soluble guanylyl cyclase

Soluble Guanylyl Cyclase (sGC) in Mechanisms of Hypotensive and Antiaggregatory Effects Induced by Teraphtal (TP, sodium salt 4,5-cardoxyphtalocyanin-cobalt)

EXPERIMENTAL RESEARCH , , , , , ,

ТА Sidorova1, NV Pyatakova2, IS Severina2, ОL Kaliya3, GK Gerasimova1

1 N.N. Blokhin Russian Cancer Research Center, 24 Kashirskoye sh., Moscow, Russian Federation, 115478

2 V.N. Orekhovich Institute of Biomedical Chemistry, 10 bld. 8, Pogodinskaya str., Moscow, Russian Federation, 119121

3 State Scientific Center NIOPIC, 1 Bol’shaya Sadovaya str., Moscow, Russian Federation, 123995

For correspondence: Tat’yana Aleksandrovna Sidorova, PhD, 24 Kashirskoye sh., Moscow, Russian Federation, 115478; Tel.: +7(499)612-79-92; e-mail: tatsid@yahoo.com

For citation: Sidorova TA, Pyatakova NV, Severina IS, et al. Soluble Guanylyl Cyclase (sGC) in Mechanisms of Hypotensive and Antiaggregatory Effects Induced by Teraphtal (TP, sodium salt 4,5-cardoxyphtalocyanin-cobalt). Clinical oncohematology. 2016;9(2):138–47 (In Russ).

DOI: 10.21320/2500-2139-2016-9-2-138-147

ABSTRACT

Background & Aims. Many antitumor drugs produces not only the variety of therapeutic effects but also a broad spectrum of side effects, including acute hemodynamic dysfunctions (hypotension/hypertension, coagulation disorders). The aim of the paper is to investigate the role of soluble guanylyl cyclase (sGC) in mechanisms of hypotensive and antiaggregatory effects induced by teraphtal (TP) under experimental conditions in the clinic.

Methods. The effect of different products on the basal activity of sGC isolated from platelets of human peripheral blood was assessed by the immunoenzyme method based on production of cyclic guanosine monophosphate (cGMP). The effect of TP on ADP-induced human platelet aggregation was evaluated by the turbidimetric Born method using an aggregometer.

Results. In the presence of TP, the basal sGC activity increased by the average of 2.5-fold. The TF-induced dose-response curve of sGC activation displays a bell-shaped behavior with maximal stimulation effect achieved at a concentration of 1 mmol/L. TP does not affect the sGC activation induced by known sGC regulators, such as sodium nitroprusside (SNP) and YC-1. On the other hand, after preliminary incubation of sGC with TP, the ability of YC-1 to potentiate the enzyme stimulation induced by SNP decreased by about 33 %. In vitro tests demonstrated the ability of TP to inhibit the ADP-induced platelet aggregation and established the IC50 value for TP (15 mmol/L).

Conclusion. TF is a direct sGC activator and therefore is able to participate in regulation of the NO®sGC®cGMP signaling pathway that controls the basal vascular tone and aggregatory platelet properties. Taking into account the TP characteristics, the paper discusses the involvement of additional mechanisms in the development of hypotension and hemostatic disorders induced by the drug.

Keywords: human platelets, soluble guanylyl cyclase, teraphtal, sodium nitroprusside, YC-1, hypotension, ADP-induced platelet aggregation.

Received: April 24, 2015

Accepted: February 25, 2016

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