Bucindolol displays intrinsic sympathomimetic activity in human myocardium

Peter Andreka, Nambi Aiyar, Leslie C. Olson, Jianqin Wei, Mark S. Turner, Keith A Webster, Eliot H. Ohlstein, Nanette Bishopric

Research output: Contribution to journalArticle

61 Citations (Scopus)

Abstract

Background - Most clinical studies have shown that β-adrenergic receptor antagonists improve long-term survival in heart failure patients. Bucindolol, a nonselective β-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 β-adrenergic antagonists and agonists and assayed for cAMP. In both rat and human strips, the full β-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 β-adrenergic agonist activity of xamoterol in normal human myocardial tissue.

Original languageEnglish
Pages (from-to)2429-2434
Number of pages6
JournalCirculation
Volume105
Issue number20
DOIs
StatePublished - May 21 2002

Fingerprint

Sympathomimetics
Human Activities
Myocardium
Adrenergic Agonists
Xamoterol
Adrenergic Antagonists
Heart Failure
Metoprolol
Isoproterenol
Propranolol
bucindolol
Histology
Clinical Trials
Survival
Mortality

Keywords

  • Bucindolol
  • Heart failure
  • Pharmacology
  • Receptors
  • Xamoterol

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Andreka, P., Aiyar, N., Olson, L. C., Wei, J., Turner, M. S., Webster, K. A., ... Bishopric, N. (2002). Bucindolol displays intrinsic sympathomimetic activity in human myocardium. Circulation, 105(20), 2429-2434. https://doi.org/10.1161/01.CIR.0000016050.79810.18

Bucindolol displays intrinsic sympathomimetic activity in human myocardium. / Andreka, Peter; Aiyar, Nambi; Olson, Leslie C.; Wei, Jianqin; Turner, Mark S.; Webster, Keith A; Ohlstein, Eliot H.; Bishopric, Nanette.

In: Circulation, Vol. 105, No. 20, 21.05.2002, p. 2429-2434.

Research output: Contribution to journalArticle

Andreka, P, Aiyar, N, Olson, LC, Wei, J, Turner, MS, Webster, KA, Ohlstein, EH & Bishopric, N 2002, 'Bucindolol displays intrinsic sympathomimetic activity in human myocardium', Circulation, vol. 105, no. 20, pp. 2429-2434. https://doi.org/10.1161/01.CIR.0000016050.79810.18
Andreka, Peter ; Aiyar, Nambi ; Olson, Leslie C. ; Wei, Jianqin ; Turner, Mark S. ; Webster, Keith A ; Ohlstein, Eliot H. ; Bishopric, Nanette. / Bucindolol displays intrinsic sympathomimetic activity in human myocardium. In: Circulation. 2002 ; Vol. 105, No. 20. pp. 2429-2434.
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AU - Ohlstein, Eliot H.

AU - Bishopric, Nanette

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N2 - Background - Most clinical studies have shown that β-adrenergic receptor antagonists improve long-term survival in heart failure patients. Bucindolol, a nonselective β-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 β-adrenergic antagonists and agonists and assayed for cAMP. In both rat and human strips, the full β-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 β-adrenergic agonist activity of xamoterol in normal human myocardial tissue.

AB - Background - Most clinical studies have shown that β-adrenergic receptor antagonists improve long-term survival in heart failure patients. Bucindolol, a nonselective β-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 β-adrenergic antagonists and agonists and assayed for cAMP. In both rat and human strips, the full β-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 β-adrenergic agonist activity of xamoterol in normal human myocardial tissue.

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