The goal of the current work is to study the molecular mechanisms underlay the action of 5- amino-exo-3-azatricyclo[5.2.1.0(2,6)]decan-4-one (P-11) with combined antiarrhythmic,
nootropic, anti-inflammatory and anaesthetic activities. The
aconitine-induced experimental rat model of
cardiac arrhythmia has been used in our study.
Aconitine was administered once intravenously in a dose 50 microg/kg whereas experimental animal group received
P-11 in a dose 0.3 mg/kg (the compound was injected intravenously 2 min before acute
aconitine treatment). Expression macroarray (Atlas Rat
cDNA Expression Array, #7738-1; BD Biosciences) was used to identify the target genes for
P-11 compound. Comparative analysis of changes in the status of expression of genes in the heart of rats induced by
P-11 against the simulated in vivo
arrhythmia identified 16 genes that reproducibly alter the level of expression.These genes encode the
extracellular matrix proteins (
glypican 1, Gpc1;
tissue inhibitor of metalloproteinase 2, 3, Timp2, Timp 3); intracellular signaling molecules (
rho GTPase activating protein 7, Dlc1;
protein tyrosine phosphatase 4a1, Ptp4a1;
phosphodiesterase 4D, PDE4D;
PI3-kinase regulatory subunit alpha, PIK3R1;
guanine nucleotide binding protein alpha 12, Gna12) and
protein of intermediate junctions (
junction plakoglobin, Jup),
proteins involved in glycolysis (
phosphofructokinase I, Pfk1) and hemostasis (
tissue plasminogen activator, Plat), plasma membrane transporters (Solute carrier family 16, member 1, Slc16a1;
ATPase, Na+/K+ transporting, Atp1a), and ets. (c-fos protooncogene, c-fos;
telomerase protein component 1, tlp;
Annexin 1, anxa 1). Thus, the data about the selective effect of
P-11 on genes whose products are involved in the aritmogenesys mechanisms, allow us to consider this compound as a promising means of pathogenetically oriented
pharmacotherapy of
cardiac arrhythmias.