Published online before print May 6, 2002, doi: 10.1161/01.CIR.0000016050.79810.18
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Circulation. 2002;105:2429.)
© 2002 American Heart Association, Inc.
Basic Science Reports |
Bucindolol Displays Intrinsic Sympathomimetic Activity in Human Myocardium
From the Departments of Molecular and Cellular Pharmacology and Medicine (P.A., J.Q.W., M.S.T., K.A.W., N.H.B.) and the Organ Procurement Organization, Department of Surgery (L.C.O.), University of Miami School of Medicine, Miami, Fla; Cardiovascular Pharmacology, Glaxo SmithKline Pharmaceuticals, King of Prussia, Pa (N.A., E.H.O.); and the Second Department of Medicine, Semmelweis University Faculty of Medicine, Budapest, Hungary (P.A.).
Correspondence to Nanette H. Bishopric, MD, Associate Professor of Pharmacology and Medicine, Department of Molecular and Cellular Pharmacology, University of Miami School of Medicine (R-189), PO Box 016189, Miami, FL 33101. E-mail n.bishopric{at}miami.edu
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Background— Most clinical studies have shown that ß-adrenergic receptor antagonists improve long-term survival in heart failure patients. Bucindolol, a nonselective ß-receptor blocker, however, failed to reduce heart failure mortality in a recent large clinical trial. The reasons for this failure are not known. Bucindolol has partial agonist properties in rat myocardium, but whether it has agonist activity in human heart is controversial. To address this, we measured the ability of bucindolol to increase cAMP accumulation in human myocardium.
Methods and Results— Myocardial strips (
1 mm3) obtained from rat and nonfailing human hearts were confirmed to be viable for 
48 hours in normoxic tissue culture by MTT assay and histology. Freshly isolated strips were exposed to ß-adrenergic antagonists and agonists and assayed for cAMP. In both rat and human strips, the full ß-adrenergic agonist isoproterenol raised cAMP levels by >2.5-fold at 15 minutes. Carvedilol and propranolol had no effect on basal cAMP levels, whereas metoprolol reduced basal cAMP by 25%. In contrast, bucindolol and xamoterol increased cAMP levels in a concentration-dependent manner in both rat and human myocardium (maximum 1.64±0.25-fold and 2.00±0.27-fold over control, respectively, P<0.01 for human tissue).
Conclusions— Bucindolol exhibits 60% of the ß-adrenergic agonist activity of xamoterol in normal human myocardial tissue.
Key Words: heart failure • pharmacology • receptors • bucindolol • xamoterol
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Neurohormonal activation is an early and harmful compensatory response to heart failure, marked by increased blood levels of norepinephrine, angiotensin II, vasopressin, endothelin-1, and other vasoconstrictor factors. As a consequence of chronic catecholamine excess, ß1-adrenoceptors are phosphorylated and downregulated, 1,2 both ß1- and ß2-adrenoceptors become uncoupled,1,2 inhibitory Gi proteins are upregulated,1,3 ß-adrenoceptor phosphorylation is increased, 2 and myocardial catecholamine uptake and release are altered. Although sympathetic activation maintains cardiac output in the short term, it is now recognized as a major factor in CHF progression and mortality.4 Blockade of sympathetic drive has thus become a major goal of current therapy.
The benefits of ß-adrenergic blockade in heart failure were first demonstrated in 19755 and have since been confirmed in several large randomized, double-blind, placebo-controlled trials. Both ß1-selective and nonselective ß-blockers, including metoprolol, bisoprolol, and carvedilol, have produced striking reductions in mortality, together with improvements in clinical status and hemodynamics.6–11
Despite the abundant evidence in favor of ß-blockers, their deployment remains incomplete. Negative inotropic therapy for heart failure is counterintuitive, and concerns persist about withdrawal of adrenergic support, especially in the sickest patients. Adding to these concerns, the nonselective ß1- and ß2-adrenoceptor antagonist bucindolol recently failed to decrease long-term mortality compared with placebo in a large multicenter trial, the Beta-Blocker Evaluation of Survival Trial (BEST).12 It is unclear whether the BEST trial failed because of population differences in the response to ß-blockers (eg, NYHA functional class III versus class IV heart failure, black versus nonblack) or whether bucindolol itself has unique properties that might make it less useful in this clinical setting.
Bucindolol is a nonselective ß-adrenergic antagonist with vasodilatory and sympatholytic properties.13–15 Studies in a variety of animal models have indicated that bucindolol, like xamoterol, can behave as a partial agonist at the ß-adrenergic receptor (ßAR) and therefore exhibits intrinsic sympathomimetic activity (ISA).13,16–18 To date, however, there has been scant and conflicting evidence that bucindolol has ISA in human myocardium.19–24 The question is significant, because partial agonist activity could have negated some of the potential benefits of bucindolol in the BEST study. Here, we describe a short-term tissue culture system in which the ISA of bucindolol and other adrenergic agents can be measured directly via accumulation of intracellular cAMP levels in myocardial tissue strips. Using this method, we find that bucindolol has significant concentration-dependent ISA in both rat and normal human myocardium.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Adult Rat and Human Myocardial Strip Culture
Adult rats (Simonson, Gilroy, Calif) were anesthetized with pentobarbital according to a protocol approved by the University of Miami Animal Care and Use Committee. The hearts were rapidly removed and placed into sterile, ice-cold, oxygenated, Ca2+-free Tyrode’s solution (mmol/L: 140 NaCl, 4 KCl, 0.5 MgCl2, 0.33 NaH2PO4, 5.5 glucose, 5.5 HEPES). Under a laminar flow hood, hearts were perfused with the same solution to remove blood from the chambers and coronary system.
Nonfailing human myocardium was obtained from donors whose hearts were not used for transplantation (Table 1). Written informed consent for organ donation for research purposes was obtained from the next of kin by one of us (L.O.). The tissue was used within 2 to 3 hours of cross-clamping of the aorta.
|
Freshly harvested myocardial tissue was carefully trimmed with fine scissors into very small (1- to 2-mm3) pieces in the above solution on ice. The strips were separated into 35-mm tissue culture dishes (100 strips per dish) and maintained in DMEM supplemented with 10% FCS, nonessential amino acids, insulin, penicillin, and streptomycin. Culture dishes were incubated in a humidified 37°C tissue culture incubator with 5% CO2 and ambient oxygen. The medium was changed every other day.
MTT Assay
MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) was added to myocardial tissue strips (0.28 µg/µL final concentration) and incubated in the tissue culture incubator for 2.5 hours. The strips were then washed with PBS, and 1 mL 100% DMSO was added for 50 minutes with vigorous shaking to dissolve the resulting formazan crystals.25 Color production was measured by spectrophotometry at 560 nm.
Histology
After the strips had been incubated with ß-blockers, the samples were fixed in paraformaldehyde and dehydrated by immersion in increasing concentrations of ethanol. Paraffin sections (6 µm) were stained with hematoxylin-eosin and analyzed by light microscopy.
cAMP Induction Assays
Samples of 200 mg tissue (100 strips) were allotted into microfuge tubes and stabilized in oxygenated, nominally Ca2+-free Tyrode’s solution in a 37°C shaking water bath for 10 minutes. IBMX (0.1 mmol/L) was then added to the buffer, and the strips were shaken at 37°C for 10 more minutes. Finally, xamoterol (0.5 to 5 µmol/L), bucindolol, forskolin, isoproterenol, carvedilol (each 0.01 to 10 µmol/L), propranolol (10 µmol/L), metoprolol (10 µmol/L), or vehicle was added, and incubation was continued at 37°C for a further 15 minutes. Reactions were stopped by addition of 300 µL of 10% ice-cold trichloroacetic acid. cAMP levels were determined by radioimmunoassay according to the manufacturer’s protocol (Perseptive Diagnostics).
Statistical Analysis
Results are expressed as mean±SEM. Differences between columns were evaluated by 2-tailed Mann-Whitney test. ANOVA was carried out with InStat 2.0 for Macintosh.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Myocardial Strip Viability
The MTT assay was used to characterize the viability of myocardial tissue cultures over a period of 0 to 8 days. In living cells, mitochondrial reductases convert the water-soluble, yellow tetrazolium salt (MTT) into a water-insoluble formazan precipitate.25 The production of formazan was linearly related to the amount of myocardial tissue in each assay (Figure 1A). As shown in Figure 1B, formazan production was stable over the first 24 hours and remained >90% of starting levels between days 0 and 3 of culture, indicating preserved metabolic activity and viability for
72 hours. Identical results were obtained with rat myocardial strips (not shown).
|
Histological analysis of human myocardial strips after short-term (6 hours) culture and exposure to adrenergic agents revealed normal myocardial morphology with occasional lipofuscin pigment, consistent with the age of the donors (Figure 1C).
On the basis of these observations, we concluded that myocardial strips in short-term culture would serve as a valid model system for testing myocardial cellular responses to exogenous agents. Subsequent assays were performed on the first day of tissue culture to maximize viability.
cAMP Stimulation in Adult Rat Myocardial Strips
In rat myocardium, both forskolin and isoproterenol increased myocardial cAMP levels by 2.6- and 2.2-fold, respectively, indicating intact receptor and postreceptor coupling to adenylate cyclase (Figure 2). Xamoterol, a ß-adrenergic antagonist with known partial agonist properties, also increased myocardial cAMP levels in a concentration-dependent manner, with maximum ISA at 5.0 µmol/L (1.92±0.27-fold over control, P<0.01). Bucindolol also produced a concentration-dependent increase in tissue cAMP, with a maximum effect at 10 µmol/L (2.46±0.42-fold over control, P<0.01), consistent with results in neonatal rat myocyte cultures.18 Three other ß-adrenergic antagonists, carvedilol, propranolol, and metoprolol, however, had no effect on cAMP levels (Figure 2).
|
cAMP Stimulation in Normal Human Myocardial Strips
We then studied cAMP accumulation in normal human myocardium in response to treatment with the above ß-adrenergic agonists and antagonists and with forskolin, which acts downstream of the receptor. Both isoproterenol and forskolin induced significant increases in myocardial cAMP (maximum 3.26- and 2.85-fold over control, respectively, P<0.01; see Table 2). In this system, 10 µmol/L forskolin was roughly equipotent to 4 µmol/L isoproterenol. There was a much wider range of responses to isoproterenol compared with forskolin, however, suggesting that states of receptor sensitization varied significantly among samples. These results confirm that the human myocardial tissue samples used in these assays have intact agonist-dependent ß-adrenoceptor coupling to cAMP generation.
|
A summary of the results is displayed in Figure 3. These results reflect values obtained in 6 donor hearts. Equal numbers of samples from left and right ventricles and interventricular septa were used in each condition. Both xamoterol and bucindolol displayed partial ß-adrenergic agonist activity, as reflected by significantly increased tissue cAMP levels. Consistent with earlier reports, the ISA of both xamoterol and bucindolol was most evident at lower concentrations.13 Xamoterol 0.5 µmol/L increased cAMP levels by 2.00±0.27-fold over control (P<0.01), whereas 5.0 µmol/L xamoterol had only a minimal effect (1.29±0.12-fold, P=NS) Similarly, the effects of bucindolol were less prominent at 10 µmol/L (1.48±0.13-fold over control, P<0.05) than at 0.1 or 1.0 µmol/L (1.64±0.26- and 1.52±0.16-fold, respectively, both P<0.01). A wide range of cAMP levels was obtained at each concentration of bucindolol, suggesting individual variations in susceptibility to this effect (Figure 3A). Furthermore, concentration dependence appeared to vary significantly from the left to the right ventricle (Figure 3,B–D). Bucindolol was observed to increase cAMP above control levels, however, at all concentrations >0.01 µmol/L and in samples from each of the 6 hearts examined (cAMPbucindolol > cAMPcontrol in 32 of 36 samples overall). In contrast, no ISA was observed at comparable concentrations of 3 other ß-adrenergic antagonists (Figure 3, A–D). Metoprolol appeared to reduce basal tissue levels of cAMP by 25%, consistent with its previously reported inverse agonist properties (0.75±0.06-fold, P<0.01).26 Carvedilol (0.01 to 10 µmol/L) had no effect on myocardial cAMP levels (Figure 3). Propranolol likewise had no significant ISA by this detection method (cAMP 1.14±0.11-fold of control, P=NS)
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The studies presented here show that both bucindolol and xamoterol have ISA in human myocardium. Both of these compounds increased myocardial levels of cAMP, a hallmark of ß-adrenergic agonist activity and a crucial effector of the potentially deleterious effects of ß-adrenergic stimulation. Three other ß-adrenergic antagonists did not show this activity. We also show that metoprolol significantly depresses basal myocardial cAMP levels in both human and rat heart, consistent with its previously reported inverse agonist properties.24,27 Inverse agonists exist for many classes of G protein-coupled receptors; these ligands appear to stabilize the inactive conformation of their receptors and thereby reduce basal, agonist-independent signaling.26,28 The clinical significance of this property of metoprolol is not clear, although inverse agonists have been shown to induce both homologous and heterologous receptor upregulation.28,29
There have been 2 exceptions to the general observation that ß-adrenergic antagonists are beneficial in heart failure. Xamoterol, an agent with partial agonist activity, improved clinical status, exercise capacity, and overall quality of life but significantly increased mortality in patients with congestive heart failure.30 Bucindolol also had significant beneficial effects on quality of life31–36 but failed to improve mortality in a long-term trial.12 The reasons for the failure of the BEST trial are not clear, but several explanations have been considered, including the possibility that ß-adrenergic blockade is not beneficial for all subsets of patients. It is at least theoretically possible that racial or genetic differences influence the response to heart failure therapy. In the BEST trial, mortality benefits were observed only in nonblack patients, and the study population had a lower percentage of nonblacks than in many previous studies of ß-blockers. A recent trial, however, identified no racial differences in the therapeutic benefits of carvedilol,8 suggesting that this observed differential effect of bucindolol may have occurred by chance or may be specific to bucindolol. Other possibilities include the marked central sympatholytic effects of bucindolol and a greater proportion of class IV patients vulnerable to the loss of sympathetic drive.12
Another possibility is suggested by our finding that bucindolol has clinically relevant sympathomimetic properties. Bucindolol previously has been proposed to act as a partial agonist in animal models; it exhibited ß-adrenergic agonist characteristics in anesthetized dogs and rats,13,16 increased heart rate in pithed rats,17 and increased cAMP levels in neonatal rat cardiomyocytes.18 Bucindolol also has agonist-like (guanine nucleotide-sensitive) receptor binding properties14 at the human ßAR.23 In 3 separate clinical studies of hypertensive males, bucindolol failed to decrease heart rate at rest or during exercise,19–21 suggestive of a partial agonist effect. Bucindolol also increased HDL cholesterol levels, a characteristic of ß-blockers with ISA.22 Direct evidence for bucindolol ISA in human myocardium, however, has been limited and inconclusive. Hershberger et al14 found that bucindolol did not increase myocardial membrane adenylate cyclase activity or increase the force of contraction in failing right ventricular papillary muscles. Conversely, bucindolol was reported to mediate a very small increased force of contraction in catecholamine-depleted human atrial trabecula37 and significantly increased contractile force in a subset of failing human left ventricular papillary muscle strips.23 Despite these conflicting findings, it is widely reported that bucindolol lacks clinically relevant ISA in human myocardium.12
Using cAMP accumulation as a sensitive end point, we show here that bucindolol has a significant amount of intrinsic agonist behavior in clinically normal human myocardium. The apparent conflict of our results with those of Hershberger et al14 may be due to differences in the integrity of the material used, the conditions of the assay, the activation state of the receptors in each case, or a combination of the 3. Also, the use of failing myocardium in earlier studies may have led to underestimation of ß-agonist activity, because more than half of the ß-adrenergic signaling capacity is lost from the failing heart through desensitization and uncoupling. Our use of nonfailing myocardium was designed to enhance the sensitivity of these assays for detection of ß-adrenergic agonist activity in candidate compounds.
Both qualitative and quantitative changes in ßAR subtypes occur during the course of heart failure. Bucindolol binds nonselectively to ß1 and ß2 subtypes, but it is possible that its agonist activity is mediated by only one of these, with the result that changing receptor subtype populations would affect the behavior of bucindolol. Despite this uncertainty, the combined observations from our studies and those of Maack et al23 in failing myocardium indicate that bucindolol is likely to have significant partial agonist activity in human myocardium across a wide spectrum of contractile function.
Clinical experience with ß-adrenergic agonists and partial agonists in chronic heart failure has been disappointing. These agents, like others acting downstream in the same pathway (eg, forskolin, phosphodiesterase III inhibitors), have short-term positive effects on hemodynamics and quality of life.30 None have reduced mortality, however, and most have worsened survival in heart failure.38 Stimulation of ßARs raises intracellular cAMP and predisposes the myocyte to calcium overloading by both cAMP-dependent and -independent means.39 Sustained ß-adrenergic stimulation and elevation of cAMP have been linked to cardiac myocyte apoptosis both in vitro and in vivo.40,41 The presence of partial agonist activity would thus be likely to reduce the beneficial effects of a ß-adrenergic antagonist in long-term use. The preponderance of the data now supports the "adrenergic hypothesis" that chronic heart failure is best treated by agents with the most comprehensive antiadrenergic properties.4 We would further propose that compounds with partial ß-adrenergic agonist properties are likely to be detrimental in mortality studies and that drugs should be specifically screened for this activity in human myocardium before their deployment in heart failure therapy.
|
Acknowledgments |
|---|
This work was supported by grants from the American Heart Association (Dr Bishopric) and the Miami Heart Research Institute (Dr Bishopric), and by additional funds from Glaxo SmithKline. Dr Andreka is supported by a postdoctoral fellowship from the American Heart Association. This work is dedicated to the memory of M.U., a friend and colleague, who gave his heart for science.
|
Footnotes |
|---|
Drs Ohlstein and Aiyar are employees of Glaxo SmithKline, King of Prussia, Pa. Dr Bishopric has been a consultant for Glaxo SmithKline.
Received January 10, 2002; revision received February 27, 2002; accepted February 28, 2002.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Bristow MR, Hershberger RE, Port JD, et al. ß-Adrenergic pathways in nonfailing and failing human ventricular myocardium. Circulation. 1990; 82: 82(suppl I): I-12–I-25.
2.
Ungerer M, Bohm M, Elce JS, et al. Altered expression of ß-adrenergic receptor kinase and ß1-adrenergic receptors in the failing human heart. Circulation. 1993; 87: 454–463.
3.
Bohm M, Gierschik P, Jakobs KH, et al. Increase of Gi
in human hearts with dilated but not ischemic cardiomyopathy. Circulation. 1990; 82: 82: 1249–1265.
4.
Bristow MR. ß-Adrenergic receptor blockade in chronic heart failure. Circulation. 2000; 101: 558–569.
5.
Waagstein F, Hjalmarson A, Varnauskas E, et al. Effect of chronic ß-adrenergic receptor blockade in congestive cardiomyopathy. Br Heart J. 1975; 37: 1022–1036.
6.
Packer M, Bristow MR, Cohn JN, et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group [see comments]. N Engl J Med. 1996; 334: 1349–1355.
7. Australia/New Zealand Heart Failure Research Collaborative Group. Randomised, placebo-controlled trial of carvedilol in patients with congestive heart failure due to ischaemic heart disease. Lancet. 1997; 349: 375–380.[CrossRef][Medline] [Order article via Infotrieve]
8.
Yancy CW, Fowler MB, Colucci WS, et al. Race and the response to adrenergic blockade with carvedilol in patients with chronic heart failure. N Engl J Med. 2001; 344: 1358–1365.
9.
Packer M, Coats AJS, Fowler MB, et al. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med. 2001; 344: 1651–1658.
10. MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet. 1999; 353: 2001–2007.[CrossRef][Medline] [Order article via Infotrieve]
11. CIBIS Investigators and Committees. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet. 1999; 353: 9–13.[CrossRef][Medline] [Order article via Infotrieve]
12.
The Beta-Blocker Evaluation of Survival Trial Investigators. A trial of the beta-blocker bucindolol in patients with advanced chronic heart failure. N Engl J Med. 2001; 344: 1659–1667.
13. Marwood JF, Stokes GS. Studies on the vasodilator actions of bucindolol in the rat. Clin Exp Pharmacol Physiol. 1986; 13: 59–68.[Medline] [Order article via Infotrieve]
14. Hershberger RE, Wynn JR, Sundberg L, et al. Mechanism of action of bucindolol in human ventricular myocardium. J Cardiovasc Pharmacol. 1990; 15: 959–967.[Medline] [Order article via Infotrieve]
15. Eichhorn EJ. Effects of bucindolol in heart failure. Am J Cardiol. 1993; 71: 65C–70C.[CrossRef][Medline] [Order article via Infotrieve]
16. Deitchman D, Perhach JL, Snyder RW. ß-Adrenoceptor and cardiovascular effects of MJ 13105 (bucindolol) in anesthetized dogs and rats. Eur J Pharmacol. 1980; 61: 263–277.[CrossRef][Medline] [Order article via Infotrieve]
17. Willette RN, Mitchell MP, Ohlstein EH, et al. Evaluation of intrinsic sympathomimetic activity of bucindolol and carvedilol in rat heart. Pharmacology. 1998; 56: 30–36.[CrossRef][Medline] [Order article via Infotrieve]
18.
Willette RN, Aiyar N, Yue TL, et al. In vitro and in vivo characterization of intrinsic sympathomimetic activity in normal and heart failure rats. J Pharmacol Exp Ther. 1999; 289: 48–53.
19. Rotmensch HH, Locci ML, Vlasses PH, et al. Bucindolol, a ß-adrenoceptor blocker with vasodilatory action: its effect in systemic hypertension. Am J Cardiol. 1984; 54: 353–356.[CrossRef][Medline] [Order article via Infotrieve]
20. Conner DP, Vlasses PH, Clementi RA, et al. Hemodynamic effects during rest and exercise of bucindolol in hypertensive men. J Clin Pharmacol. 1987; 27: 300–303.[Abstract]
21. Kimura S, DeQuattro V, Edmiston WA, et al. Efficacy of bucindolol in systemic hypertension. Am J Cardiol. 1987; 60: 1083–1086.[CrossRef][Medline] [Order article via Infotrieve]
22. Lehtonen A, Tanskanen A, Temmerman J. Effect of bucindolol on plasma HDL cholesterol subfractions and other plasma lipids in essential hypertensive patients. Int J Clin Pharmacol Ther Toxicol. 1987; 25: 448–451.[Medline] [Order article via Infotrieve]
23. Maack C, Cremens B, Flesch M, et al. Different intrinsic activities of bucindolol, carvedilol and metoprolol in human failing myocardium. Br J Pharmacol. 2000; 130: 1131–1139.[CrossRef][Medline] [Order article via Infotrieve]
24. Maack C, Tyroller S, Schnabel P, et al. Characterization of ß1-selectivity, adrenoceptor-Gs-protein interaction and inverse agonism of nebivolol in human myocardium. Br J Pharmacol. 2001; 132: 1817–1826.[CrossRef][Medline] [Order article via Infotrieve]
25. Ferrera R, Larese A, Berthod F, et al. Quantitative reduction of MTT by heart biopsies in vitro is an index of viability. J Mol Cell Cardiol. 1993; 25: 1090–1099.
26. Chidiac P, Hebert TE, Valiquette M, et al. Inverse agonist activity of ß-adrenergic antagonists. Mol Pharmacol. 1994; 45: 490–499.[Abstract]
27. Varma DR, Shen H, Deng XF, et al. Inverse agonist activities of ß-adrenoceptor antagonists in rat myocardium. Br J Pharmacol. 1999; 127: 895–902.[CrossRef][Medline] [Order article via Infotrieve]
28. Daeffler L, Landry Y. Inverse agonism at heptahelical receptors: concept, experimental approach and therapeutic potential. Fund Clin Pharmacol. 2000; 14: 73–87.[Medline] [Order article via Infotrieve]
29.
Zhang SJ, Cheng H, Zhou YY, et al. Inhibition of spontaneous ß-2-adrenergic activation rescues ß-1-adrenergic contractile response in cardiomyocytes overexpressing ß-2-adrenoceptor. J Biol Chem. 2000; 275: 21773–21779.
30. Cruickshank JM. The xamoterol experience in the treatment of heart failure. Am J Cardiol. 1993; 71: 61C–64C.[CrossRef][Medline] [Order article via Infotrieve]
31. Gilbert EM, Anderson JL, Deitchman D, et al. Long-term ß-blocker vasodilator therapy improves cardiac function in idiopathic dilated cardiomyopathy: a double-blind, randomized study of bucindolol versus placebo. Am J Med. 1990; 88: 223–229.[CrossRef][Medline] [Order article via Infotrieve]
32.
Eichhorn EJ, Bedotto JB, Malloy CR, et al. Effect of ß-adrenergic blockade on myocardial function and energetics in congestive heart failure. Circulation. 1990; 82: 473–483.
33.
Woodley SL, Gilbert EM, Anderson JL, et al. ß-Blockade with bucindolol in heart failure caused by ischemic versus idiopathic dilated cardiomyopathy. Circulation. 1991; 84: 2426–2441.
34. Anderson JL, Gibert EM, O’Connell JB, et al. Long-term (2 year) beneficial effects of ß-adrenergic blockade with bucindolol in patients with idiopathic dilated cardiomyopathy. J Am Coll Cardiol. 1991; 17: 1373–1381.[Abstract]
35.
Bristow MR, O’Connell JB, Gilbert EM, et al. Dose-response of chronic ß-blocker treatment in heart failure from either idiopathic dilated or ischemic cardiomyopathy. Bucindolol Investigators. Circulation. 1994; 89: 1632–1642.
36. Heesch CM, Marcoux M, Hatfield B, et al. Hemodynamic and energetic comparison of bucindolol and metoprolol for the treatment of congestive heart failure. Am J Cardiol. 1995; 75: 360–364.[CrossRef][Medline] [Order article via Infotrieve]
37. Trochu JN, Erfanian M, Khandoudi N, et al. Carvedilol produces contractile effects different from those of bucindolol in human atria. Circulation. 1999; 100 (suppl I): I-439.Abstract.
38. The Xamoterol in Severe Heart Failure Study Group. Xamoterol in severe heart failure. Lancet. 1990; 336: 1–6.[CrossRef][Medline] [Order article via Infotrieve]
39. Port DJ, Bristow MR. Altered ß-adrenergic receptor gene regulation and signaling in chronic heart failure. J Mol Cell Cardiol. 2001; 33: 887–905.[CrossRef][Medline] [Order article via Infotrieve]
40.
Communal C, Singh K, Sawyer DB, et al. Opposing effects of ß1- and ß2-adrenergic receptors on cardiac myocyte apoptosis: role of a pertussis toxin-sensitive G protein. Circulation. 1999; 100: 2210–2212.
41.
Vatner DE, Yang GP, Geng YJ, et al. Determinants of the cardiomyopathic phenotype in chimeric mice overexpressing cardiac Gs. Circ Res. 2000; 86: 86: 802–806.
This article has been cited by other articles:
 |
|
 |
|
  S. B. Liggett, J. Mialet-Perez, S. Thaneemit-Chen, S. A. Weber, S. M. Greene, D. Hodne, B. Nelson, J. Morrison, M. J. Domanski, L. E. Wagoner, et al. A polymorphism within a conserved beta1-adrenergic receptor motif alters cardiac function and beta-blocker response in human heart failure PNAS, July 25, 2006; 103(30): 11288 - 11293. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Lechat The evolution of heart failure management over recent decades: from CONSENSUS to CIBIS Eur. Heart J. Suppl., June 1, 2006; 8(suppl_C): C5 - C12. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Funck-Brentano Beta-blockade in CHF: from contraindication to indication Eur. Heart J. Suppl., June 1, 2006; 8(suppl_C): C19 - C27. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Maack, M. Bohm, L. Vlaskin, E. Dabew, K. Lorenz, H.-J. Schafers, M. J. Lohse, and S. Engelhardt Partial Agonist Activity of Bucindolol Is Dependent on the Activation State of the Human {beta}1-Adrenergic Receptor Circulation, July 22, 2003; 108(3): 348 - 353. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Bouzamondo, J.-S. Hulot, P. Sanchez, and P. Lechat Beta-blocker benefit according to severity of heart failure Eur J Heart Fail, June 1, 2003; 5(3): 281 - 289. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. G. Shekelle, M. W. Rich, S. C. Morton, Col. S. W. Atkinson, W. Tu, M. Maglione, S. Rhodes, M. Barrett, G. C. Fonarow, B. Greenberg, et al. Efficacy of angiotensin-converting enzyme inhibitors and beta-blockers in the management of left ventricular systolic dysfunction according to race, gender, and diabetic status: A meta-analysis of major clinical trials J. Am. Coll. Cardiol., May 7, 2003; 41(9): 1529 - 1538. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Bristow Antiadrenergic Therapy of Chronic Heart Failure: Surprises and New Opportunities Circulation, March 4, 2003; 107(8): 1100 - 1102. [Full Text] [PDF]
|
|
|
|
 |
|
 M. L. Kukin {beta}-Blockers in Chronic Heart Failure: Considerations for Selecting an Agent Mayo Clin. Proc., November 1, 2002; 77(11): 1199 - 1206. [Abstract] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||