taken from Bohm et al.35 36 37

Fig 5 summarizes the immunodetectable amount of G_i 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 G_i proteins. These findings provide evidence that the increase of G_i 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 G_i proteins. Because inhibition of G_i 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 G_i proteins in hypertensive heart disease. The studies available on myocardial G protein expression are summarized elsewhere.^{24 34}

View larger version (35K): [in this window] [in a new window]   Figure 5. Immunochemical detection of Gi protein -subunits (Gi) in myocardial membranes from control (Ctr) and hypertensive rats. Different forms of hypertension were investigated as defined in Fig 4. In SHR, 1K-1C, DOCA, and RRM rats, a radioimmunoassay was applied to measure Gi proteins. In TG(mREN2)27 rats, Gi was determined on immunoblot by densitometric analysis of immunoreactive bands. Note that in each model, an increased protein content of Gi was detected. Data taken from Bohm et al.35 36 37

	Development of Hypertensive Heart Disease and Cardiac ß-Adrenergic Dysfunction

Top Abstract Introduction General Architecture of the... Regulation of the... Alterations of the Cardiac... Postreceptor Events in... Development of Hypertensive... Conclusions and Perspectives References

 
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 G_i 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 G_i 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 inhibitors^{43 44 45} or Ca²⁺ antagonists,^{43 44} the sympathetic activation as judged from circulating and cardiac norepinephrine⁴⁵ or neuropeptide Y⁴³ concentrations, the increase of G_i,^{44 45} and adenylyl cyclase desensitization^{43 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 G_i 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 G_i 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.

	Conclusions and Perspectives

Top Abstract Introduction General Architecture of the... Regulation of the... Alterations of the Cardiac... Postreceptor Events in... Development of Hypertensive... Conclusions and Perspectives References

 
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

	Selected Abbreviations and Acronyms

 

AR = adrenergic receptor ß-ARK = ß-adrenergic receptor kinase CRE = cAMP-responsive element PKA = protein kinase A SHR = spontaneously hypertensive rat(s)

	Acknowledgments

 
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.

	Footnotes

 
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;

	References

Top Abstract Introduction General Architecture of the... Regulation of the... Alterations of the Cardiac... Postreceptor Events in... Development of Hypertensive... Conclusions and Perspectives References

 

1. Schwinn DA, Caron MG, Lefkowitz RJ. The beta-adrenergic receptor as a model for molecular structure-function relationships in G-protein-coupled receptors. In: Fozzard HA, Habes E, Jennings RB, Katz A, Morgan HE, eds. The Heart and Cardiovascular System. 2nd ed. New York, NY: Raven Press Publishers; 1992:1657-1684.
2. Susanni EE, Vatner DE, Homcy CJ. Beta-adrenergic receptor/adenylyl cyclase system. In: Fozzard HA, Habes E, Jennings RB, Katz A, Morgan HE, eds. The Heart and Cardiovascular System. 2nd ed. New York, NY: Raven Press Publishers; 1992:1685-1708.
3. Schubert B, VanDongen AMJ, Kirsch GE, Brown AM. ß-Adrenergic inhibition of cardiac sodium channels by dual G-protein pathways. Science.. 1989;245:516-519.[Abstract/Free Full Text]
4. Schluter KD, Millar BC, McDermott BJ, Piper HM. Regulation of protein synthesis and degradation in adult ventricular cardiomyocytes. Am J Physiol. 1995;269:C1347-C1355.[Abstract/Free Full Text]
5. Schluter KD, Zhou XJ, Piper HM. Trophic coupling to ß₂-adrenoceptor stimulation in adult cardiomyocytes is induced by transforming-growth-factor-ß (TGF-ß). Pflugers Arch. 1994;426(suppl 6):R117. Abstract.
6. Schluter KD, Zhou XJ, Piper HM. Induction of hypertrophic responsiveness to isoprenaline by TGF-ß in adult rat cardiomyocytes. Am J Physiol. 1995;269:C1311-C1316.[Abstract/Free Full Text]
7. Collins S, Bouvier M, Bolanowski MA, Caron MG, Lefkowitz RJ. Cyclic AMP stimulates transcription of the ß₂-adrenergic receptor gene in response to short term agonist exposure. Proc Natl Acad Sci U S A.. 1989;86:4853-4857.[Abstract/Free Full Text]
8. Hadock JR, Wang H, Malbon CC. Agonist induced destabilization of ß-adrenergic receptor mRNA: attenuation of glucocorticoid-induced up-regulation of ß-adrenergic receptors. J Biol Chem.. 1989;264:19928-19933.[Abstract/Free Full Text]
9. Foulkes SN, Borelli E, Sassone-Corsi P. CREM gene: use of alternative DNA-binding domains generates multiple antagonists of cAMP-induced transcription. Cell.. 1991;64:739-749.[Medline] [Order article via Infotrieve]
10. Hausdorff WP, Caron MG, Lefkowitz RJ. Turning off the signal: desensitization of ß-adrenergic receptor function. FASEB J.. 1990;4:2881-2889.[Abstract]
11. Lohse MJ. Mechanisms of ß-adrenergic receptor desensitization. In: Hargave PA, Hofmann KP, Kaupp UB, eds. Signal Transmission in Photoreceptor Systems. Berlin, Germany: Springer-Verlag; 1992:160-171.
12. Muller FU, Boheler KR, Eschenhagen T, Schmitz W, Scholz H. Isoprenaline stimulates gene transcription of the inhibitory G-protein alpha-subunit Gi-alpha-2 in rat heart. Circ Res.. 1993;72:696-700.[Abstract/Free Full Text]
13. Weinstein LA, Spiegel AM, Carter AD. Cloning and characterization of the human gene for a -subunit of Gi₂, a GTP-binding signal transducing protein. FEBS Lett.. 1988;232:333-340.[Medline] [Order article via Infotrieve]
14. Imagawa M, Chiu R, Karin M. Transcription factor AP-2 mediates induction of the different signal transduction pathways: protein kinase C and cAMP. Cell.. 1987;51:251-260.[Medline] [Order article via Infotrieve]
15. Clark RB, Kunkel MW, Friedman J, Goka TJ, Johnson JA. Activation of cAMP-dependent protein kinase is required for heterologous desensitization of adenylyl cyclase in S49 wild type lymphoma cells. Proc Natl Acad Sci U S A.. 1988;85:1442-1446.[Abstract/Free Full Text]
16. Esler MG, Hasking GJ, Wilet IR, Leonard PK, Jennings GL. Noradrenaline release and sympathetic nervous system activity. J Hypertens.. 1988;3:117-119.
17. de Champlain J. Pre- and postsynaptic adrenergic dysfunction in hypertension. J Hypertens. 1990;8(suppl 7):S77-S85.
18. Esler M, Jennings G, Lambert A. Overflow of catecholamine neurotransmitters to the circulation: source, fate and functions. Physiol Rev.. 1990;70:963-985.[Free Full Text]
19. Floras JS. Epinephrine and the genesis of hypertension. Hypertension.. 1992;19:1-18.[Abstract/Free Full Text]
20. Hall JA, Petch MC, Brown MJ. Intracoronary injections of salbutamol demonstrate the presence of functional ß₂-adrenoceptors in the human heart. Circ Res.. 1989;65:546-553.[Abstract/Free Full Text]
21. Feldman RD. ß-Adrenergic receptor alterations in hypertension: physiological and molecular correlates. Can J Physiol Pharmacol.. 1987;65:1666-1672.[Medline] [Order article via Infotrieve]
22. Michel MC, Brodde OE, Insel PA. Peripheral adrenergic receptors in hypertension. Hypertension.. 1990;16:107-120.[Abstract/Free Full Text]
23. Mullins JJ, Peters J, Ganten D. Fulminant hypertension in transgenic rats harbouring the mouse Ren-2 gene. Nature.. 1990;344:541-544.[Medline] [Order article via Infotrieve]
24. Bohm M. Sympathetic neuroeffector mechanisms in the failing and hypertrophied myocardium. In: Dhalla NS, Pierce GN, Panagia V, Beamish RE, eds. Heart Hypertrophy and Failure. Boston, Mass: Kluwer Academic Publishers; 1995:403-417.
25. Kurtz TW, Montano M, Chan L, Kabra P. Molecular evidence of genetic heterogeneity in Wistar-Kyoto rats: implications for research with the spontaneously hypertensive rat. Hypertension.. 1989;13:188-192.[Abstract/Free Full Text]
26. Castellano M, Beschi M, Rizzoni D, Paul M, Bohm M, Mantero G, Bettoni G, Porteri E, Albertini A, Agabiti-Rosei E. Gene expression of cardiac ß₁-adrenergic receptors during the development of hypertension in spontaneously hypertensive rats. J Hypertens.. 1993;11:787-791.[Medline] [Order article via Infotrieve]
27. Bohm M, Castellano M, Paul M, Erdmann E. Cardiac norepinephrine, ß-adrenoceptors and Gi-proteins in prehypertensive and hypertensive spontaneously hypertensive rats. J Cardiovasc Pharmacol.. 1994;23:980-987.[Medline] [Order article via Infotrieve]
28. Samama P, Cotecchia S, Costa T, Lefkowitz RJ. A mutation-induced activated state of the ß₂-adrenergic receptor. J Biol Chem.. 1993;268:4625-4636.[Abstract/Free Full Text]
29. Cotecchia S, Exum S, Caron MG, Lefkowitz RJ. Regions of the ₂-adrenergic receptor involved in coupling to phosphoinositol hydrolysis and enhanced sensitivity of biological function. Proc Natl Acad Sci U S A.. 1990;87:2896-2900.[Abstract/Free Full Text]
30. Zee RYL, Morris BJ, Griffiths LR. Association analyses of RFLPs for the ₂- and ß₁-adrenoceptor genes in essential hypertension. Hypertens Res.. 1992;15:57-60.
31. Milano CA, Allen LF, Rockman HA, Dolber PC, McMinn TR, Chien KR, Johnson TD, Bond RA, Lefkowitz RJ. Enhanced myocardial function in transgenic mice overexpressing the ß₂-adrenergic receptor. Science.. 1994;264:582-586.[Abstract/Free Full Text]
32. Ungerer M, Bohm M, Elce JS, Erdman E, Lohse MJ. Altered expression of ß-adrenergic receptors in the failing human heart. Circulation.. 1993;87:454-463.[Abstract/Free Full Text]
33. Koch WJ, Rockman HA, Samama P, Hamilton R, Bond RA, Milano CA, Lefkowitz RJ. Reciprocally altered cardiac function in transgenic mice overexpressing the ß-adrenergic receptor kinase or a ßARK inhibitor. Science.. 1995;268:1350-1353.[Abstract/Free Full Text]
34. Michel C, Brodde OE, Insel PA. Are cardiac G-proteins altered in rat models of hypertension? J Hypertens.. 1993;11:355-363.[Medline] [Order article via Infotrieve]
35. Bohm M, Gierschik P, Knorr A, Larisch K, Weismann K, Erdmann E. Desensitization of adenylate cyclase and increase of Gi in cardiac hypertrophy due to acquired hypertension. Hypertension.. 1992;20:103-112.[Abstract/Free Full Text]
36. Bohm M, Gierschik P, Knorr A, Larisch K, Weismann K, Erdmann E. Role of altered G-protein expression in the regulation of spontaneous hypertensive cardiomyopathy in rats. J Hypertens.. 1992;10:1115-1128.[Medline] [Order article via Infotrieve]
37. Bohm M, Moll M, Schmid B, Paul M, Ganten D, Castellano M, Erdmann E. ß-Adrenergic neuroeffector mechanisms in cardiac hypertrophy of renin transgenic rats. Hypertension.. 1994;24:653-662.[Abstract/Free Full Text]
38. Kannel WB, Castelli WP, McNamara PM, McKee PA, Feinleib M. Role of blood pressure in the development of congestive heart failure: the Framingham Study. N Engl J Med.. 1972;287:781-787.
39. Grossman W, Jones D, McLaurin KP. Wall stress and patterns of hypertrophy in the human left ventricle. J Clin Invest.. 1975;58:56-64.
40. Spann JF Jr, Buccino RA, Sonnenblick EH, Braunwald E. Contractile state of cardiac muscle obtained from cats with experimentally produced ventricular hypertrophy and heart failure. Circ Res.. 1967;21:341-343.[Abstract/Free Full Text]
41. Goldstein DS, Kopin IJ. The autonomic nervous system and catecholamines in normal blood pressure control and in hypertension. In: Laragh JH, Brenner BM, eds. Hypertension: Pathophysiology, Diagnosis and Management. New York, NY: Raven Press Publishers; 1990:711-747.
42. Head RJ, Cassis LA, Robinson RL, Westfall DP, Stitzel RE. Altered catecholamine contents in vascular and nonvascular tissues in genetically hypertensive rats. Blood Vessels.. 1985;22:196-204.[Medline] [Order article via Infotrieve]
43. Bohm M, Grabel C, Knorr A, Erdmann E. Treatment in hypertensive cardiac hypertrophy, I: neuropeptide Y and ß-adrenoceptors. Hypertension.. 1995;25:954-961.[Abstract/Free Full Text]
44. Bohm M, Grabel C, Flesch M, Knorr A, Erdmann E. Treatment in hypertensive cardiac hypertrophy, II: postreceptor events. Hypertension.. 1995;25:962-970.[Abstract/Free Full Text]
45. Bohm M, Castellano M, Agabiti-Rosei E, Flesch M, Paul M, Erdmann E. Dose-dependent dissociation of ACE-inhibitor effects on blood pressure, on cardiac hypertrophy and on ß-adrenergic signal transduction. Circulation.. 1995;92:3006-3013.[Abstract/Free Full Text]
46. Bohm M, Kirchmayr R, Erdmann E. Myocardial Gi-protein levels in patients with hypertensive cardiac hypertrophy, ischemic heart disease and cardiogenic shock. Cardiovasc Res.. 1996;30:611-618.
47. Capasso JM, Palackal T, Olivetti G, Anversa P. Left ventricular failure induced by long-term hypertension in rats. Circ Res.. 1990;66:1400-1412.[Abstract/Free Full Text]
48. Moriaki I, Kihara Y, Moril I, Fujiwara H, Sasayama S. Transition from compensatory hypertrophy to dilated, failing left ventricles in Dahl salt-sensitive rats. Am J Physiol.. 1994;267:H2471-H2482.[Abstract/Free Full Text]
49. Brodde OE. ß₁- and ß₂-Adrenoceptors in the human heart: properties, function and alterations in chronic heart failure. Pharmacol Rev.. 1991;43:203-242.[Medline] [Order article via Infotrieve]
50. Bohm M. Alterations of ß-adrenoceptor-G-protein-regulated adenylyl cyclase in heart failure. Mol Cell Biochem.. 1995;147:147-160.[Medline] [Order article via Infotrieve]
51. Packer M, Bristow MR, Cohn JN, Colucci WS, Fowler MB, Gilbert M, for the US Heart Failure Study Group. Effect of carvedilol on morbidity and mortality in chronic heart failure. N Engl J Med.. 1996;334:1349-1355.[Abstract/Free Full Text]
52. Packer M. Neurohormonal interactions and adaptations in congestive heart failure. Circulation.. 1988;77:721-730.[Free Full Text]

This article has been cited by other articles:

				S. M. MacDonnell, G. Garcia-Rivas, J. A. Scherman, H. Kubo, X. Chen, H. Valdivia, and S. R. Houser Adrenergic Regulation of Cardiac Contractility Does Not Involve Phosphorylation of the Cardiac Ryanodine Receptor at Serine 2808 Circ. Res., April 25, 2008; 102(8): e65 - e72. [Abstract] [Full Text] [PDF]

				S. Perlini, I. Ferrero, G. Palladini, R. Tozzi, C. Gatti, M. Vezzoli, F. Cesana, M. B. Janetti, F. Clari, G. Busca, et al. Survival Benefits of Different Antiadrenergic Interventions in Pressure Overload Left Ventricular Hypertrophy/Failure Hypertension, July 1, 2006; 48(1): 93 - 97. [Abstract] [Full Text] [PDF]

				S. M. MacDonnell, H. Kubo, D. L. Crabbe, B. F. Renna, P. O. Reger, J. Mohara, L. A. Smithwick, W. J. Koch, S. R. Houser, and J. R. Libonati Improved Myocardial {beta}-Adrenergic Responsiveness and Signaling With Exercise Training in Hypertension Circulation, June 28, 2005; 111(25): 3420 - 3428. [Abstract] [Full Text] [PDF]

				M. Kozakova, A. G. Fraser, S. Buralli, A. Magagna, A. Salvetti, E. Ferrannini, and C. Palombo Reduced Left Ventricular Functional Reserve in Hypertensive Patients With Preserved Function at Rest Hypertension, April 1, 2005; 45(4): 619 - 624. [Abstract] [Full Text] [PDF]

				F. Labarthe, M. Khairallah, B. Bouchard, W. C. Stanley, and C. Des Rosiers Fatty acid oxidation and its impact on response of spontaneously hypertensive rat hearts to an adrenergic stress: benefits of a medium-chain fatty acid Am J Physiol Heart Circ Physiol, March 1, 2005; 288(3): H1425 - H1436. [Abstract] [Full Text] [PDF]

				D. Bell, A. R. Allen, E. J. Kelso, A. Balasubramaniam, and B. J. McDermott Induction of Hypertrophic Responsiveness of Cardiomyocytes to Neuropeptide Y in Response to Pressure Overload J. Pharmacol. Exp. Ther., November 1, 2002; 303(2): 581 - 591. [Abstract] [Full Text] [PDF]

				S. Bartel, B. Hoch, D. Vetter, and E.-G. Krause Expression of Human Angiotensinogen-Renin in Rat: Effects on Transcription and Heart Function Hypertension, February 1, 2002; 39(2): 219 - 223. [Abstract] [Full Text] [PDF]

				U. Schotten, K. Filzmaier, B. Borghardt, S. Kulka, F. Schoendube, C. Schumacher, and P. Hanrath Changes of beta -adrenergic signaling in compensated human cardiac hypertrophy depend on the underlying disease Am J Physiol Heart Circ Physiol, June 1, 2000; 278(6): H2076 - H2083. [Abstract] [Full Text] [PDF]

				C. A. Walker, F. A. Crawford Jr, and F. G. Spinale MYOCYTE CONTRACTILE DYSFUNCTION WITH HYPERTROPHY AND FAILURE: RELEVANCE TO CARDIAC SURGERY J. Thorac. Cardiovasc. Surg., February 1, 2000; 119(2): 388 - 400. [Full Text] [PDF]

P.A. van Zwieten The influence of antihypertensive drug treatment on the prevention and regression of left ventricular hypertrophy Cardiovasc Res, January 1, 2000; 45(1): 82 - 91.