Influence of a Decrease in Blood Viscosity on Arterial Pressure in Normotensive and Spontaneously Hypertensive Rats.

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.

Effect of IQ-1 on the Infarct Size and the Parameters of Cardiodynamic Indicators in the Acute Period after Myocardial Ischemia/Reperfusion in Rats.

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/dtmax and -dP/dtmax). 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/dtmax by 23%, voltage-time index by 12%, -dP/dtmax by 43%, and the minimum pressure in the left ventricle decreased by 3.4 times.

Effects of a New Antithrombotic Drug GRS, a Soluble Guanylate Cyclase Stimulator, on Endothelial Dysfunction in Rats with Myocardial Infarction.

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.

A New In Vitro Blood Hyperviscosity Model.

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.

Neuroprotective Activity of D-HES in Transient Global Cerebral Ischemia in Rats.

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.

Dihydroquercetin Improves Microvascularization and Microcirculation in the Brain Cortex of SHR Rats during the Development of Arterial Hypertension.

The effects of dihydroquercetin (50 mg/kg intragastrically daily for 6 weeks) on the density of capillary network (mean number of capillaries per mm2), 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.

Modes of Hypotensive Action of Dihydroquercetin in 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 (10-8-10-6M) 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.

[EFFECT OF CAPTOPRIL ON THE ARTERIAL PRESSURE AND RHEOLOGICAL PROPERTIES OF BLOOD, THE VASODILATOR ACTIVITY OF ENDOTHELIUM, AND RELATIONSHIP OF THESE INDICES IN SHR RATS.]

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.

[Specificity of the Hemodynamic Indices' Shift in SHR Line Rats at Different Age].

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.

[DYNAMICS OF BLOOD PRESSURE AND QUANTITY INDICES OF ERYTHROCYTES IN SHR IN EARLY PERIOD OF ARTERIAL HYPERTENSION FORMING].

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.

Quantitative Indexes of Leukocytes in Spontaneously Hypertensive Rats During Various Periods of Arterial Hypertension Development.

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.

Dynamics of Blood Pressure Elevation and Endothelial Dysfunction in SHR Rats During the Development of Arterial Hypertension.

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).

Effect of dihydroquercetin on the tone of isolated rat veins.

Dihydroquercetin effects on the tone of isolated segments of the portal vein of rats were studied. Dihydroquercetin did not modify the basal venous tone, but reduced the amplitude of contractions induced by KCl and norepinephrine hydrotartrate.

Antioxidant composition causes antiexsudorific effect in the model of chronic venous insufficiency.

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.