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

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 TP-induced dose-response curve of sGC activation displays a bell-shaped behavior with maximal stimulation effect achieved at a concentration of 1 μmol/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 μmol/L). Conclusion. TP 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.