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 language | English |
|---|---|
| Pages (from-to) | 2429-2434 |
| Number of pages | 6 |
| Journal | Circulation |
| Volume | 105 |
| Issue number | 20 |
| DOIs | |
| State | Published - May 21 2002 |
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Keywords
- Bucindolol
- Heart failure
- Pharmacology
- Receptors
- Xamoterol
ASJC Scopus subject areas
- Physiology
- Cardiology and Cardiovascular Medicine
Cite this
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 journal › Article
}
TY - JOUR
T1 - Bucindolol displays intrinsic sympathomimetic activity in human myocardium
AU - Andreka, Peter
AU - Aiyar, Nambi
AU - Olson, Leslie C.
AU - Wei, Jianqin
AU - Turner, Mark S.
AU - Webster, Keith A
AU - Ohlstein, Eliot H.
AU - Bishopric, Nanette
PY - 2002/5/21
Y1 - 2002/5/21
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.
KW - Bucindolol
KW - Heart failure
KW - Pharmacology
KW - Receptors
KW - Xamoterol
UR - http://www.scopus.com/inward/record.url?scp=0037150153&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0037150153&partnerID=8YFLogxK
U2 - 10.1161/01.CIR.0000016050.79810.18
DO - 10.1161/01.CIR.0000016050.79810.18
M3 - Article
C2 - 12021232
AN - SCOPUS:0037150153
VL - 105
SP - 2429
EP - 2434
JO - Circulation
JF - Circulation
SN - 0009-7322
IS - 20
ER -