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We studied the radical-binding and antioxidant activities of the alkaloid tryptanthrin (TR) and its new synthetic derivative tryptanthrin oxime (TR-Ox), as well as the cytoprotective activity of TR-Ox under conditions of oxidative stress. The antiradical activity of TR-Ox was revealed in the test of binding with stable chromogen radical 2,2-diphenyl-1-picrylhydrazyl and in the superoxide radical generation test (riboflavin photoreduction reaction with detection by NBT reduction). TR-Ox was inferior to ionol and dihydroquercetin by the antiradical activity. In these tests, TR did not exhibit antiradical activity. TR-Ox did not show iron-chelating activity (in the test with the formation of the o-phenanthroline-Fe 2+ complex and its destruction in the presence of chelating agents). In brain homogenate, TR-Ox significantly reduced the increase in spontaneous chemiluminescence. Under conditions of oxidative stress induced by 15 mM H 2 O 2 in the SH-SY5Y neuroblastoma cell culture, TR-Ox exhibited cytoprotective activity and increased the number of viable cells., (© 2024. Springer Science+Business Media, LLC, part of Springer Nature.)

In experiments on Wistar rats, the effect of a new selective JNK inhibitor tryptanthrin oxime (TR-Ox) on parameters of systemic hemodynamics, cardiohemodynamics, and post-infarction fibrosis was studied 4 months after acute myocardial ischemia (1 h) followed by reperfusion. TR-Ox was administered intraperitoneally at a dose of 12 mg/kg 20 min before reperfusion, and then once a day for the next 4 days. Administration of TR-Ox to animals in the acute phase of myocardial infarction contributed to more complete preservation of myocardial viability in the delayed period: a relative increase of muscle elements proportion in the scar, a decrease in the formation of connective tissue areas with complete and >50% replacement of the myocardium, and deceleration of fibrotic scarring in myocardium areas distant from the focus of injury, resulting in improved systolic and diastolic myocardial function. Four months after myocardial infarction, significant improvement in systemic hemodynamics and cardiohemodynamics parameters was observed in the group treated with TR-Ox: stroke volume, cardiac output, left ventricular systolic pressure, maximum rates of left ventricle pressure rise and fall significantly increased and the left ventricle end-diastolic pressure decreased in comparison with the corresponding parameters in the control group., (© 2024. Springer Science+Business Media, LLC, part of Springer Nature.)

The effect of a new JNK inhibitor IQ-1 (11H-indeno[1,2-b]quinoxalin-11-one oxime) was studied in male Wistar rats in a model of acute myocardial ischemia/reperfusion. Area at risk and myocardial infarct zones were studied in two series of experiments: 16 h after a single dose of IQ-1 (25 mg/kg intraperitoneally during cardiac ischemia) and on day 5 after its course administration (25 mg/kg intraperitoneally during cardiac ischemia and daily over 4 days). On day 5 after ischemia/reperfusion, cardiodynamic indicators were also studied: systolic, end-diastolic, and minimum pressure in the left ventricle, stress-time index, as well as the maximum rates of pressure rise and fall in the left ventricle (+dP/dt max and -dP/dt max ). In 16 h after ischemia/reperfusion, the infarct area in the control was 24±2% of the total area of the sections, while after administration of IQ-1 this parameter was 14±1% (p<0.05). On day 5, the infarct area in the control group was 25±1% of the total area of myocardial sections. A course of IQ-1 administration led to a significant reduction in the infarct area to 10±2% of the total area of myocardial slices. Course administration of IQ-1 led to improvement in contractile function and weakening of the diastolic dysfunction of the left ventricle: systolic pressure in the left ventricle increased by 20%, +dP/dt max by 23%, voltage-time index by 12%, -dP/dt max by 43%, and the minimum pressure in the left ventricle decreased by 3.4 times., (© 2024. Springer Science+Business Media, LLC, part of Springer Nature.)

We investigated the effect of a decrease in blood viscosity on the mean BP during isovolumic hemodilution and vasodilating activity of the endothelium in normotensive Wistar rats and spontaneously hypertensive rats (SHR). Blood viscosity was reduced by isovolumic hemodilution (replacement of 10% of circulating blood with an equal volume of plasma). Hemodilution caused the same reduction in blood viscosity by 16% in both groups of rats. In Wistar rats, a decrease in blood viscosity did not significantly change in the mean BP; no significant correlations between blood viscosity and mean BP were observed before and after hemodilution. In SHR, a decrease in blood viscosity led to a significant decrease in the mean BP by 18%. Correlations were found between the mean BP and blood viscosity in SHR before (r=0.63; p=0.028) and after (r=0.71; p=0.009) isovolumic hemodilution. In SHR, a decrease in the index of vasodilating activity of the endothelium due to a decrease in the vasodilatory response to intravenous administration of the endothelium-dependent vasodilator acetylcholine was revealed. In SHR, BP passively follows the change, in this case, the decrease in blood viscosity, which attests to impaired BP regulation in response to changes in shear stress on the vascular endothelium caused by the development of endothelial dysfunction in hypertensive animals., (© 2024. Springer Science+Business Media, LLC, part of Springer Nature.)

We studied the action of a new indolinone derivative GRS, acetylsalicylic acid (ASA), and their combination on platelet aggregation, vasodilatory endothelial function, neurological status, and cerebral infarction area in experimental focal cerebral ischemia/reperfusion in rats. GRS compound (10 mg/kg), ASA (10 mg/kg), and their combination in the same doses were administered orally once a day as a suspension in 1% starch solution over 5 days after pathology modeling. Sham-operated and control animals were administered 1% starch solution. On day 5 after pathology modeling, platelet aggregation and brain damage area were studied in a half of rats in each group, and the vasodilatory function of the endothelium was studied in the other half. Neurological deficit was assessed 4 h and 1, 3, and 5 days after pathology modeling. GRS compound and ASA equally effectively prevent platelet aggregation and the development of neurological deficit in rats. GRS compound restores the vasodilatory effects of the endothelium, but only ASA contributes to reduction of the cerebral infarction area. In case of combined administration, GRS and ASA do not exhibit synergy in their antiaggregant effect., (© 2023. Springer Science+Business Media, LLC, part of Springer Nature.)

The activation of c -Jun N-terminal kinase (JNK) plays an important role in stroke outcomes. Tryptanthrin-6-oxime (TRYP-Ox) is reported to have high affinity for JNK and anti-inflammatory activity and may be of interest as a promising neuroprotective agent. The aim of this study was to investigate the neuroprotective effects of TRYP-Ox in a rat model of transient focal cerebral ischemia (FCI), which involved intraluminal occlusion of the left middle cerebral artery (MCA) for 1 h. Animals in the experimental group were administered intraperitoneal injections of TRYP-Ox 30 min before reperfusion and 23 and 47 h after FCI. Neurological status was assessed 4, 24, and 48 h following FCI onset. Treatment with 5 and 10 mg/kg of TRYP-Ox decreased mean scores of neurological deficits by 35-49 and 46-67% at 24 and 48 h, respectively. At these doses, TRYP-Ox decreased the infarction size by 28-31% at 48 h after FCI. TRYP-Ox (10 mg/kg) reduced the content of interleukin (IL) 1β and tumor necrosis factor (TNF) in the ischemic core area of the MCA region by 33% and 38%, respectively, and attenuated cerebral edema by 11% in the left hemisphere, which was affected by infarction, and by 6% in the right, contralateral hemisphere 24 h after FCI. TRYP-Ox reduced c -Jun phosphorylation in the MCA pool at 1 h after reperfusion. TRYP-Ox was predicted to have high blood-brain barrier permeability using various calculated descriptors and binary classification trees. Indeed, reactive oxidant production was significantly lower in the brain homogenates from rats treated with TRYP-Ox versus that in control animals. Our data suggest that the neuroprotective activity of TRYP-Ox may be due to the ability of this compound to inhibit JNK and exhibit anti-inflammatory and antioxidant activity. Thus, TRYP-Ox may be considered a promising neuroprotective agent that potentially could be used for the development of new treatment strategies in cerebral ischemia.

Activation of c-Jun N-terminal kinases (JNKs) is involved in myocardial injury, left ventricular remodeling (LV), and heart failure (HF) after myocardial infarction (MI). The aim of this research was to evaluate the effects of a selective JNK inhibitor, 11 H -indeno [1,2- b ]quinoxalin-11-one oxime (IQ-1), on myocardial injury and acute myocardial ischemia/reperfusion (I/R) in adult male Wistar rats. Intraperitoneal administration of IQ-1 (25 mg/kg daily for 5 days) resulted in a significant decrease in myocardial infarct size on day 5 after MI. On day 60 after MI, a significant (2.6-fold) decrease in LV scar size, a 2.2-fold decrease in the size of the LV cavity, a 2.9-fold decrease in the area of mature connective tissue, and a 1.7-fold decrease in connective tissue in the interventricular septum were observed compared with the control group. The improved contractile function of the heart resulted in a significant (33%) increase in stroke size, a 40% increase in cardiac output, a 12% increase in LV systolic pressure, a 28% increase in the LV maximum rate of pressure rise, a 45% increase in the LV maximum rate of pressure drop, a 29% increase in the contractility index, a 14% increase in aortic pressure, a 2.7-fold decrease in LV end-diastolic pressure, and a 4.2-fold decrease in LV minimum pressure. We conclude that IQ-1 has cardioprotective activity and reduces the severity of HF after MI.

The c-Jun N -terminal kinases (JNKs) regulate many physiological processes, including inflammatory responses, morphogenesis, cell proliferation, differentiation, survival, and cell death. Therefore, JNKs represent attractive targets for therapeutic intervention. In an effort to develop improved JNK inhibitors, we synthesized the lithium salt of 11 H -indeno[1,2- b ]quinoxaline-11-one oxime ( IQ-1L ) and evaluated its affinity for JNK and biological activity in vitro and in vivo. According to density functional theory (DFT) modeling, the Li + ion stabilizes the six-membered ring with the 11 H -indeno[1,2- b ]quinoxaline-11-one ( IQ-1 ) oximate better than Na + . Molecular docking showed that the Z isomer of the IQ-1 oximate should bind JNK1 and JNK3 better than ( E )- IQ-1 . Indeed, experimental analysis showed that IQ-1L exhibited higher JNK1-3 binding affinity in comparison with IQ-1S . IQ-1L also was a more effective inhibitor of lipopolysaccharide (LPS)-induced nuclear factor-κB/activating protein 1 (NF-κB/AP-1) transcriptional activity in THP-1Blue monocytes and was a potent inhibitor of proinflammatory cytokine production by MonoMac-6 monocytic cells. In addition, IQ-1L inhibited LPS-induced c-Jun phosphorylation in MonoMac-6 cells, directly confirming JNK inhibition. In a rat model of focal cerebral ischemia (FCI), intraperitoneal injections of 12 mg/kg IQ-1L led to significant neuroprotective effects, decreasing total neurological deficit scores by 28, 29, and 32% at 4, 24, and 48 h after FCI, respectively, and reducing infarct size by 52% at 48 h after FCI. The therapeutic efficacy of 12 mg/kg IQ-1L was comparable to that observed with 25 mg/kg of IQ-1S, indicating that complexation with Li + improved efficacy of this compound. We conclude that IQ-1L is more effective than IQ-1S in treating cerebral ischemia injury and thus represents a promising anti-inflammatory compound.

New antithrombotic drug GRS, a soluble guanylate cyclase stimulator, after repeated administration in a dose of 10 mg/kg alleviates the symptoms of endothelial dysfunction in rats with myocardial infarction; it restores antiplatelet activity of the blood vessel wall and vasodilatory function of the endothelium without producing significant effect on endothelium-independent vasodilation. GRS also has direct antiaggregant and antihypertensive effects in therapeutic doses. The obtained data suggest that GRS can be therapeutically useful in patients with cardiovascular diseases accompanied by endothelial dysfunction., (© 2022. Springer Science+Business Media, LLC, part of Springer Nature.)

We developed a model of blood hyperviscosity avoiding extreme impact on the blood. The model shows reproducibility in rat blood under common storage conditions (4±1°C; stabilization with citrate-phosphate-glucose additive solution). Storage of rat blood under these condition leads to impairment of its rheological properties, which manifested in an increase in blood viscosity in a wide range of shear rates (3-300 sec -1 ). An increase in blood viscosity appeared the first day of storage and reached a maximum on the third day. During further 11-day storage, the blood viscosity did not change significantly. A hybrid macromolecular compound O-(3-(3,5-di-tert-butyl-4-hydroxyphenyl)propanoyl)-(1→6)-α-D-glucan improved the hemorheological properties during storage. The most pronounced effect was observed on the third day of storage and manifested in a decrease in blood viscosity in the range of shear rates of 50-300 sec -1 . Thus, storage of rat blood with citrate-phosphate-glucose additive solution for 3 days at 4±1°C reproduces the phenomenon of blood hyperviscosity; this model can be used to screen agents with hemorheological activity., (© 2022. Springer Science+Business Media, LLC, part of Springer Nature.)

c-Jun N-terminal kinases (JNKs) are involved in the myocardial and aortic remodeling, increased arterial tone, and arterial blood pressure elevation associated with hypertension. The aim of the present study was to investigate the antihypertensive effect of a new JNK inhibitor, 1H-indeno[1,2-b]quinoxalin-11-one oxime sodium salt (IQ-1S), on spontaneously hypertensive rats (SHRs). Experiments were performed using normotensive Wistar-Kyoto (WKY) rats and SHRs. Experimental groups of SHRs received IQ-1S intragastrically for 6 weeks in daily doses of 5 and 50 mg/kg; experimental groups of WKY rats received 50 mg/kg IQ-1S according to the same regimen. The IQ-1S administration regimen induced decreases in systolic blood pressure, mean arterial blood pressure, total peripheral resistance, blood viscosity, hematocrit, myocardial cell cross-sectional area, and aortic wall thickness in SHRs vs untreated SHRs. There were no significant differences in systolic blood pressure values between the control and experimental groups of WKY rats during the treatment period. A concentration-dependent decrease in the tone of carotid arterial rings isolated from SHRs was observed after JNK inhibitor application in vitro. Application of the JNK inhibitor diminished endothelin-1 secretion by human umbilical vein endothelial cells in vitro. The main mechanisms of the antihypertensive effect of IQ-1S included the attenuation of blood viscosity due to decreased hematocrit, a vasodilatory effect on arterial smooth muscle cells, and a decrease in endothelin-1 production by endothelial cells.

A novel specific inhibitor of c-Jun N-terminal kinase, 11 H -indeno[1,2- b ]quinoxalin-11-one oxime sodium salt (IQ-1S), has a high affinity to JNK3 compared to JNK1/JNK2. The aim of this work was to study the mechanisms of neuroprotective activity of IQ-1S in the models of reversible focal cerebral ischemia (FCI) in Wistar rats. The animals were administered with an intraperitoneal injection of IQ-1S (5 and 25 mg/kg) or citicoline (500 mg/kg). Administration of IQ-1S exerted a pronounced dose-dependent neuroprotective effect, not inferior to the effects of citicoline. Administration of IQ-1S at doses of 5 and 25 mg/kg reduced the infarct size by 20% and 50%, respectively, 48 h after FCI, whereas administration of citicoline reduced the infarct size by 34%. The administration of IQ-1S was associated with a faster amelioration of neurological status. Control rats showed a 2.0-fold increase in phospho-c-Jun levels in the hippocampus compared to the corresponding values in sham-operated rats 4 h after FCI. Administration of IQ-1S at a dose of 25 mg/kg reduced JNK-dependent phosphorylation of c-Jun by 20%. Our findings suggest that IQ-1S inhibits JNK enzymatic activity in the hippocampus and protects against stroke injury when administered in the therapeutic and prophylactic regimen in the rat model of FCI.

Background New therapeutic strategies, such as the use of agents to correct rheological disorders, are needed for the prevention and treatment of angiopathy in diabetic patients. The aim of this work was to study the antihyperglycaemic, haemorheologic and antioxidant activities of an extract from the flowering plant Lychnis chalcedonica L. (ELC) and 20-hydroxyecdysone using the streptozotocin-induced model of diabetic rats. Methods The streptozotocin-induced model of diabetes was produced using streptozotocin at a dose of 50 mg/kg (ip). Animals from the experimental groups were treated with ELC (150 mg/kg) or 20-hydroxyecdysone (1.1 mg/kg) intragastrically in 1% aqueous starch mucilage daily, for 14 days; rats of control groups received an equal volume of starch mucilage. The following parameters were measured: glucose concentration (GC) in blood, whole blood viscosity (WBV), conjugated dienes in RBC membranes. Macro- and microrheological indicators (viz. plasma viscosity, haematocrit, RBC aggregation (T1/2) and the RBC elongation index (EI)) were additionally measured in rats that received ELC, and in the control group. Results After treatment with ELC, the GC in rats was 19% lower than that in the control group (14.7 ± 0.9 mM compared to 18.2 ± 1.1 mM). Rats with streptozotocin-induced diabetes have hyperviscosity syndrome, which is characterized by increased WBV, increased RBC aggregation and decreased deformability. ELC treatment reduced WBV at shear rates of 10-90 s-1 by 5-8%, and T1/2 and EI in the experimental group were 31% and 5-10% higher compared to the control group. 20-Hydroxyecdysone decreased WBV at shear rates of 10-90 s-1 by 3-11%. Finally, ELC and 20-hydroxyecdysone lowered the content of conjugated dienes by 27% and by 26% compared to the control groups. Conclusion In the streptozotocin-induced diabetic rat model, ELC showed measurable antihyperglycaemic activity; ELC and 20-hydroxyecdysone demonstrated similar haemorheological, and antioxidant activities.

c-Jun N-terminal kinase (JNK) is activated by various brain insults and is implicated in neuronal injury triggered by reperfusion-induced oxidative stress. Some JNK inhibitors demonstrated neuroprotective potential in various models, including cerebral ischemia/reperfusion injury. The objective of the present work was to study the neuroprotective activity of a new specific JNK inhibitor, IQ-1S (11 H -indeno[1,2- b ]quinoxalin-11-one oxime sodium salt), in the model of global cerebral ischemia (GCI) in rats compared with citicoline (cytidine-5'-diphosphocholine), a drug approved for the treatment of acute ischemic stroke and to search for pleiotropic mechanisms of neuroprotective effects of IQ-1S. The experiments were performed in a rat model of ischemic stroke with three-vessel occlusion (model of 3VO) affecting the brachiocephalic artery, the left subclavian artery, and the left common carotid artery. After 7-min episode of GCI in rats, 25% of animals died, whereas survived animals had severe neurological deficit at days 1, 3, and 5 after GCI. At day 5 after GCI, we observing massive loss of pyramidal neurons in the hippocampal CA1 area, increase in lipid peroxidation products in the brain tissue, and decrease in local cerebral blood flow (LCBF) in the parietal cortex. Moreover, blood hyperviscosity syndrome and endothelial dysfunction were found after GCI. Administration of IQ-1S (intragastrically at a dose 50 mg/kg daily for 5 days) was associated with neuroprotective effect comparable with the effect of citicoline (intraperitoneal at a dose of 500 mg/kg, daily for 5 days).The neuroprotective effect was accompanied by a decrease in the number of animals with severe neurological deficit, an increase in the number of animals with moderate degree of neurological deficit compared with control GCI group, and an increase in the number of unaltered neurons in the hippocampal CA1 area along with a significant decrease in the number of neurons with irreversible morphological damage. In rats with IQ-1S administration, the LCBF was significantly higher (by 60%) compared with that in the GCI control. Treatment with IQ-1S also decreases blood viscosity and endothelial dysfunction. A concentration-dependent decrease (IC 50 = 0.8 ± 0.3 μM) of tone in isolated carotid arterial rings constricted with phenylephrine was observed after IQ-1S application in vitro. We also found that IQ-1S decreased the intensity of the lipid peroxidation in the brain tissue in rats with GCI. 2.2-Diphenyl-1-picrylhydrazyl scavenging for IQ-1S in acetonitrile and acetone exceeded the corresponding values for ionol, a known antioxidant. Overall, these results suggest that the neuroprotective properties of IQ-1S may be mediated by improvement of cerebral microcirculation due to the enhanced vasorelaxation, beneficial effects on blood viscosity, attenuation of the endothelial dysfunction, and antioxidant/antiradical IQ-1S activity.

To study rheological properties of blood in patients with acute ischemic stroke treated with mexidol., Material and Methods: Sixty patients with acute stroke, including 32 patients who received mexidol (500 mg/IV/20 days) and 28 people who received magnesium sulfate (2000 mg/IV/20 days) were examined. The control group included 20 people without a cardiovascular pathology. Blood rheology (viscosity of whole blood, plasma viscosity, hematocrit, aggregation and deformability of erythrocytes, fibrinogen level) was evaluated in patients three times: for the first 12 hours, 3-5 days and 18-20 days after hospitalization., Results: Hyperviscosity syndrome was observed in all patients with stroke. A significant decrease in blood viscosity was found in patients treated with mexidol: in the 3-5th day at low shear rates and in the 18-20th day at 3-100 s -1 shear rates. Significant differences in hematocrit (p=0.026) and fibrinogen levels (p=0.017) in patients treated with different drugs were found in the 18-20th day of the disease. Higher erythrocyte deformability index was recorded in patients treated with mexidol in the 3-5th day at shear rates of 90 and 890 s -1 , in the 18-20th day at shear rates of 90-360 s -1 ., Conclusion: The study confirms the impact of mexidol on the fluidity of blood during the acute cerebral ischemia and shows its efficacy in reducing blood viscosity, decreasing the level of hematocrit and fibrinogen, increasing the deformability of erythrocytes.

We studied the effect of O-((((4-hydroxy-3,5-di(1,7,7-trimethylbicyclo[2.2.1]hept-exo-2-yl) benzyl)oxy)ethyl)-O-(2-hydroxyethyl)-(1→4)-α-D-glucan (D-HES, 80 mg/kg, intravenously) and reference preparation ethylmethylhydroxypyridine succinate (EMHP-S, 50 mg/kg, intravenously) on rat survival and neurological deficit in 24 h after transient global cerebral ischemia in Wistar rats. Intravenous administration of D-HES and EMHP-S significantly increased the number of survivors by 68 and 78%, respectively, in comparison with the control group. In groups treated with D-HES and EMHP-S, the number of animals with severe neurological deficit was significantly lower and the number of animals moderate or mild neurological deficit was significantly higher than in the control group.

Background: Many pathological mechanisms are involved in the development of arterial hypertension; disturbance of the rheological properties of blood and microvascular rarefaction are among those mechanisms., Objective: The effect of p-tyrosol (Tyr) on hemorheological parameters and microvascularization in the cerebral cortex of spontaneously hypertensive rats (SHRs) at the stage of blood pressure rising (5-11 weeks) was studied., Methods: Blood viscosity (BV), plasma viscosity (PV), hematocrit, erythrocyte aggregation and deformability, the oxygen transport capacity index (OTCI), and the capillary network in the cerebral cortex after the course of treatment of Tyr (50 mg/kg daily i.g. for 6 weeks) were studied. Control normotensive Wistar-Kyoto (WKY) rats and control SHRs received an equivalent amount of 1% starch mucilage., Results: In comparison with WKY rats, disturbances of rheological blood parameters and a decrease in OTCI were revealed in control SHRs at the 11 weeks of life. By the end of the experiment, brain microvascular rarefaction was observed in the control SHRs (the average density of the capillary bed was reduced due to a decrease in the number of capillaries with a diameter of 3-7 μm). In SHRs rats treated with Tyr, BV and PV, the indices of erythrocyte aggregation were lower, and OTCI was higher in comparison with control SHRs. The density of the capillary network and the number of capillaries of 3-7 μm in the cerebral cortex of SHRs rats receiving Tyr were significantly higher than the corresponding values in control SHRs., Conclusion: When Tyr is administered to young SHRs during the development of hypertension, it limits the development of hyperviscosity syndrome, improves the oxygen transport capacity and eliminates microvascular rarefaction in the cerebral cortex., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The rheological properties of blood play a significant role in the onset and progression of arterial hypertension. The aim of our work was to evaluate the effect of the angiotensin-converting enzyme inhibitor captopril (20 mg/kg/d), pentoxifylline (PTX; 100 mg/kg/d), and the combination of captopril + PTX (20 + 100 mg/kg/d) on the hemodynamic and hemorheological parameters in spontaneously hypertensive rats (SHRs) during the development of arterial hypertension. In the group of animals that received captopril, the mean arterial pressure (MAP) was significantly lower by 30% due to a decrease in cardiac output of 23% and in total peripheral resistance (TPR) of 26% compared with the control group, whereas blood viscosity did not change significantly. PTX-treated SHRs had significantly lower MAP and TPR (by 19% and 31%, respectively) and blood viscosity (by 4%-6%) and a higher erythrocyte deformability index (by 1.5%-2%) than the control group. In the group of animals that received captopril + PTX, MAP and TPR were significantly lower, by 41% and 46%, than those in the control group, and by 16% and 27% than those in the captopril group. The combination of the angiotensin-converting enzyme inhibitor captopril and the hemorheological agent PTX, affecting various systems that are involved in blood pressure regulation, exhibits synergism and prevents an increase in arterial blood pressure during the development of arterial hypertension in SHRs (ie, from 5 to 11 weeks of life)., (Copyright © 2017 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.)

Objectives: The effect of course administration of amlodipine on whole blood viscosity and on macro- and microrheological parameters was evaluated., Materials and Methods: SHRs were treated intragastrically with amlodipine at a dose of 10 mg/kg for 6 weeks. After finishing the course, hemodynamic and hemorheological parameters were measured., Results: The antihypertensive treatment with amlodipine resulted in a significant decrease in mean blood pressure by 29% and left ventricular to body weight mass index by 7%. Nevertheless, BV tended to increase. The administration of amlodipine had no effect on PV, plasma fibrinogen concentration, RBC aggregation, and RBC deformability, but hematocrit was higher (by 6%) than it was in control group., Conclusions: These results demonstrate that amlodipine has no positive hemorheological improvements when administered to SHRs., Competing Interests: There are no conflicts of interest.

We developed an improved three-vessel occlusion model of global cerebral ischemia in rats. This method consists in cessation of cerebral blood flow by accessing a. carotis communis sinistra through the ventral surface of the neck as well as tr. brachiocephalicus and a. subclavia sinistra through the first intercostal space, bypassing the pleural cavity and excluding pneumothorax. After the occlusion of the vessels that resulted in interruption of their blood flow, according to laser-Doppler flowmetry, there was a sharp decline in local cerebral blood flow in the visual cortex to 4±1% of the initial level. After restoring the level of local cerebral blood flow at the 5th minute, 10th minute, 20th minute and 24th hour of reperfusion, the levels of local cerebral blood flow were 51±7%, 41±5%, 35±8% and 54±9% of the initial level, respectively. Histo-quantitative analysis of changes in neurons of the hippocampus of rats showed that after ischemic injury, the numerical density of neurons in hippocampal zone CA1 in the observed 1mm 2 region decreased by 29%, 22%, and 35%, respectively, compared to sham-operated animals (p<0.05). By the first day after global cerebral ischemia, the experimental group had shown a mean neurological deficit score equal to 7.5±1.0 and 7.9±0.7 points, followed by a decrease up to score 6.5±1.1 and 5.9±0.7 on the third day, 4.6±0.8 and 4.7±0.5 on the fifth day (on chloral hydrate and propofol anesthesia correspondently)., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The effects of dihydroquercetin (50 mg/kg intragastrically daily for 6 weeks) on the density of capillary network (mean number of capillaries per mm 2 ), mean capillary diameter, structure of capillary network, capillary diameter distribution (<3, 3-5, 5-7, and 7-9 μ), and local cerebral blood flow (by laser Doppler) in the visual cortex were studied in SHR rats during the development of arterial hypertension (from the 6th to the 12th week of life). Normally, the systolic and diastolic BP progressively increased in SHR rats during this period. Dihydroquercetin did not affect the development of arterial hypertension. At the same time, the drug significantly increased the mean diameter of capillaries (by 11%), capillary network density (by 23%), and in the percentage of capillaries with a diameter of 3-9 μ (passable for erythrocytes; by 42%). Positive effects of dihydroquercetin on the structure of microcirculatory bed improved microcirculation: local cerebral blood flow in the visual cortex of SHR rats was significantly higher (by 36%) than in rats receiving no flavonoid and close to the value in Wistar-Kyoto rats. Dihydroquercetin improved microvascularization and microcirculation in the cerebral cortex of SHR rats during the formation of arterial hypertension.

The most common form of hypertension in young adults is isolated diastolic hypertension. Diastolic arterial pressure is determined by the total peripheral resistance and depends on both vascular hindrance and blood viscosity. The aim of our work was to study the efficiency of pentoxifylline (PTX) in young spontaneously hypertensive rats (SHRs) during the development of arterial hypertension. The effects of a treatment course with PTX (100 mg/kg/day p.o. for 6 weeks, from 5 to 11 weeks old) on the mean, systolic, and diastolic blood pressure (BP); stroke volume; cardiac output; total peripheral resistance (TPR); whole blood viscosity (BV); plasma viscosity; hematocrit; RBC aggregation and deformability; local cerebral blood flow (lCBF); and microvascularization of the visual cortex were studied in SHRs in comparison with control SHRs and Wistar Kyoto rats. PTX-treated SHRs had significantly lower systolic, diastolic, and mean BP (by 24%, 26%, and 15%, respectively) and BV (by 5-9%) and a higher erythrocyte deformability index (by 1.5-2%), lCBF (by 42%), average diameter of capillaries (by 11%), density of the capillary network (by 23%), and percentage of capillaries with a diameter of 3-7 µm in comparison with control SHRs. In conclusion, PTX exerted positive effects on the hemodynamic, hemorheological, and microcirculatory parameters in SHRs during the development of arterial hypertension.

We studied the effect of dihydroquercetin (20 mg/kg/day intragastrically for 6 weeks) on mean BP and macro- and microrheological blood parameters in hypertensive SHR rats; in vitro effect of dihydroquercetin on the tone in thoracic aorta rings isolated from hypertensive SHR rats were also examined. At the end of the treatment course, the mean BP in the experimental rats decreased by 11%; the left ventricular mass index by 2%, and whole blood viscosity by 7-10% in comparison with control SHR rats; erythrocyte aggregation half-time increased by 15%; plasma viscosity, hematocrit, and erythrocyte deformability did not change. In in vitro experiments, dihydroquercetin (10 -8 -10 -6 M) induced relaxation of the isolated thoracic aorta rings in a dose-dependent manner. Hence, the antihypertensive effect of dihydroquercetin results from the decrease in blood viscosity and vasodilation.

Specificities of the changes in the systemic hemodynamics indices in the spontaneously hypertensive line SHR rats have been studied in comparison with the normotensive line WKY rats. It was demonstrated that an increase in blood pressure observed in the young hypertensive male rats, which have completed puberty (8 weeks old), is associated with the development of the hyperkinetic type arterial hypertension, which is characterized by increased cardiac minute output. It has been shown that SHR line male rats reveal the establishment of stable arterial hypertension due to a significant increase in the total peripheral resistance with the simultaneous recovery of the cardiac minute output by the 25th week of life. SHR line rats at the age of 15 weeks may be regarded as being in the period of transition from the hyperkinetic type arterial hypertension to stable arterial hypertension.

Background: Systemic arterial pressure (AP) depends on two physiological variables: cardiac output (CO) and total peripheral resistance (TPR). The latter depends on vascular hindrance and blood viscosity (BV). However, the relative contributions of the vascular and rheological factors to TPR remain unclear., Objective: The aim of our work was to study the haemodynamic and haemorheologic effects of a treatment course with pentoxifylline (PTX) in SHRs in an effort to assess the impact of the rheological factor on TPR and AP., Methods: The effects of the treatment course with PTX (100 mg/kg/day p.o. for six weeks) on BV, plasma viscosity, haematocrit, erythrocyte aggregation and deformability, mean AP (MAP), stroke volume (SV), CO, and TPR were studied in SHRs and in control Wistar Kyoto (WKY) rats., Results: PTX-treated SHRs had a lower BV, lower erythrocyte aggregation, and higher erythrocyte deformability index compared with the controls. The TPR level was higher by 43% compared with that in WKY rats and did not differ from the values obtained from control SHRs. In SHRs, moderate and strong positive correlations were found between BV and MAP and between BV and TPR. PTX-treated SHRs did not have any significant correlations between the above mentioned parameters., Conclusions: Treatment with PTX attenuated whole blood viscosity, but did not affect the AP and hemodynamic parameters in the experimental SHRs compared with the control SHRs. The magnitude of the rheologic effects of PTX was insufficient to cause appreciable decreases in TPR and AP.

The studies were performed in hypertensive rats (SHR strain) during the period of hypertension development (7-8 weeks) and stable high blood pressure (16-17 weeks) and in normotensive rats (WKY strain) of corresponding ages. The average number of capillaries per square millimeter, the average capillaries diameter, and the capillary network structure following the estimation of capillaries distribution based on capillaries diameter within the following ranges (up to 3, from 3 to 5, from 5 to 7 and from 7 to 9 μm) were investigated using the morphological approach. The average diameter of capillaries and capillary network structure in SHRs during the development of hypertension did not differ from the respective values in WKY rats of the same age. SHR rats showed disturbed microvascularisation by structural and functional rarefaction in the stable high blood pressure period, which was manifested in lower average capillaries density and average capillaries diameter as well as in substantial (2.5 times) increase in plasmatic capillaries as compared to WKY rats of the same age.

Background: Postmenopausal women often develop hemorheological disorders which may affect the systemic blood circulation and present a cardiovascular risk factor., Objective: We evaluated effects of secoisolariciresinol (SECO), a phytoestrogen, on hemorheological parameters and lipid peroxidation in a model of the age-related and/or surgical menopause induced by ovariectomy in rats., Methods: Arterial blood was sampled from sham-operated female rats, ovariectomized rats (OVX), and OVX treated with SECO (OVXSECO) (20 mg/kg/day intragastrically for two weeks). Plasma estrogen concentration and the following hemorheological parameters were measured: RBC aggregation (half-time of aggregation, T1/2; amplitude of aggregation, AMP; aggregation index, AI), RBC deformability (elongation index, EI), whole blood viscosity at the shear rate of 3-300 s-1, plasma viscosity, hematocrit, plasma fibrinogen. Lipid peroxidation was evaluated by measuring conjugated dienes (CD) and thiobarbituric acid reactive substances (TBARS) in plasma., Results: Ovariectomy in rats caused a 60% decrease in plasma estrogen level and triggered the development of macro- and microhemorheological abnormalities. Blood viscosity increased by 12-31%, RBC elongation index reduced by 16-28%, and T1/2 and AI increased by 35% and 29% respectively. The increase in blood viscosity correlated predominantly with reduced RBC deformability. Plasma CD and TBARS were elevated by 47% and 104% respectively. SECO therapy for OVX rats reduced blood viscosity by 9-18% and T1/2 by 32%, and increased EI by 4-17%. SECO therapy disrupted the correlation between blood viscosity and RBC deformability. Lipid peroxidation was significantly inhibited, as shown by the reduction in CD and TBARS plasma concentrations by 89% and 70% respectively. SECO did not affect plasma viscosity, estrogen or fibrinogen levels., Conclusions: SECO treatment for OVX rats improves blood macro- and microrheological parameters, possibly through antioxidant protection of RBC.

Prevention of cardiovascular complications is one of the objectives of antihyperiensive therapy. However, the expected effect cannot be fully achieved by me- ans of the blood pressure control only. The authors studied the effect of captopril administration in SHR rats by monitoring the following parameters: arterial blood pressure, rheological properties of blood, and endothelial index of vasodilator activity (IVA), as well as their correlations. In SHR rats, the systolic blood pressure (SBP) and diastolic blood pressure (DBP) were higher by 28 - 33% as compared to WKY rats. In comparison to normotensive animals, the blood vis- cosity (BV) at shear rates from 30 to 450 sec -1 in SHR rats was increased by 12 - 15% (p = 0.020), the aggregation of red blood cells was increased by 22% (p = 0.012), and their plasticity in the range of shear stresses within 3 - 20 Pa was decreased by 2 - 8% (p = 0.028). The IVA value in SHR rats was lower by 26 % (p = 0.030) than that in WKY rats. The administration of captopril decreased the SBP and DBP values down to the level in normotensive animals, but did not influence the rheological properties of blood and its IVA value. In WKY rats, the BV exhibited reliable correlation with IVA (with r from +0.60 ai +0.67, p <0.05) at shear rates ranging within 30 - 450 sec -1, while the rheological parameters were correlated with neither SBP nor DBP. In SHR rats, the BV corre- lated with IVA only at 450 sec -1 (with r =+0.50, p = 0.025), and there were relationships between SBP and BV (r = + 0.64, p = 0.008) and the aggregation in- dex (r = +0.69, p = 0.003). Rats treated with captopril showed no correlations between hemorheological and hemodynamic parameters. Therefore, captopril decreases the arterial blood pressure, but it also violates the contour of vascular tone regulation associated with changes in shear stress on the vascular wall, which plays an important role in ensuring adequate local blood flow.

SHR rats were examined in the period before arterial hypertension development (5th week), during the increase in BP (6th-10th weeks), and under conditions of constantly elevated BP (11th-12th weeks). The total number of leukocytes did not differ in SHR and normotensive WKY rats. However, the relative number of lymphocytes and monocytes was shown to differ in various periods of arterial hypertension development. Our results suggest that white blood cells (primarily lymphocytes) are involved in the development of arterial hypertension.

Hyperviscosity syndrome was described in Brattleboro rats. The aim of this study was to investigate the possibility of Brattleboro rats using, as a test system for the study of agents with hemorheological activity. Under conditions of this model of high blood viscosity syndrome in Brattleboro rats, Lychnis chalcedonica L. extract (150 mg/kg) administered intragastrically for 10 days exhibited hemorheological activity by modulating macro- (plasma viscosity, fibrinogen concentration) and microrheological (erythrocyte aggregation and deformability parameters. Hence, Brattleboro rats are an adequate model of hyperviscosity syndrome that can be used for search and testing of substances with hemorheological activity.

The dynamics of systolic and diastolic BP and vasodilatory activity of the endothelium in SHR and Wistar-Kyoto rats was studied from the 5th to the 12th week of life. Systolic and diastolic BP did not differ in 5-week-old SHR and Wistar-Kyoto rats. After the 6th week of life, two stages of arterial hypertension development were observed in SHR. Stage 1 (weeks 6-8) was characterized by a significant increase in systolic and diastolic BP that exceeded the corresponding parameters in Wistar-Kyoto rats by 26-32%. Vasodilatory activity of the endothelium was similar in rats of both strains at the age of 5-7 weeks. Stage 2 (weeks 9-12) in SHR rats was characterized by further increase in systolic and diastolic BP that exceeded the corresponding parameters in Wistar-Kyoto rats by 54-89%. The increase in BP during this period was accompanied by a significant decrease in endothelium-dependent relaxation (by 14-16% compared to that in Wistar-Kyoto rats of the same age).

The dynamics of arterial blood pressure and hematological parameters (RBC volume, RBC count, hematocrit) in young rats SHR and WKY strains in the period from the 5th to the 8th week after birth was investigated. At the age of 5 weeks, the levels of arterial blood pressure in rats studied strains were not significantly different. Starting from 6 weeks, systolic and diastolic blood pressure in SHR rats were significantly higher than the corresponding values of WKY rats of the same age. During the entire period of observation (from the 5th to 8th week) the number of red blood cells and hematocrit in SHR rats was significantly increased compared with the value of these parameters in WKY rats. Probably, an increased hematocrit can be one of the reasons of increasing the blood pressure in the early stages of hypertension development.

Rheohaemapheresis aims to normalize major rheological parameters and is used to treat patients with dry age-related macular degeneration (AMD). While effective, this approach is invasive and requires specially trained personnel. Therefore, the search for novel effective compounds with hemorheological properties that can be taken orally to treat AMD is justified. The use of a robust rodent model of AMD with high blood viscosity is crucial to test the efficacy of potential hemorheological drugs to treat this disease. The objective of this study was to investigate whether OXYS rats, generally used as an animal model of AMD, have hyperviscosity syndrome. The results of this study show that blood viscosity in OXYS rats at low (3-10 s -1) and high (45-300 s -1) shear rates were 14-20% and 7-10% higher than in Wistar rats, while hematocrit and plasma viscosity were not different. Red blood cells (RBCs) in OXYS rats were more prone to aggregation as shown by 39% shorter half-time than in Wistar rats. RBCs were also more rigid in OXYS than in Wistar rats as shown by 21-33% lower index of elongation at the shear stress of 1-7 Pa. These data indicate that OXYS rats have hyperviscosity syndrome as the result of abnormal RBC deformability and aggregation. We propose to use OXYS rats as an animal model for preclinical studies to test compounds with hemorheological properties aimed to treat AMD.

Venous hypertension and swelling of the hind limbs was demonstrated to develop in rat model of chronic venous insufficiency. It was found that 14-day course of dihydroquercetin (50 mg/kg) and lipoic acid (50 mg/kg) administered intragastrically prevented the increase in hind limb volume and reduced the severity of edema of rat muscle tissue in chronic venous insufficiency.

The administration of the extract from Rhaponticum carthamoides (150 mg/kg, p.o., for 10 days) in combination with dosed low-power exercise in rats with experimental myocardial infarction led to an improvement of hemorheological indices, which was manifested by a decrease in the whole blood viscosity, aggregation of erythrocytes, and increase in erythrocyte deformability. In particular, the extract from R. carthamoides contributed to an increase in the hematocrit/blood viscosity, which was indicative of an improvement of the blood overall oxygen transport capacity. In addition, administration of the extract in combination with dosed exercise favored normalization of the lactate and pyruvate concentrations in blood of rats with myocardial infarction.

The effect of flaxseed extract (FSE) containing 42% secoisolariciresinol diglucoside on the blood plasma estradiol level and theological properties of blood in female Wistar rats after ovariectomy was investigated by measuring hematocrit, fibrinogen concentration, platelet aggregation and deformability, and the whole blood and plasma viscosity. Bilateral ovariectomy in rats led (in comparison to sham-operated animals) to a decrease in the estrogen level to 59% and produced a 5-9% increase in the whole blood viscosity, which was caused by impairment of the erythrocyte deformability and aggregation. The efficacy of oxygen transport to tissues was decreased by 4-7%. The treatment of ovariectomized rats with FSE (peroral administration at a daily dose of 40 mg/kg for 14 days) reduced the whole blood viscosity by 4-11% and increased the coefficient of oxygen transport to tissues by 5-11%, but did not restore the estrogen level. Thus, the hemorheological effect of FSE reduces to the improvement of microrheological parameters (decrease in erythrocyte aggregation and increase in their deformability) without the modification ofmacrorheological parameters (hematocrit, plasma viscosity and fibrinogen level).

Optimum design of preclinical research for pharmacological agents influencing the rheological properties of blood is presented. Models of hyperviscosity syndrome and approaches to studying the hemorheological activity mechanisms are described.

We demonstrated in experiments on rats with left coronary artery occlusion that intravenous administration of 20 mg/kg n-tyrosol during ischemia limited manifestations of oxidative stress in myocardial tissue during early post reperfusion period: content of diene and triene conjugates lowered 16 and 20%, respectively. This was associated with higher preservation of cardiomyocytes and reduction of the infarction zone.

We studied the antithrombotic and thrombolytic effects of Trombovazim, a highly-purified proteolytic enzyme preparation obtained by immobilization of bacterial proteinases (Bacillus) on polyethylene oxide with a molecular weight of 1.5 kDa. Blood absorption of the preparation was evaluated after intragastric administration. In vitro experiments showed that Trombovazim produces anticoagulant and thrombolytic effects, which manifested in inhibition of fibrin clot formation and acceleration of its lysis. Drug concentration in the blood was elevated from the 4th to the 7th hour after intragastric administration of Trombovazim in a dose of 2250 U/kg, being maximum by the 5th hour (0.044+/-0.011 U/ml). Course treatment with Trombovazim (1000 U intragastrically, twice daily for 3 days) had a thrombolytic effect on rats with experimental intravascular thrombosis. This effect was manifested in a decrease in thrombus weight and increase in the percent of rats with recanalization of the occluded carotid artery.

Antithrombogenic and antiplatelet effects of a new drug, containing isoflavonoids (extract from the wood of Maackia amyrensis, a Far Eastern plant), were studied. A course (200 mg/kg intragastrically during 14 days) of Maackia amyrensis extract prevented intravascular clotting, initiated by application of 10% iron chloride solution on the vessel. The drug increased antiaggregant activity of the vascular wall and potentiated endothelium-dependent vasodilatation in ovariectomied rats. The reference drug ethinylestradiol (25 mug/kg intragastrically during 14 days) potentiated the antiaggregant effect of the endothelium, but was inferior to Maackia amyrensis extract in the capacity to induce endothelium-dependent vasodilatation in ovariectomied rats.

Ovariectomy reduces blood levels of sex hormones and considerably increases blood viscosity due to an increase in hematocrit and plasma fibrinogen content, disorders in viscoelastic characteristics of erythrocytes, and increase of their aggregation activity. Changes in the macrorheology are mainly responsible for the development of the hyperviscosity syndrome.

Cerebral ischemia in rats was accompanied by an increase in erythrocyte degradation, which results from changes in lipid composition of their membranes. The content of lipids and phospholipid fraction (phosphatidylcholine, sphingomyelin, and phosphatidylserine) decreased, while the relative content of lysophospholipids increased in erythrocyte membranes. The course of treatment with Rhaponticum carthamoides extract (150 mg/kg perorally, 5 days) contributed to an increase in the contents of total lipids and phospholipids (primarily of sphingomyelin and phosphatidylserine) and decrease in the ratio of lysophospholipids in the erythrocyte membrane of rats with cerebral ischemia. Morphological characteristics of erythrocytes returned to normal, which manifested in an increase in the number of discocytes and decrease in the count of degenerated cells.

It has been experimentally established that a single impact of carbon mono-oxide in concentration 4000 mg/m3 during 75 minutes (CL50) in rats is accompanied with disturbance of functional activities of blood red cells in the form of a decrease of deformability and an increase of aggregative capacity of erythrocytes which are most evident to the end of the first day after carbon mono-oxide administration. These changes are combined with structural modification and changes in metabolism of erythrocytic membrane. The signs of structural modification of erythrocytic membrane in rats exposed to acute effect of carbon mono-oxide in a mean lethal concentration stay long remaining during elimination of carboxyhemoglobinemia (up to 14-21 days).

Antiarrhythmic activity of n-tyrosol was demonstrated on the model of early occlusion and reperfusion arrhythmia. The preparation reduces the incidence of ventricular tachycardia and fibrillation, increases the percent of animals without ventricular arrhythmia, and moderates the severity of developing ventricular arrhythmias.

Inclusion of polyethox, a medicinal form of high-molecular (4,5 x 10(6) Da) poly(ethylene oxide), into infusion-transfusion therapy of massive hemorrhage (33% of blood volume) in cats leads to an increase in the stroke and cardiac indices, restores antiturbulent and hemorrheological properties of blood, increases systemic oxygen transport, and reduces hypoxic acid-base balance disturbances.

The course of treatment with Alchemilla vulgaris extract increased the concentrations of lipids and phospholipids in erythrocyte membranes, decreased the number of abnormal erythrocytes, and improved deformability of red blood cells in rats with arterial hypertension.

The effect of granulocytic CSF on myocardial tissue recovery after acute myocardial infarction was studied on rats. A course of granulocytic CSF after ligation of the left coronary artery normalized ECG parameters and morphological picture of the myocardium 1 month after treatment. It was shown on mouse model of myocardial infarction that this process was associated with more intensive mobilization and homing of mesenchymal stem cells in the heart.

Electron microscopy and electrophysiological data reveal pronounced structural and functional disturbances in cerebral cortex of rats with model brain ischemia. A 5-day treatment with a dry extract from Rhaponticum carthamoides (Willd.) Iljin. in a daily dose of 150 mg/kg (p.o.) equivalent to 2.7 mg ecdysterone per kg body weight reduced manifestations of the ischemic damage, improved the structure of neurons, and restored brain activity (EEG parameters).

The effect of Neutrostim (preparation of granulocytic colony-stimulating factor) on recovery of myocardial tissue after acute myocardial infarction was studied in rats. A course of Neutrostim after ligation of the left coronary artery led to normalization of electrocardiographic and morphological parameters of the myocardium after one month.

Rats with model cerebral ischemia were treated over 5 days with acetylsalicylic acid (in a single daily dose of 50 mg/kg via a gastric tube). This treatment decreased the level of platelet aggregation, while producing no statistically significant effect upon hemorheogical indices. The combined treatment with a complex of acetylsalicylic acid and diquertin (50 and 10 mg/kg via a gastric tube, respectively) also produced the antiaggregant effect, but additionally reduced the blood viscosity, erythrocyte aggregation, and fibrinogen content in the blood plasma.