Bucindolol displays intrinsic sympathomimetic activity in human myocardium.
BACKGROUND
Most clinical studies have shown that beta-adrenergic receptor antagonists improve long-term survival in heart failure patients. Bucindolol, a nonselective beta-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.


RESULTS
Myocardial strips ( approximately 1 mm(3)) obtained from rat and nonfailing human hearts were confirmed to be viable for > or = 48 hours in normoxic tissue culture by MTT assay and histology. Freshly isolated strips were exposed to beta-adrenergic antagonists and agonists and assayed for cAMP. In both rat and human strips, the full beta-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 approximately 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 approximately 60% of the beta-adrenergic agonist activity of xamoterol in normal human myocardial tissue.
Andreka
Peter
P
Department of Molecular and Cellular Pharmacology, University of Miami School of Medicine, Miami, FL 33101, USA.
Aiyar
Nambi
N
Olson
Leslie C
LC
Wei
Jian Qin
JQ
Turner
Mark S
MS
Webster
Keith A
KA
Ohlstein
Eliot H
EH
Bishopric
Nanette H
NH
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000328:Adult; D000368:Aged; D000818:Animals; D002470:Cell Survival; D005576:Colforsin / Q000494:pharmacology; D046508:Culture Techniques; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007424:Intracellular Fluid / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D011412:Propanolamines / Q000494:pharmacology*; D051381:Rats; D013566:Sympathomimetics / Q000494:pharmacology*; D017307:Xamoterol / Q000494:pharmacology
D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D011412:Propanolamines; D013566:Sympathomimetics; D005576:Colforsin; D017307:Xamoterol; D000242:Cyclic AMP; C024307:bucindolol