Abstract：
:Due to the limited results achieved in the clinical treatment of heart failure, a new inotropic strategy of myosin motor activation has been developed. The lead molecule of myosin activator agents is omecamtiv mecarbil, which binds directly to the heavy chain of the cardiac β-myosin and enhances cardiac contractility by lengthening the lifetime of the acto-myosin complex and increasing the number of the active force-generating cross-bridges. In the absence of relevant data, the effect of omecamtiv mecarbil on canine cardiac ryanodine receptors (RyR 2) has been investigated in the present study by measuring the electrical activity of single RyR 2 channels incorporated into planar lipid bilayer. When applying 100nM Ca2+ concentration on the cis side ([Ca2+]cis) omecamtiv mecarbil (1-10µM) significantly increased the open probability and opening frequency of RyR 2, while the mean closed time was reduced. Mean open time was increased moderately by 10µM omecamtiv mecarbil. When [Ca2+]cis was elevated to 322 and 735nM, the effect of omecamtiv mecarbil on open probability was evident only at higher (3-10µM) concentrations. All effects of omecamtiv mecarbil were fully reversible upon washout. Omecamtiv mecarbil (up to 10µM) had no effect on the open probability of RyR 1, isolated from either canine or rabbit skeletal muscles. It is concluded that the direct stimulatory action of omecamtiv mecarbil on RyR 2 has to be taken into account when discussing the mechanism of action or the potential side effects of the compound.
journal_name
Eur J Pharmacoljournal_title
European journal of pharmacologyauthors
Nánási P Jr,Gaburjakova M,Gaburjakova J,Almássy Jdoi
10.1016/j.ejphar.2017.05.027subject
Has Abstractpub_date
2017-08-15 00:00:00pages
73-79eissn
0014-2999issn
1879-0712pii
S0014-2999(17)30347-3journal_volume
809pub_type
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