(Hypertension. 1997;29:715-722.)
© 1997 American Heart Association, Inc.
Articles |
Scienze Mediche, Universita degli Studi di Brescia (Italy) (M.C.), and Klinik III fur Innere Medizin der Universitat zu Koln (Germany) (M.B.).
| Abstract |
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Key Words: hypertrophy sympathetic nervous system receptors, adrenergic, beta G proteins heart failure
| Introduction |
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-ARs, which are coupled to phospholipase C. | General Architecture of the ß-ARActivated Pathway |
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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
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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-ARmediated 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-ARActivated Pathway |
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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-CREBmodulated 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-ARmediated 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
.
| Alterations of the Cardiac ß-ARActivated Pathway in Hypertensive Heart Disease |
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Cardiac ß-ARMediated 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-ARmediated 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 ProteinCoupled 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 messengerdependent protein kinases such as PKA or protein kinase C and a family of specific G proteincoupled 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 proteincoupled 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 |
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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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-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.
| Conclusions and Perspectives |
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| Selected Abbreviations and Acronyms |
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| Acknowledgments |
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| Footnotes |
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Received May 13, 1996;
first decision June 3, 1996;
first decision September 25, 1996;
| References |
|---|
|
|
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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.
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.
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.
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.
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.
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.
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.
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.
19.
Floras JS. Epinephrine and the genesis of hypertension. Hypertension.. 1992;19:1-18.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
44.
Bohm M, Grabel C, Flesch M, Knorr A, Erdmann E. Treatment in hypertensive cardiac hypertrophy, II: postreceptor events. Hypertension.. 1995;25:962-970.
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.
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.
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.
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.
52.
Packer M. Neurohormonal interactions and adaptations in congestive heart failure. Circulation.. 1988;77:721-730.
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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] |
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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] |
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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. [Abstract] [Full Text] [PDF] |
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N. Dzimiri Regulation of beta -Adrenoceptor Signaling in Cardiac Function and Disease Pharmacol. Rev., September 1, 1999; 51(3): 465 - 502. [Abstract] [Full Text] [PDF] |
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E. Cerbai, R. Pino, M. L Rodriguez, and A. Mugelli Modulation of the pacemaker current If by {beta}-adrenoceptor subtypes in ventricular myocytes isolated from hypertensive and normotensive rats Cardiovasc Res, April 1, 1999; 42(1): 121 - 129. [Abstract] [Full Text] [PDF] |
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K. M. Anderson, A. D. Eckhart, R. N. Willette, and W. J. Koch The Myocardial ß-Adrenergic System in Spontaneously Hypertensive Heart Failure (SHHF) Rats Hypertension, January 1, 1999; 33(1): 402 - 407. [Abstract] [Full Text] [PDF] |
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M. Bohm, M. Castellano, M. Flesch, C. Maack, M. Moll, M. Paul, F. Schiffer, and O. Zolk Chamber-Specific Alterations of Norepinephrine Uptake Sites in Cardiac Hypertrophy Hypertension, November 1, 1998; 32(5): 831 - 837. [Abstract] [Full Text] [PDF] |
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L. Levesque and S. T. Crooke Depletion of Protein Kinase C-alpha by Antisense Oligonucleotides Alters Beta-Adrenergic Function and Reverses the Phorbol Ester-Induced Reduction of Isoproterenol-Induced Adenosine 3'-5'-Cyclic Monophosphate Accumulation in Murine Swiss 3T3 Fibroblasts. J. Pharmacol. Exp. Ther., October 1, 1998; 287(1): 425 - 434. [Abstract] [Full Text] |
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M. Bohm, S. Ettelbruck, M. Flesch, W. H van Gilst, A. Knorr, C. Maack, Y. M Pinto, M. Paul, A. C.H Teisman, and O. Zolk {beta}-Adrenergic signal transduction following carvedilol treatment in hypertensive cardiac hypertrophy Cardiovasc Res, October 1, 1998; 40(1): 146 - 155. [Abstract] [Full Text] [PDF] |
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O. Zolk, M. Flesch, G. Nickenig, P. Schnabel, and M. Bohm Alteration of intracellular Ca2+-handling and receptor regulation in hypertensive cardiac hypertrophy: insights from Ren2-transgenic rats Cardiovasc Res, July 1, 1998; 39(1): 242 - 256. [Abstract] [Full Text] [PDF] |
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