Receptor Function in Heart Failure MARCGEORGE BOGAERT, M.D., N.
FRAEYMAN,
M.D.,
Gent, Be/g/urn
In patients with congestive heart failure, down-regulation of /3-adrenoceptors is present, probably as a result of sympathetic overstimulation. In end-stage dilated cardiomyopathy, /3,-adrenoceptor density is markedly reduced, while Pz-adrenoceptor density is normal. This latter finding does not necessarily imply normal sensitivity to &stimulation, due to possible alterations in the P-adrenoceptorladenylate cyclase complex beyond the receptor. In some disease states, such as ischemic cardiomyopathy and mitral valve disease, there seems to be a concomitant reduction of the pl- and & adrenoceptor density. The finding of fi-adrenoceptor down-regulation has stimulated the search for novel therapeutic approaches in heart failure patients. Beta-agonists could even further down-regulate p receptors, and this perhaps explains why they seem not to be useful in long-term use. Agents that directly stimulate adenylate cyclase activity, such as forskolin, or that increase cyclic adenosine monophosphate degradation, such as the phosphodiesterase inhibitors, are being tested. Beta-adrenoceptor blocking agents were used in treatment of heart failure before /I-adrenoceptor down-regulation was recognized in these patients. It is tempting to speculate that the beneficial clinical and hemodynamic effects seen in these patients treated with metoprolol is indeed due to an antagonism of the P-adrenoceptor down-regulation. Studies testing whether P-adrenoceptor blocking agents can improve survival in congestive heart failure patients are on-going.
ompensatory processes, such as activation of the renin-angiotensin-aldosterone system and increased activity of the sympathetic nervous system, occur in patients with congestive heart failure. These processes have been reported to be accompanied by changes-e.g., an increase (upregulation) or a decrease (down-regulation) in the number of P-adrenoceptors-in a number of studies [l]. In this article, recent findings on down-regulation of cardiac P-adrenoceptors in congestive heart failure and use of this knowledge to advance therapy in this disease state will be reviewed. Data on cardiac P-adrenoceptors in humans, on other adrenoceptor types [2], and on peripheral adrenoceptors [3] are still scarce. Data obtained on cardiac tissue and on lymphocytes, with their dominantly Pa-adrenoceptor type, do not reflect the situation in the myocardial tissue, with its pi- and P,-adrenoceptors [4]. Chronotropic and inotropic functions in human cardiac tissue have traditionally been ascribed to the pladrenoceptor, but it is now known that Pa-type adrenoceptors are also present and involved in chronotropic and inotropic stimulation of the heart.
C
SYMPATHETICNERVOUSSYSTEMACTIVATION It has been established that plasma norepinephrine levels are increased and have a prognostic value [5] in patients with heart failure [6]. The increased norepinephrine plasma concentrations activate the sympathetic nervous system. It was first suggested in 1981, based on data obtained with lymphocytes, that /3-adrenergic adrenoceptors in the failing human heart are down-regulated [7]. This was confirmed by Bristow et al. [81, who demonstrated decreased p-adrenergic adrenoceptor density in the failing human heart and concomitant decrease in sensitivity toward catecholamines.
THE BETA-ADRENOCEPTOR-ADENYLATE CYCLASECOMPLEX
From the Heymans Institute of Pharmacology, Gent, Belgium. Requests for reprints should be addressed to Marc George Bogaert, M.D., Heymans Institute of Pharmacology, University of Gent Medical School, De Pintelaan 185 B-9000 Gent, Belgium.
5510s
May 29, 1991
The American Journal of Medicine
The p-adrenoceptor-adenylate cyclase complex [9] has been presented (Figure 1). The padrenoceptor complex consists of three components: a) the p-adrenoceptor binding site; b) the guanine nucleotide protein (G-protein); and c) adenylate cyclase. This three-protein complex, or “/3adrenergic signal transduction system,” is situated in the plasma membrane of the cells, with the agonist binding site at the outer surface of the cell, and
Volume 90 (suppl 5B)
SYMPOSIUM
ON IBOPAMINE / BOGAERT and FRAEYMAN
Agonists WV +++ tt ttt t -
Nomdrenaline Adrenaline Isoprenaline Fenoterol Pracaterol
metobolites Figure 1. Representation of the steps between the activation of padrenoceptors and the functlonal response in tissues (G, is the stlmulatory guanine nucleotide regulatory protein; C is the catalytic unit of adenylate cyclase). Regulation of p-adrenoceptor-mediated functional responses could, in theory, occur as a result of changes in one or more of the following: (1) receptor numbers; (2) the affinity of the receptors for agonists; (3) the coupling of the receptors to adenylate cyclase; (4) the coupling of stimulus to response; (5) phosphodiesterase activity; (6) monoamine oxidase (MAO) and/or catechol-0methyl transferase (COMT) activity (although only when using agonists that are substrates for these enzymes). Mechanisms 1, 2, and 3 might be expected to result in a differential regulation of responses mediated by the P-adrenoceptor subtypes (PI and p2). There is no evidence at present to suggest that mechanisms 4, 5, or 6 might differentiate between subtype-mediated responses.
c AMP-dependent protein kinases
t ttt ++t ttt ttt
0
I
Functional
the adenylate cyclase enzyme active site at the cytoplasmic site. Binding of an agonist to the binding site leads to an increased adenylate cyclase activity, involving synthesis of cyclic adenosine monophosphate (CAMP). The coupling between padrenoceptors and adenylate cyclase is triggered by the stimulatory G-protein. The physiologic response, i.e., the chronotropic and inotropic effects in cardiac tissue, is stimulated by a cascade of intracellular enzymatic reactions, being initiated by the activation of a CAMP-dependent protein kinase. Regulation of the functional response to /?-adrenoceptor stimulation occurs at different levels of this complex.
BETA-ADRENOCEPTOR-ADENYLATE CYCLASE COMPLEXIN HEART FAILURE The first direct evidence of a change in this complex in heart failure patients was shown by Bristow et al. I$]. They noted that a reduction in the padrenoceptor density, in maximal isoproterenolmediated adenylate cyclase stimulation and in maximal isoproterenol-stimulated muscle contraction, occurred in the left ventricle of the failing heart. These changes were explained as down-regulation, due to exposure to increased levels of catecholamines. Other studies have confirmed the findings by Bristow’s group. In some studies a good correlation
Response
between the down-regulation of the cardiac /?adrenoceptor and the severity of the heart failure was found [lo]. Many more studies have expanded our knowledge of this phenomenon, especially concerning the mechanism [ll-131. The p-adrenoceptors in the myocardium are of the &- and pZsubtypes. It has been consistently shown that in patients with end-stage dilated cardiomyopathy, P1-adrenoceptor density is greatly reduced, while &-adrenoceptor density appears to be generally normal [14,15]. This selective down-regulation may be explained by the fact that, in contrast to the pZadrenoceptor, the myocardial P,-adrenoceptor is innervated, being associated with the noradrenergic nerve terminals and neuronally released epinephrine. In ischemic cardiomyopathy and in mitral valve disease, there is a concomitant reduction of pl- and &-adrenoceptors [14,15]. While more data on &adrenoceptor density are being obtained, there is increasing interest in the possibility that post-adrenoceptor changes of the P-adrenoceptor-adenylate cyclase complex could contribute to changes of adrenergic responsiveness [9]. Study of post-adrenoceptor events-for example, alterations in the G-proteins, in adenylate cyclase, and in protein kinase-requires elaborate and complicated techniques. Until now, most data on G-proteins have been obtained with lymphocytes and not with myocardial tissue. These lymphocyte
May 29, 1991
The Amencan Journal of Medicine
Volume 90 (suppl 58)
5511s
SYMPOSIUM
ON IBOPAMINE / BOGAERT and FRAEYMAN
data suggest important changes in the stimulatory G-protein levels in congestive heart failure [16,17]. Researchers [IS] have been attempting to determine the role of these alterations with agents, such as forskolin, that directly stimulate the adenylate cyclase and hence bypass some stages of the complex. Bristow et al. [19] have found in patients with congestive myopathy the expected reduction of pladrenoceptor density, with normal Pa-adrenoceptor number. Using highly selective antagonists, they showed subsensitivity to both p1 and pa stimulation. They have explained the p1 subsensitivity by selective P,-adrenoceptor down-regulation, and the p2 subsensitivity by partial uncoupling of pZadrenoceptors from the p,-adrenergic complex.
THERAPEUTICIMPLICATIONS The decrease of the adrenergic responsiveness of the heart in patients with heart failure is in itself unfavorable. The finding of adrenergic subsensitivity in heart failure patients has led to therapeutic hypotheses that are being currently tested. The incompleteness of our knowledge in this field, arising from difficulty in obtaining myocardial material, heterogeneity of patient population to be studied, difficulty of finding adequate control subjects, and analytic problems of approaching postadrenoceptor events, must be noted. There is a good possibility that other cardiac adrenoceptor systems may change and that adrenoceptor alterations in the periphery may play an important role. Drug treatment directly or indirectly affects adrenoceptor regulation. In patients with end-stage congestive cardiomyopathy, the myocardial P-adrenoceptor downregulation is p1 selective, and it was thought that use of pa agonists seemed a reasonable strategy for stimulating the heart. Clinical data obtained on the above are not convincing. Moreover, data suggest that there is a p2 hyporesponsiveness, due to the post-adrenoceptor phenomenon [19]. The significance of /3 agonists in the treatment of heart failure patients can only be learned from carefully controlled efficacy evaluations. Realizing the influence of /? agonists, as well as other agents, on the P-adrenoceptor-adenylate cyclase complex presents difficulty because of the indirect effects that these agents have on the system. A 0 agonist may initially improve the hemodynamic situation and lessen the compensatory sympathetic overstimulation. Nonetheless, the p agonist may eventually influence the complex and consequently not reflect the true effect of the agonist as would be found in the organ bath or test tube. Caution should be exercised in drawing conclusions about the effect of par-
5512s
May 29, 1991
The Amerlcan Journal of Medicine
tial p agonists on the regulation of p adrenoceptors. Another possible therapeutic approach is based on the use of agents, such as forskolin, that stimulate adenylate cyclase activity directly by bypassing the P-adrenoceptor and coupling between padrenoceptor and adenylate cyclase [18,20]. Cyclic AMP content can also be increased by phosphodiesterase inhibitors. Whether these agents present therapeutic approaches has yet to be established. There has been interest in the use of angiotensin converting enzyme (ACE) inhibitors to stimulate P-adrenoceptors. An increase in P-adrenoceptor density was found, together with an increase in the stimulatory G-protein, in lymphocytes [16]. Assuming that these lymphocytic changes sufficiently reflect the mode of activity in myocardial cells, there still could be an indirect effect of the ACE inhibitors arising from improvement of hemodynamics by a peripheral mechanism and a decrease in compensatory sympathetic hyperstimulation, resulting in lowering of down-regulation. Favorable results obtained with P-adrenoceptor blocking agents in patients with heart failure may be explained by the down-regulation that is observed in those patients. It is well known that administration of /?-blockers can selectively (pl versus &) up-regulate all P-adrenoceptors in the body [21], and there is good evidence that the downregulation in heart failure patients may be counteracted by administration of p-blockers [22]. Such an effect could be favorable, by restoring the responsiveness of the myocardium toward the noradrenergic stimulus. It should be mentioned that early studies with P-blocking agents in heart failure were carried out in the 1970s [23,24], before down-regulation of myocardial @-adrenoceptors was clearly understood. Beta-blocking agents were not used to restore responsiveness but to decrease the potential toxic effect of sympathetic hyperstimulation. The recognition, in the 1980s of /3-adrenoceptor down-regulation has strengthened enthusiasm initiated by the largely uncontrolled studies of the 1970s. A number of controlled studies have been performed by different groups and they suggest that long-term beneficial clinical and hemodynamic effects can be obtained in patients with dilated cardiomyopathy with the p,-selective blocker, metopro101 [25-271. There has been concern with regard to tolerance for this treatment in these patients, requiring a careful and gradual increase in dosage. The beneficial effects observed on down-regulation of the P-adrenoceptors by metoprolol treatment are not clear. Similarly, it is not known whether pblocker therapy in congestive heart failure influences survival [24].
Volume 90 (suppl 58)
SYMPOSIUM
CONCLUSION In patients with congestive heart failure, alterations in the /3-adrenoceptor density have been observed, but changes in other components of the padrenoceptor-adenylate cyclase complex are now being determined. These findings suggest novel therapeutic approaches, but well-controlled efficacy studies are needed to confirm whether these therapeutic approaches are indeed valid.
REFERENCES 1. Strasser RH, Krimmer J, Marquetant R: Regulation of p-adrenergic receptors: Impaired desensitization rn myocardial ischemia. J Cardlovasc Pharmacol 1988; 12 (suppl 1): s15-524. 2. Bristow MR, Minobe W, Rasmussen R, Hershberger RE, Hoffman BB: Alpha-l adrenergrc receptors in the nonfailing and failing human heart. J Pharm Exp Ther 1988; 247: 1039-45. 3. Forster C, Carter S, Armstrong P: Vascular smooth muscle responsiveness to noradrenaline and phenylephrine followrng experimental heart farlure in dogs. Cardrovasc Res 1989; 23: 489-97. 4. Brodde OE, Michel MC, Gordon EP, Sandoval A, Grlbert EM, Bnstow MR: Betaadrenoceptor regulation in the human heart Can it be monitored in circulating lymphocytes? Eur Heart J 1989; 10 (suppl 8): Z-10. 5. Cohn JN, Levine B, Olivarr MT, eta/: Plasma norepinephrrne as a guide to prognosis in patrents with chronic congestive heart farlure. N Engl J Med 1984; 311: 819-23. 6. Chidsey CA, Harrison DC, Braunwald E: Augmentation of the plasma norepinephrune response to exercise in patients wrth congestrve heart failure. N Engl J Med 1962; 267: 650-4. 7. Colucci WS, Alexander RW, Williams GH, et al: Decreased lymphocyte beta-adrenergrc-receptor density in patients with heart failure and tolerance to the beta-adrenergic agonist pirbuterol. N Engl J Med 1981; 305: 185-90. 8. Brrstow MR, Ginsburg R, Mrnobe W, et al: Decreased catecholamine sensrtrvity and P-adrenergic-receptor densrty in falling human hearts. N Engl J Med 1982; 307: 205-11. 9. O’Donnell SR, Wanstall JC: Functional evidence for drfferentral regulatron of padrenoceptor subtypes. Trends Pharmacol Sci 1987; 8: 265-8. 10. Bdhm M, Beuckelmann D, Brown L, et al: Reduction of beta-adrenoceptor density and evaluation of positive inotropic responses in isolated, drseased human myocardium. Eur Heart J 1988; 9: 844-52. 11. Limas CJ, Goldenberg IF, Limas C: Autoantibodies against P-adrenoceptors In
ON IBOPAMlNEi
BOGAERT and FRAEYMAN
human idiopathrc dilated cardiomyopathy. Circ Res 1989; 64: 97-103. 12. Limas CJ, Limas C, Goldenberg IF: Intracellular distribution of adrenoceptors rn the failing human myocardium. Am Heart J 1989; 117: 1310-6. 13. Murphee SS, Saffitz JE: Distribution of P-adrenergrc receptors in failing human myocardium. Circulation 1989; 79: 1214-25. 14. Brodde OE, Zerkowski HR, Borst HG, Maier W, Mrchel MC: Drug- and diseaseinduced changes of human cardiac pr- and /3*-adrenoceptors. Eur Heart J 1989; 10 (suppl B): 38-44. 15. Bristow MR, Port JD, Hershberger RE, Gilbert EM, Feldman AM: The padrenergic receptor-adenylate cyclase complex as a target for therapeutrc mterveniron in heart failure. Eur Heart J 1989; 10 (suppl B): 45-54. 16. Horn EM, Corwln SJ, Steinberg SF, et al. Reduced lymphocyte stimulatory guanone nucleotide regulatory protein and /3-adrenergic receptors in congestive heart failure and reversal with angiotensin converttng enzyme inhibitory therapy. Circulatron 1988; 78: 1373-9. 17. lnsel PA, Ransnas LA: G proteins and cardiovascular drsease. Crrculatlon 1988; 78: 1511-3. 18. Seamon KB, Daly JW: Forskolin, cyclic AMP and cellular physiology. Trends Pharmacol Sci 1988; 4: 120-3. 19. Brrstow MR, Hershberger RE, Port JD, Minobe W, Rasmussen R: PI- and pzadrenergic receptor-mediated adenylate cyclase strmulation in nonfarlrng and failing human ventricular myocardium. Mol Pharmacol 1989; 35: 295-303. 20. Erne P, Lipkin D, Maser1 A: Impaired beta-adrenergic receptor and normal postreceptor responsiveness in congestive heart failure. Am J Cardrol 1988; 61: 11324. 21. Michel MC, Prngsmann A, Beckeringh JJ, Zerkowskl HR, Doetsch N, Brodde OE: Seiectrve regulation of PI- and p,-adrenoceptors in the human heart by chronrc &adrenoceptor antagonist treatment. Br J Pharmacol 1988; 94: 685-92. 22. Waagstern F, Caidahl K, Wallentin I, Bergh CH, Hjalmarson A: Long-term pblockade in dilated cardromyopathy. Effects of short and long-term metoprolol treatment followed by withdrawal and readmrnrstratron of metoprolol. Circulation 1989; 80: 551-63. 23. Waagstern F, HJalmarson A, Varnauskas E, Wallentrn I: Effect of chronrc betaadrenergic receptor blockade In congestive cardiomyopathy. Br Heart J 1975; 37: 1022-36. 24. Swedberg K, Hjalmarson A, Waagstein F, Wallentrn I: Beneficial effects of longterm beta-blockade rn congestive cardiomyopathy. Br Heart J 1980; 44: 117-33. 25. Anderson JL, Lutz JR, Gilbert EM, et ai: A randomrzed trial of low-dose betablockade therapy for idropathic dilated cardiomyopathy. Am J Cardrol 1985; 55: 471-5. 26. Swedberg K, Hjalmarson A, Waagstein F, Wallentrn I: Prolongation of survwal rn congestive cardromyopathy by beta-receptor blockade. Lancet 1979; 1: 1374-6. 27. Engelmeier RS, O’Connell JB, Walsh R, Rad N, Scanlon PJ, Gunnar RM: Improvement in symptoms and exercise tolerance by metoprolol in patients wrth drlated cardiomyopathy: A double-blind, randomized, placebo-controlled trial. Crrculation 1985; 72: 536-46.
May 29, 1991
The Amerrcan Journal of Medrcine
Volume 90 (suppl 56)
5Eb13s
FRAEYMAN,
M.D.,
Gent, Be/g/urn
In patients with congestive heart failure, down-regulation of /3-adrenoceptors is present, probably as a result of sympathetic overstimulation. In end-stage dilated cardiomyopathy, /3,-adrenoceptor density is markedly reduced, while Pz-adrenoceptor density is normal. This latter finding does not necessarily imply normal sensitivity to &stimulation, due to possible alterations in the P-adrenoceptorladenylate cyclase complex beyond the receptor. In some disease states, such as ischemic cardiomyopathy and mitral valve disease, there seems to be a concomitant reduction of the pl- and & adrenoceptor density. The finding of fi-adrenoceptor down-regulation has stimulated the search for novel therapeutic approaches in heart failure patients. Beta-agonists could even further down-regulate p receptors, and this perhaps explains why they seem not to be useful in long-term use. Agents that directly stimulate adenylate cyclase activity, such as forskolin, or that increase cyclic adenosine monophosphate degradation, such as the phosphodiesterase inhibitors, are being tested. Beta-adrenoceptor blocking agents were used in treatment of heart failure before /I-adrenoceptor down-regulation was recognized in these patients. It is tempting to speculate that the beneficial clinical and hemodynamic effects seen in these patients treated with metoprolol is indeed due to an antagonism of the P-adrenoceptor down-regulation. Studies testing whether P-adrenoceptor blocking agents can improve survival in congestive heart failure patients are on-going.
ompensatory processes, such as activation of the renin-angiotensin-aldosterone system and increased activity of the sympathetic nervous system, occur in patients with congestive heart failure. These processes have been reported to be accompanied by changes-e.g., an increase (upregulation) or a decrease (down-regulation) in the number of P-adrenoceptors-in a number of studies [l]. In this article, recent findings on down-regulation of cardiac P-adrenoceptors in congestive heart failure and use of this knowledge to advance therapy in this disease state will be reviewed. Data on cardiac P-adrenoceptors in humans, on other adrenoceptor types [2], and on peripheral adrenoceptors [3] are still scarce. Data obtained on cardiac tissue and on lymphocytes, with their dominantly Pa-adrenoceptor type, do not reflect the situation in the myocardial tissue, with its pi- and P,-adrenoceptors [4]. Chronotropic and inotropic functions in human cardiac tissue have traditionally been ascribed to the pladrenoceptor, but it is now known that Pa-type adrenoceptors are also present and involved in chronotropic and inotropic stimulation of the heart.
C
SYMPATHETICNERVOUSSYSTEMACTIVATION It has been established that plasma norepinephrine levels are increased and have a prognostic value [5] in patients with heart failure [6]. The increased norepinephrine plasma concentrations activate the sympathetic nervous system. It was first suggested in 1981, based on data obtained with lymphocytes, that /3-adrenergic adrenoceptors in the failing human heart are down-regulated [7]. This was confirmed by Bristow et al. [81, who demonstrated decreased p-adrenergic adrenoceptor density in the failing human heart and concomitant decrease in sensitivity toward catecholamines.
THE BETA-ADRENOCEPTOR-ADENYLATE CYCLASECOMPLEX
From the Heymans Institute of Pharmacology, Gent, Belgium. Requests for reprints should be addressed to Marc George Bogaert, M.D., Heymans Institute of Pharmacology, University of Gent Medical School, De Pintelaan 185 B-9000 Gent, Belgium.
5510s
May 29, 1991
The American Journal of Medicine
The p-adrenoceptor-adenylate cyclase complex [9] has been presented (Figure 1). The padrenoceptor complex consists of three components: a) the p-adrenoceptor binding site; b) the guanine nucleotide protein (G-protein); and c) adenylate cyclase. This three-protein complex, or “/3adrenergic signal transduction system,” is situated in the plasma membrane of the cells, with the agonist binding site at the outer surface of the cell, and
Volume 90 (suppl 5B)
SYMPOSIUM
ON IBOPAMINE / BOGAERT and FRAEYMAN
Agonists WV +++ tt ttt t -
Nomdrenaline Adrenaline Isoprenaline Fenoterol Pracaterol
metobolites Figure 1. Representation of the steps between the activation of padrenoceptors and the functlonal response in tissues (G, is the stlmulatory guanine nucleotide regulatory protein; C is the catalytic unit of adenylate cyclase). Regulation of p-adrenoceptor-mediated functional responses could, in theory, occur as a result of changes in one or more of the following: (1) receptor numbers; (2) the affinity of the receptors for agonists; (3) the coupling of the receptors to adenylate cyclase; (4) the coupling of stimulus to response; (5) phosphodiesterase activity; (6) monoamine oxidase (MAO) and/or catechol-0methyl transferase (COMT) activity (although only when using agonists that are substrates for these enzymes). Mechanisms 1, 2, and 3 might be expected to result in a differential regulation of responses mediated by the P-adrenoceptor subtypes (PI and p2). There is no evidence at present to suggest that mechanisms 4, 5, or 6 might differentiate between subtype-mediated responses.
c AMP-dependent protein kinases
t ttt ++t ttt ttt
0
I
Functional
the adenylate cyclase enzyme active site at the cytoplasmic site. Binding of an agonist to the binding site leads to an increased adenylate cyclase activity, involving synthesis of cyclic adenosine monophosphate (CAMP). The coupling between padrenoceptors and adenylate cyclase is triggered by the stimulatory G-protein. The physiologic response, i.e., the chronotropic and inotropic effects in cardiac tissue, is stimulated by a cascade of intracellular enzymatic reactions, being initiated by the activation of a CAMP-dependent protein kinase. Regulation of the functional response to /?-adrenoceptor stimulation occurs at different levels of this complex.
BETA-ADRENOCEPTOR-ADENYLATE CYCLASE COMPLEXIN HEART FAILURE The first direct evidence of a change in this complex in heart failure patients was shown by Bristow et al. I$]. They noted that a reduction in the padrenoceptor density, in maximal isoproterenolmediated adenylate cyclase stimulation and in maximal isoproterenol-stimulated muscle contraction, occurred in the left ventricle of the failing heart. These changes were explained as down-regulation, due to exposure to increased levels of catecholamines. Other studies have confirmed the findings by Bristow’s group. In some studies a good correlation
Response
between the down-regulation of the cardiac /?adrenoceptor and the severity of the heart failure was found [lo]. Many more studies have expanded our knowledge of this phenomenon, especially concerning the mechanism [ll-131. The p-adrenoceptors in the myocardium are of the &- and pZsubtypes. It has been consistently shown that in patients with end-stage dilated cardiomyopathy, P1-adrenoceptor density is greatly reduced, while &-adrenoceptor density appears to be generally normal [14,15]. This selective down-regulation may be explained by the fact that, in contrast to the pZadrenoceptor, the myocardial P,-adrenoceptor is innervated, being associated with the noradrenergic nerve terminals and neuronally released epinephrine. In ischemic cardiomyopathy and in mitral valve disease, there is a concomitant reduction of pl- and &-adrenoceptors [14,15]. While more data on &adrenoceptor density are being obtained, there is increasing interest in the possibility that post-adrenoceptor changes of the P-adrenoceptor-adenylate cyclase complex could contribute to changes of adrenergic responsiveness [9]. Study of post-adrenoceptor events-for example, alterations in the G-proteins, in adenylate cyclase, and in protein kinase-requires elaborate and complicated techniques. Until now, most data on G-proteins have been obtained with lymphocytes and not with myocardial tissue. These lymphocyte
May 29, 1991
The Amencan Journal of Medicine
Volume 90 (suppl 58)
5511s
SYMPOSIUM
ON IBOPAMINE / BOGAERT and FRAEYMAN
data suggest important changes in the stimulatory G-protein levels in congestive heart failure [16,17]. Researchers [IS] have been attempting to determine the role of these alterations with agents, such as forskolin, that directly stimulate the adenylate cyclase and hence bypass some stages of the complex. Bristow et al. [19] have found in patients with congestive myopathy the expected reduction of pladrenoceptor density, with normal Pa-adrenoceptor number. Using highly selective antagonists, they showed subsensitivity to both p1 and pa stimulation. They have explained the p1 subsensitivity by selective P,-adrenoceptor down-regulation, and the p2 subsensitivity by partial uncoupling of pZadrenoceptors from the p,-adrenergic complex.
THERAPEUTICIMPLICATIONS The decrease of the adrenergic responsiveness of the heart in patients with heart failure is in itself unfavorable. The finding of adrenergic subsensitivity in heart failure patients has led to therapeutic hypotheses that are being currently tested. The incompleteness of our knowledge in this field, arising from difficulty in obtaining myocardial material, heterogeneity of patient population to be studied, difficulty of finding adequate control subjects, and analytic problems of approaching postadrenoceptor events, must be noted. There is a good possibility that other cardiac adrenoceptor systems may change and that adrenoceptor alterations in the periphery may play an important role. Drug treatment directly or indirectly affects adrenoceptor regulation. In patients with end-stage congestive cardiomyopathy, the myocardial P-adrenoceptor downregulation is p1 selective, and it was thought that use of pa agonists seemed a reasonable strategy for stimulating the heart. Clinical data obtained on the above are not convincing. Moreover, data suggest that there is a p2 hyporesponsiveness, due to the post-adrenoceptor phenomenon [19]. The significance of /3 agonists in the treatment of heart failure patients can only be learned from carefully controlled efficacy evaluations. Realizing the influence of /? agonists, as well as other agents, on the P-adrenoceptor-adenylate cyclase complex presents difficulty because of the indirect effects that these agents have on the system. A 0 agonist may initially improve the hemodynamic situation and lessen the compensatory sympathetic overstimulation. Nonetheless, the p agonist may eventually influence the complex and consequently not reflect the true effect of the agonist as would be found in the organ bath or test tube. Caution should be exercised in drawing conclusions about the effect of par-
5512s
May 29, 1991
The Amerlcan Journal of Medicine
tial p agonists on the regulation of p adrenoceptors. Another possible therapeutic approach is based on the use of agents, such as forskolin, that stimulate adenylate cyclase activity directly by bypassing the P-adrenoceptor and coupling between padrenoceptor and adenylate cyclase [18,20]. Cyclic AMP content can also be increased by phosphodiesterase inhibitors. Whether these agents present therapeutic approaches has yet to be established. There has been interest in the use of angiotensin converting enzyme (ACE) inhibitors to stimulate P-adrenoceptors. An increase in P-adrenoceptor density was found, together with an increase in the stimulatory G-protein, in lymphocytes [16]. Assuming that these lymphocytic changes sufficiently reflect the mode of activity in myocardial cells, there still could be an indirect effect of the ACE inhibitors arising from improvement of hemodynamics by a peripheral mechanism and a decrease in compensatory sympathetic hyperstimulation, resulting in lowering of down-regulation. Favorable results obtained with P-adrenoceptor blocking agents in patients with heart failure may be explained by the down-regulation that is observed in those patients. It is well known that administration of /?-blockers can selectively (pl versus &) up-regulate all P-adrenoceptors in the body [21], and there is good evidence that the downregulation in heart failure patients may be counteracted by administration of p-blockers [22]. Such an effect could be favorable, by restoring the responsiveness of the myocardium toward the noradrenergic stimulus. It should be mentioned that early studies with P-blocking agents in heart failure were carried out in the 1970s [23,24], before down-regulation of myocardial @-adrenoceptors was clearly understood. Beta-blocking agents were not used to restore responsiveness but to decrease the potential toxic effect of sympathetic hyperstimulation. The recognition, in the 1980s of /3-adrenoceptor down-regulation has strengthened enthusiasm initiated by the largely uncontrolled studies of the 1970s. A number of controlled studies have been performed by different groups and they suggest that long-term beneficial clinical and hemodynamic effects can be obtained in patients with dilated cardiomyopathy with the p,-selective blocker, metopro101 [25-271. There has been concern with regard to tolerance for this treatment in these patients, requiring a careful and gradual increase in dosage. The beneficial effects observed on down-regulation of the P-adrenoceptors by metoprolol treatment are not clear. Similarly, it is not known whether pblocker therapy in congestive heart failure influences survival [24].
Volume 90 (suppl 58)
SYMPOSIUM
CONCLUSION In patients with congestive heart failure, alterations in the /3-adrenoceptor density have been observed, but changes in other components of the padrenoceptor-adenylate cyclase complex are now being determined. These findings suggest novel therapeutic approaches, but well-controlled efficacy studies are needed to confirm whether these therapeutic approaches are indeed valid.
REFERENCES 1. Strasser RH, Krimmer J, Marquetant R: Regulation of p-adrenergic receptors: Impaired desensitization rn myocardial ischemia. J Cardlovasc Pharmacol 1988; 12 (suppl 1): s15-524. 2. Bristow MR, Minobe W, Rasmussen R, Hershberger RE, Hoffman BB: Alpha-l adrenergrc receptors in the nonfailing and failing human heart. J Pharm Exp Ther 1988; 247: 1039-45. 3. Forster C, Carter S, Armstrong P: Vascular smooth muscle responsiveness to noradrenaline and phenylephrine followrng experimental heart farlure in dogs. Cardrovasc Res 1989; 23: 489-97. 4. Brodde OE, Michel MC, Gordon EP, Sandoval A, Grlbert EM, Bnstow MR: Betaadrenoceptor regulation in the human heart Can it be monitored in circulating lymphocytes? Eur Heart J 1989; 10 (suppl 8): Z-10. 5. Cohn JN, Levine B, Olivarr MT, eta/: Plasma norepinephrrne as a guide to prognosis in patrents with chronic congestive heart farlure. N Engl J Med 1984; 311: 819-23. 6. Chidsey CA, Harrison DC, Braunwald E: Augmentation of the plasma norepinephrune response to exercise in patients wrth congestrve heart failure. N Engl J Med 1962; 267: 650-4. 7. Colucci WS, Alexander RW, Williams GH, et al: Decreased lymphocyte beta-adrenergrc-receptor density in patients with heart failure and tolerance to the beta-adrenergic agonist pirbuterol. N Engl J Med 1981; 305: 185-90. 8. Brrstow MR, Ginsburg R, Mrnobe W, et al: Decreased catecholamine sensrtrvity and P-adrenergic-receptor densrty in falling human hearts. N Engl J Med 1982; 307: 205-11. 9. O’Donnell SR, Wanstall JC: Functional evidence for drfferentral regulatron of padrenoceptor subtypes. Trends Pharmacol Sci 1987; 8: 265-8. 10. Bdhm M, Beuckelmann D, Brown L, et al: Reduction of beta-adrenoceptor density and evaluation of positive inotropic responses in isolated, drseased human myocardium. Eur Heart J 1988; 9: 844-52. 11. Limas CJ, Goldenberg IF, Limas C: Autoantibodies against P-adrenoceptors In
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May 29, 1991
The Amerrcan Journal of Medrcine
Volume 90 (suppl 56)
5Eb13s
