Аннотация
BACKGROUND: In contrast to other beta-blockers, bucindolol has failed
to reduce mortality in patients with chronic heart failure. It is
currently debated whether this is due to partial agonist activity
of this agent. We investigated whether conflicting results previously
reported concerning the intrinsic activity of bucindolol can be explained
by species differences or by different activation states of beta-adrenergic
receptors (beta-ARs) in the respective tissues. METHODS AND RESULTS:
On isolated right atria from transgenic mice with cardiac overexpression
of human beta1-ARs, bucindolol led to a greater increase in beating
frequency (P<0.05) compared with wild-type mice. The increase amounted
to 47% of the effect of xamoterol and was blocked by propranolol.
On isolated, electrically stimulated, left ventricular muscle-strip
preparations from failing human myocardium, bucindolol did not change
the force of contraction under control conditions. In myocardial
preparations pretreated with metoprolol (30 micromol/L, 90 minutes,
subsequent washout), bucindolol significantly increased the force
of contraction (P<0.001 vs control). In nonfailing atrial myocardium,
isoproterenol pretreatment (1 micromol/L, 60 minutes) abolished the
positive inotropic effect of xamoterol that was present under control
conditions (P<0.05 vs control). The inotropic effects of bucindolol
or xamoterol were inversely correlated to the inotropic response
to forskolin in the respective specimens (r=-0.75 and -0.74, respectively;
P<0.005). CONCLUSIONS: We conclude that bucindolol is a partial agonist
at the human beta1-AR. In human failing myocardium, its partial agonist
activity is masked by increased activation states of beta-ARs and
is unmasked after in vitro pretreatment with metoprolol. Thus, the
partial agonist activity of bucindolol is dependent on the activation
state of the human beta1-AR.
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