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PHARMACOTHERAPEUTIC STRATEGIES FOR ENDOTHELIAL DYSFUNCTION CORRECTION WITH USE OF STATINES IN SYNDROME OF SYSTEMIC INFLAMMATORY RESPONSE

Objectives: The ways of pharmacological correction of cardiovascular complications in the syndrome of the systemic inflammatory response (SIRS) are not fully developed.

Goal: Determination of statins’ new pharmacological effects and its combination with endothelioprotectors in the SIRS correction.

Methods: In experiments on mice, rats and rabbits, the anti-inflammatory, cardioprotective and endothelioprotective effects of statins and endothelioprotectors were explored. The modeling of endotoxin-induced endothelial dysfunction (EIED) was created by infecting rats with Staphylococcus aureus (strain 13407), subcutaneously (60 billion microbial bodies). To determine the activity of the inflammatory process, the indices of the C-reactive protein used. The involvement of the cytokine link of inflammation was assessed according to the plasma levels of TNF-α and IL-6. Modeling of L-NAME-induced pathology and further evaluation of endothelial and endothelium-independent vascular reactions were carried through according to a standard protocol.

Results. Simvastatin (9, 19, 35 mg/kg), atorvastatin (5, 9, 19 mg/kg), rosuvastatin (9, 19, 35 mg/kg) and nanoparticulated rosuvastatin (3, 6.3 and 11.6 mg/kg) proved a dose-dependent antiexudative effect on the model of formalin paw edema in mice. Similarly, the anti-inflammatory effect is evident in the exudative model on rabbits. The greatest effectiveness was demonstrated by rosuvastatin and its nanoparticularized form. Simvastatin 8.5 mg/kg, atorvastatin 4.3 mg/kg, rosuvastatin 8.5 mg/kg, and nanoparticulated rosuvastatin 11.6 mg/kg demonstrate a cardioprotective effect in the coronary-occlusive modeling of infarction in rats. In the process of cardioprotective effects’ implementation the mechanisms of pharmacological preconditioning has significant importance. It was proved by the removal of effects with K + -ATP-as channels blockade with glibenclamide (5 mg/kg) and iNOS blockade with aminoguanidine (40 mg/kg).

The use of inhibitors HMG-CoA reductase of simvastatin (2.2, 4.3 and 8.5 mg/kg), atorvastatin (1.1, 2.2 and 4.3 mg/kg), rosuvastatin (2.2, 4 , 3 and 8.5 mg/kg) and nanoparticulated rosuvastatin (3, 6.3 and 11.6 mg/kg) on the background of endotoxin-induced pathology modeling leads to the development of a dose-dependent endothelioprotective effect, which is expressed in normalization of coefficient of endothelial dysfunction (CED), to prevention of adrenoreceptivity increase and to the exhaustion of the myocardial reserve, as well as to the normalization of biochemical markers of inflammation (C-reactive protein) and the level of pro-inflammatory  cytokines. At the same time, positive dynamics of the final products of NO and eNOS expression was defined.

Applying of monotherapy with donator NO L-arginine (70 and 200 mg/kg), a nonselective inhibitor of arginase BEC (5 and 10 mg/kg), a selective inhibitor of arginase-2 arginasine (1 and 3 mg/kg) and recombinant darbepoetin (50 and 500 μg/kg) in the modeling of endothelial dysfunction, has revealed their high activity, expressed in preventing the increase in CED, adrenoreactivity, preservation of the myocardial reserve and normalization of the values ​​of biochemical markers (Total NO, eNOS expression, C-reactive protein, IL-6, TNF). Herewith, the drugs had a dose-dependent effect and were approximately equally effective.

A vector analysis of the additive effects of the combined use of inhibitors of HMG-CoA reductase, simvastatin, atorvastatin, rosuvastatin and nanoparticulated rosuvastatin with L-arginine, inhibitors of arginase - BEC and arginasine, as well as darbepoetin demostrated that, with endotoxin-induced pathology, the highest probabilistic percentage of addiction was found in combination of rosuvastatin with arginasine (3 mg/kg) and darbepoetin (500 μg/kg), relatively, 31.9 ± 2.8 and 30.2 ± 2.9%.

Discussion: The inhibitors of HMG-CoA reductase have demonstrated cardioprotective (decrease of adrenoreactivity and depletion of myocardial reserve, normalization of blood pressure) and endothelioprotective (amplification of eNOS expression, increase of NO) the attributes, which manifested itself as well as in monotherapy and in combination with some endothelioprotectors (L-arginine, arginasine, BEС, darbepoetin) in varying degrees.

Иллюстрации

Fig. 1. Pathogenesis of vascular wall damage in SIRS.

Note: Pathogenesis of the formation of an inflammatory injury of the vascular wall with subsequent atherogenesis and thrombus formation. LPS binds to the Toll-receptors of the endothelial cell, enhancing the release of pro-inflammatory cytokines and the expression of adhesion receptors, to which leukocytes are attracted by β- integrins followed by iNOS activation and massive NO release, the latter forming the peroxynitrite (ONOO-) and nitrosyl chloride (NOOCl) radicals, damaging cellular structures and dissociating eNOS. As a result, intercellular contacts are destroying; oxidized by free radicals of LDL induce the cascade of reactions, leading to an even greater dissociation of eNOS. Disturbance of cells structures contributes to increased vascular permeability and migration of leukocytes, their absorption of oxidized LDL and formation of foamy cells – harbingers of atherosclerotic plaques. The destruction of the endothelium and exposure of the subendothelial layer creates conditions for the activation and aggregation of thrombocytes with thrombosis

where  Eing – the inhibitory effect,  Δ Me and Δ Mc – the average increase of the edematous foot mass in the control and experimental groups.

Table 1.  The correlation of doses of inhibitors of HMG-CoA reductase simvastatin, atorvastatin, rosuvastatin for humans and experimental animals (rabbits, rats and mice) [80].

Fig. 2. The anti-inflammatory effect of inhibitors of HMG-CoA-reductase of simvastatin, atorvastatin, rosuvastatin and nanoparticulated rosuvastatin on the model of formalin edema of the foot of mice

Fig. 3. Anti-inflammatory effect of inhibitors of HMG-CoA-reductase simvastatin, atorvastatin, rosuvastatin and nanoparticulated rosuvastatin on the model of anti-exudative action in rabbits.

Fig. 4. Cardioprotective effect of inhibitors of HMG-CoA reductase simvastatin, atorvastatin, rosuvastatin and nanoparticulated rosuvastatin on the model of coronary-occlusive infarction in rats

 

Table 2. Changes in hemodynamic parameters in animals with endotoxin-induced endothelial dysfunction (M ± m, n = 10)

Note:  SBP - systolic blood pressure (mmHg), DBP - diastolic arterial pressure (mmHg), CED - coefficient of endothelial dysfunction (unit units), * - significant difference with a group of intact animals (p <0.05).

Table 3. Changes in the values of biochemical markers (Total NO, Expression of eNOS, C-reactive protein, IL-6, TNF-α) in animals with endotoxin-induced endothelial dysfunction (EIED) (M ± m, n = 10)

Note:  NOx is the final metabolite of NO (μmol/L); eNOS expression (%); level of CRP-C-reactive protein (mg/l); IL-6 - interleukin 6 (pg/ml) TNF-α-tumor necrosis factor α (pg/ml), * - significant difference with a group of intact animals (p <0.05).

Fig.  5. Indices of endothelial dysfunction coefficient (CED) with the use of inhibitors of HMG-CoA reductase simvastatin, atorvastatin, rosuvastatin and nanoparticulated rosuvastatin on the background of endotoxin-induced endothelial dysfunction modeling 

Fig.  6. Adrenoreactivity indicators with the use of inhibitors of HMG-CoA reductase simvastatin, atorvastatin, rosuvastatin and nanoparticulated rosuvastatin on the background of modeling endotoxin-induced endothelial dysfunction 

Fig. 7. Concentration of nitrogen oxide metabolites (NOx) using the inhibitors of HMG-CoA reductase simvastatin, atorvastatin, rosuvastatin and nanoparticulated rosuvastatin on the background of endotoxin-induced endothelial dysfunction modeling

 

Fig.  8. Expression of NO-synthase (eNOS) using inhibitors of HMG-CoA reductase simvastatin, atorvastatin, rosuvastatin and nanoparticulated rosuvastatin against the background of endotoxin-induced endothelial dysfunction modeling

Fig.  9. C-reactive protein (CRP) indices with the use of inhibitors of HMG-CoA reductase simvastatin, atorvastatin, rosuvastatin and nanoparticulated rosuvastatin on the background of endotoxin-induced endothelial dysfunction modeling

Fig.  10. The concentration of proinflammatory cytokines IL-6 and TNF-α with the use of inhibitors of HMG-CoA reductase simvastatin, atorvastatin, rosuvastatin and nanoparticulated rosuvastatin on the background of endotoxin-induced endothelial dysfunction modeling

Fig. 11. Endothelioprotective effects of HMG-CoA reductase inhibitors simvastatin, atorvastatin, rosuvastatin and nanoparticulated rosuvastatin in L-NAME-induced endothelial dysfunction.

Note: BPSyst - systolic blood pressure; BPdiast - diastolic blood pressure; CED - coefficient of endothelial dysfunction; NOx is the concentration of the nitrite ion in the plasma; eNOS - expression of eNOS; AdR - adrenoreactivity; MR - myocardial reserve; MKD is the myocardiocytes diameter (% of the group of intact animals).

Table 4. Effect of monotherapy with L-arginine, BEC, arginasine and darbepoetin on the dynamics of hemodynamic parameters in animals with endotoxin-induced endothelial dysfunction (EIED) (M ± m, n = 10)

Note: SBP - systolic blood pressure (mmHg), DBP - diastolic arterial pressure (mmHg), CED - coefficient of endothelial dysfunction (unit units), * - significant difference with a group of intact animals (p <0.05); # - significant difference with the endotoxin-induced endothelial dysfunction (EIED) group (p <0.05).

 

Table 5. Effect of monotherapy with L-arginine, BEC, arginasine and darbepoetin on the dynamics of the values of biochemical markers (total NO, eNOS expression, C-reactive protein, IL-6, TNF-α) in animals with endotoxin-induced endothelial dysfunction (EIED) (M ± m, n = 10)

Note: NOx is the final metabolite of NO (μmol/L); eNOS expression (%); level of CRP-C-reactive protein (mg/l); IL-6 - interleukin 6 (pg/ml) TNF-α - tumor necrosis factor α (pg/ml), * - significant difference with a group of intact animals (p <0.05); # - significant difference with endotoxin-induced endothelial dysfunction (EIED) group (p <0.05).

Fig.  12. Endothelioprotective effects of combined use of L-arginine with inhibitors of HMG-CoA reductase simvastatin, atorvastatin, rosuvastatin and nanoparticulated rosuvastatin in L-NAME-induced endothelial dysfunction

Note: BPsyst - systolic blood pressure; BPdiast - diastolic blood pressure; CED - coefficient of endothelial dysfunction; NOx - concentration of nitrite ions in plasma; eNOS - expression of eNOS; ADR - adrenoreactivity; MR - myocardial reserve; DMK is the diameter of myocardiocytes (% of the group of intact animals).

Fig. 13. The indices of endothelial dysfunction coefficient (CED) and blood pressure (BP) when combined use of L-arginine and HMG-CoA reductase inhibitors simvastatin, atorvastatin, rosuvastatin and nanoparticulated rosuvastatin on the background of endotoxin-induced endothelial dysfunction (EIED) modeling

Fig.  14. Adrenoreactivity indicators for combined use of L-arginine and HMG-CoA reductase inhibitors simvastatin, atorvastatin, rosuvastatin and nanoparticulated rosuvastatin against the background of endotoxin-induced endothelial dysfunction modeling

Fig.  15. Nitric oxide concentration (NOx) and NO synthase expression (eNOS) in combined use of L-arginine and HMG-CoA reductase inhibitors simvastatin, atorvastatin, rosuvastatin and nanoparticulated rosuvastatin in the context of endotoxin-induced endothelial dysfunction modeling

Fig. 16. C-reactive protein (CRP) indices with combined use of L-arginine and HMG-CoA reductase inhibitors simvastatin, atorvastatin, rosuvastatin and nanoparticulated rosuvastatin in the context of endotoxin-induced endothelial dysfunction modeling.

Fig.  17. Concentration of proinflammatory cytokines IL-6 and TNF-α in combined use of L-arginine and HMG-CoA reductase inhibitors simvastatin, atorvastatin, rosuvastatin and nanoparticulated rosuvastatin on the background of modeling endotoxin-induced endothelial dysfunction (EIED)

Fig. 18. The indices of the endothelial dysfunction coefficient (CED) and arterial pressure (BP) when combined with the use of S- (2-boro-ethyl) -L-cysteine (BEC) and HMG-CoA reductase inhibitors simvastatin, atorvastatin, rosuvastatin and nanoparticulated rosuvastatin in endotoxin-induced endothelial dysfunction model 

Fig.  19. Adrenoreactivity in the combined use of S- (2-boro-ethyl) -L-cysteine (BEC) and HMG-CoA reductase inhibitors simvastatin, atorvastatin, rosuvastatin and nanoparticulated rosuvastatin against endotoxin-induced endothelial dysfunction modeling 

Fig. 20. Nitric oxide concentration (NOx) and NO synthase expression (eNOS) when combined with the use of S-(2-boro-ethyl)-L-cysteine (BEC) and HMG-CoA reductase inhibitors simvastatin, atorvastatin, rosuvastatin and nanoparticulated rosuvastatin on the background of modeling endotoxin-induced endothelial dysfunction

Fig. 21. C-reactive protein (CRP) indices in the combined use of S-(2-boro-ethyl)-L-cysteine (BEC) and HMG-CoA reductase inhibitors simvastatin, atorvastatin, rosuvastatin and nanoparticulated rosuvastatin against endotoxin- induced endothelial dysfunction

Fig.  22. Concentration of proinflammatory cytokines IL-6 and TNF-α when combined use of S- (2-boro-ethyl) -L-cysteine (BEC) and inhibitors of HMG-CoA reductase of simvastatin, atorvastatin, rosuvastatin and nanoparticulated rosuvastatin on the background of modeling endotoxin-induced endothelial dysfunction (EIED)

Fig. 23. Protective effect of the combined use of S- (2-boro-ethyl) -L-cysteine (BEC) with HMG-CoA reductase inhibitors on the model of L-NAME-induced endothelial dysfunction

Note: BPSyst - systolic blood pressure; BPdiast - diastolic blood pressure; CED - coefficient of endothelial dysfunction; NOx - concentration of nitrite ions in plasma; eNOS - expression of eNOS; ADR - adrenoreactivity; MR - myocardial reserve; DMK is the diameter of myocardiocytes (% of the group of intact animals).

Fig.  24. Indices of endothelial dysfunction coefficient (CED) and arterial pressure (BP) when combined use of arginasine and HMG-CoA reductase inhibitors simvastatin, atorvastatin, rosuvastatin and nanoparticulated rosuvastatin on the background of endotoxin-induced endothelial dysfunction (EIED) modeling 

Fig. 25. Adrenoreactivity in the combined use of arginasine and HMG-CoA reductase inhibitors simvastatin, atorvastatin, rosuvastatin and nanoparticulated rosuvastatin in the context of modeling endotoxin-induced endothelial dysfunction (EIED)

Fig. 26. Nitric oxide concentration (NOx) and NO synthase expression (eNOS) combined with the use of arginasine and HMG-CoA reductase inhibitors simvastatin, atorvastatin, rosuvastatin and nanoparticulated rosuvastatin on the background of modeling endotoxin-induced endothelial dysfunction (EIED)

Fig. 27. Concentration of C-reactive protein (CRP) with the combined use of arginasine and HMG-CoA reductase inhibitors simvastatin, atorvastatin, rosuvastatin and nanoparticulated rosuvastatin in the context of endotoxin-induced endothelial dysfunction (EIED) modeling

Fig.  28. Concentration of IL-6 TNF-α with the combined use of arginasine and HMG-CoA reductase inhibitors simvastatin, atorvastatin, rosuvastatin and nanoparticulated rosuvastatin in the context of modeling endotoxin-induced endothelial dysfunction (EIED)

Fig.  29. Protective action of combined arginine with HMG-CoA reductase inhibitors on the model of L-NAME-induced endothelial dysfunction

Note: BPsyst - systolic blood pressure; BPdiast - diastolic blood pressure; CED - coefficient of endothelial dysfunction; NOx - concentration of nitrite ions in plasma; eNOS - expression of eNOS; ADR - adrenoreactivity; MR - myocardial reserve; DMK is the diameter of myocardiocytes (% of the group of intact animals)

Fig.  30. The indices of endothelial dysfunction coefficient (CED) with the combined use of darbepoetin and HMG-CoA reductase inhibitors simvastatin, atorvastatin, rosuvastatin and nanoparticulated rosuvastatin in the context of modeling endotoxin-induced endothelial dysfunction (EIED)

Fig. 31. Nitric oxide (NOx) concentration and NO-synthase (eNOS) expression in combined use of darbepoetin and HMG-CoA reductase inhibitors simvastatin, atorvastatin, rosuvastatin and nanoparticulated rosuvastatin against endotoxin-induced endothelial dysfunction (EIED) modeling

Fig. 32. Concentration of C-reactive protein (CRP) in the combined use of darbepoetin and HMG-CoA reductase inhibitors simvastatin, atorvastatin, rosuvastatin and nanoparticulated rosuvastatin in the context of modeling endotoxin-induced endothelial dysfunction (EIED)

Fig. 33. Concentration of IL-6 and TNF-α with the combined use of darbepoetin and HMG-CoA reductase inhibitors simvastatin, atorvastatin, rosuvastatin and nanoparticulated rosuvastatin in the context of modeling endotoxin-induced endothelial dysfunction (EIED)

Fig. 34. Protective effect of the combined use of Darbepoetin with HMG-CoA reductase inhibitors on the model of L-NAME-induced endothelial dysfunction

Note: BPyst - systolic blood pressure; BPdiast - diastolic blood pressure; CED - coefficient of endothelial dysfunction; NOx - concentration of nitrite ions in plasma; eNOS - expression of eNOS; ADR - adrenoreactivity; MR - myocardial reserve; DMK is the diameter of myocardiocytes (% of the group of intact animals)

Table 6.  Probabilistic percent of additions (Padd) of the studied combinations in the modeling of ED

Note: ED - endothelial dysfunction; Padd - probability percentage of additions (%); * - p <0.005 in comparison with ED; # - p <0.005 compared with the endothelioprotective agent.

Fig. 35. Hypothetical ways of pharmacodynamic interaction of HMG-CoA reductase inhibitors, erythropoietin preparations and endothelioprotectors

DOI: 10.18413/2313-8971-2017-3-4-35-77
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