Abstract
Background and Purpose: Although β1-blockers
impressively reduce mortality in chronic heart failure (CHF), there are
concerns about negative inotropic effects and worsening of hemodynamics
in acute decompensated heart failure. May receptor theory dispel these
concerns and confirm clinical practice to use
β1-blockers? Experimental Approach: In CHF,
concentrations of catecholamines at the β1-adrenoceptors
usually exceed their dissociation constants
(KDs). The homodimeric
β1-adrenoceptors have a receptor reserve and display
negative cooperativity. We considered the binomial distribution of
occupied receptor dimers with respect to the interaction of an exogenous
β1-blocker and elevated endogenous agonist
concentrations > [KDs],
corresponding to an elevated sympathetic tone. Key Results: Modeling
based on binomial distribution suggests that in the presence of a low
concentration of the antagonist, the activation of the dimer receptors
is higher than that in its absence. This leads to increased positive
inotropic effects of endogenous catecholamines due to a
β1-blocker. Conclusion and Implications: To understand
the positive inotropic sequels of β1-blockers in CHF is
clinically relevant. This article may help to eliminate the scepticism
of clinicians about the use of β1-blockers because of
their supposed negative inotropic effect, since on the contrary a
positive inotropic effect can be expected for receptor-theoretical
reasons.