This Article Full Text Full Text (PDF) All Versions of this Article: 105/20/2429    most recent 01.CIR.0000016050.79810.18v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Andreka, P. Articles by Bishopric, N. H. Search for Related Content PubMed PubMed Citation Articles by Andreka, P. Articles by Bishopric, N. H. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Related Collections Biochemistry and metabolism Other heart failure Congestive Cardiovascular Pharmacology Receptor pharmacology

(Circulation. 2002;105:2429.)
© 2002 American Heart Association, Inc.

Basic Science Reports

Bucindolol Displays Intrinsic Sympathomimetic Activity in Human Myocardium

Peter Andreka, MD, PhD; Nambi Aiyar, PhD; Leslie C. Olson, BA; Jian Qin Wei, MD; Mark S. Turner, MD; Keith A. Webster, PhD; Eliot H. Ohlstein, PhD; Nanette H. Bishopric, MD

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

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

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]

				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]