12+

PLEYOTROPIC ANTIAGGREGANT EFFECTS OF AN INNOVATIVE ANTIARRHYTHMIC OF CLASS III SS-68, AN INDOLE DERIVATIVE

Background: A new indole derivative with the lab code-number SS-68 demonstrates a significant antiarrhythmic (anti-fibrillation) activity associated with the predominant influence on potassium and calcium conductivity of cardiomyocytes plasmalemmas. The preliminary data give evidence of SS-68 possessing an antiaggregant activity. Methods: The influence of SS-68 on the platelet formation stage of hemostasis was determined by assessment of the anti-platelet effect (measuring platelet aggregation with Born/ O’Brien method), the dynamics of intracellular concentration of calcium ions in platelets was studied with FURA-2/АМ fluorescent probe. Results: Relative efficiency of the SS-68 indole derivative influence on platelet aggregation with the use of various inducers decreases in the following order: collagen > serotonin > ADP. The influence of SS-68 on platelet activity is characterized by pleiotropic effects: calcium-blocking effect, potentiation of cAMP-response, suppression of intracellular mechanisms of transmitting a stimulating signal, caused by the activation of collagen receptors. Conclusion: G-proteins are the most likely molecular targets of pleiotropic antiaggregant effect of SS-68. A more than threefold increase in the anti-platelet effect of SS-68 in vivo suggests the development of an active metabolite (metabolites).

Иллюстрации

Fig. 1. ADP-induced platelet aggregation.

Note. The ordinate shows the change transmission of light, rel. units.

Conditions: the concentration of platelets in the sample is 250-350´109 cells/ l; Mixing speed - 800 rpm; Temperature - 370С.

Table 1.  Antiaggregant activity of SS-68 on the model of ADP-induced platelet aggregation in vitro.

Note: 1 Acetylsalicylic acid; 

          * The figures are credible compared to control (Mann-Whitney test p < 0.005)

Table 2. Antiaggregant activity of SS-68 on the model of ADP-induced platelet aggregation in vivo.

Note: 1 Dose equimolar to the dose of acetylsalicylic acid;

          * The figures are credible compared to control (Mann-Whitney test p < 0.005)

Fig. 2. Collagen-induced change in light transmission of a platelet-rich plasma.

Note. Conditions: collagen - 5 mcg / ml; 250 - 350´109 cells/liter; Mixing speed - 800 rpm; Temperature - 370С.

Fig. 3. Dependence of the light transmission speed (A) and maximum amplitude of aggregation (V) on concentration of SS-68.

Fig. 4. Dependence of the platelet aggregation rate on the inductor concentration in the absence of (1) and in the presence of SS-68 (2-1 μM, 3-5 μM), represented in the coordinates of Linuiver-Burke.

Fig. 5. The reaction of platelet disaggregation induced by sodium nitroprusside in the absence of (1) and in the presence of SS-68 (2).

Note. The abscissa is the time, min; On the ordinate axis - change of light transmission, rel. units. Conditions: concentration of sodium nitroprusside - 0.1 μM; SS-68 - 10 μM; The number of platelets is 250-350´109 cells/l; Mixing speed - 800 rpm; Temperature - 370С.

Fig. 6. Effect of SS-68 on platelet-induced disaggregation induced by adenosine.

Note. The abscissa is the time, min. On the ordinate axis - change of light transmission, rel. units. Conditions: Adenosine concentration 2.5 μM; SS-68 - 10 μM; The number of platelets is 250-350´109 cells/l; Mixing speed - 800 rpm; Temperature - 370С.

Table 3.  The SS-68 influence on stimulated calcium level in platelets.

Symbols. DСа2+ – difference between random and collagen-stimulated levels of Са2+.

                * The figures are credible compared to control (Student t-test p < 0.005).

 

 

Table 4.  Changes in intracellular ion concentration of Са2+ induced in human blood platelets with collagen (5 mcg/ml) and SS-68 (1 mcM).

Symbols. DСа2+ – difference between random and collagen-stimulated levels of Са2+.

 

                     * p<0.05 compared to samples containing only collagen;

                     ** p<0.05 compared to samples containing only SS-68.

Fig. 7. Cascade mechanism of platelet activation and possible points of application of the action of compound SS-68 on collagen-induced platelet aggregation.

DOI: 10.18413/2313-8971-2017-3-2-3-13
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