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.

The effect of a new JNK inhibitor IQ-1 (11 H -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.

The effect of p-tyrosol on the main hemodynamic parameters and contractile function of the heart was studied and a morphometric assessment of left-ventricular remodeling was performed in Wistar rats 2 months after acute 1-h myocardial ischemia followed by reperfusion. p-Tyrosol in a dose of 20 mg/kg was injected intraperitoneally 5 times: 20 min before the start of reperfusion, 4 h after the start of reperfusion, and then once a day over the next 3 days. Administration of p-tyrosol to animals in the acute period of myocardial infarction slowed down the formation of systolic and diastolic myocardial dysfunction, improved the pumping function of the heart, maintained the hemodynamic parameters at a significantly higher level, and reduced left-ventricular remodeling in the late period of myocardial infarction. In 2 months after acute myocardial ischemia modeling, the dimensions of the left-ventricular cavity, the area of the postinfarction focus, and the area of connective tissue in rats treated with p-tyrosol were significantly lower than in the control group. In the group treated with p-tyrosol, no anterior left-ventricular wall aneurysms were found.

Aim. To investigate anti-ischemic and antiarrhythmic activity of Dibornol in conditions of multiple transitory ischemia of myocardium from in vivo experiments with rats. Material and Methods. The experiment was performed on male Wistar rats with a model of myocardial ischemia caused by 5-time 3-minute occlusions of the left coronary artery, followed by 15-minute reperfusion periods. Rats of the experimental group received Dibornol 10 mg/kg intragastrically once for 4 days; control animals received an equivalent volume of 1% starch mucus. On the ECG, the magnitudes of the ST segment elevation were determined for minutes 1, 2, and 3 of each episode of ischemia and for minutes 5, 10, and 15 of reperfusion; the nature and duration of ventricular arrhythmias were determined as well. Results. In the control group, the ST segment was elevated during all five episodes of ischemia. During reperfusion periods, a decrease in the elevation of the ST segment was detected, but no normalization occurred. Ischemic and reperfusionrelated ventricular arrhythmias were observed in the rats of the control group. Mortality in the control group reached 67% (6 animals out of 9). In the experimental group, in animals receiving Dibornol at a dose of 10 mg/kg, the occlusion of the left coronary artery was associated only with a slight elevation of the ST segment and its rapid recovery during reperfusion. Magnitudes of the ST segment elevation were significantly lower than the corresponding control values during all the episodes of ischemia. During reperfusion periods, the differences with the control group were more significant during the first to fourth periods and at minute 15 of the fifth reperfusion period. The death rate in the experimental group (1 animal out of 9) was significantly lower relative to the corresponding value in the control group. Conclusion. The course preventive use of Dibornol in multiple myocardial ischemia/reperfusion had significant anti-ischemic and antiarrhythmic effects during reperfusion periods and significantly increased the survival rate in animal models.

2,6-Diisobornyl-4-methylphenol (Dibornol, 10 mg/kg intragastrically daily for 5 days after myocardial ischemia/reperfusion) 1.5-fold increased rat survival during the acute post-infarction period in comparison with the control group. In survivors, Dibornol reliably prevented post-ischemic progression of heart failure in the delayed post-infarction period (30 days after ischemia/reperfusion), which was seen from an increase in the left-ventricular developed pressure by 22%, left-ventricular contractility index by 19%, and +dP/dt by 34%. Left-ventricular end-diastolic pressure was by 39% lower than in control animals. Morphological study of heart sections from control group animals showed that Dibornol reduced the area of post-ischemic myocardial damage in the delayed period after ischemia/reperfusion to 3±1% (vs 18±2% in the control group).

We studied the cardioprotective effect of 2,6-diisobornyl-4-methylphenol under conditions of myocardial ischemia/reperfusion in rats. Daily administration of 2,6-diisobornyl-4-methylphenol (100 mg/kg intragastrically) over 3 days before and 5 days after modeling of myocardial ischemia/reperfusion prevented the increase in the infarction area by almost 2 times in comparison with the control by day 5 after recirculation. The type and severity of pathological changes in ECG parameters reflecting necrotic changes in the myocardium under the action of the compound significantly decreased by day 35 of the experiment. Animal survival rate during the first 24 h after ischemia/reperfusion modeling in the experimental group was by 29% higher than in the control group.

We studied anti-ischemic activity of n -tyrozol under conditions of repeated transient myocardial ischemia in rats caused by repeated (5×3 min) occlusion of the left coronary artery. n -Tyrozol administered intraperitoneally in a dose of 20 mg/kg daily over 4 days before the ischemia modeling (the last injection 15 min prior to the start of the experiment) produced a clear-cut anti-ischemic effect: it reduced ST elevation and promoted more complete recovery of ECG during reperfusion. During reperfusion periods, n -tyrozol significantly decreased the risk of ventricular fibrillation and shortened the duration of tachyarrhythmia episodes (ventricular tachycardia and fibrillation).

We studied the effects of novel sterically hindered phenol, 4-methyl-2,6-diisobornyl phenol (dibornol) on the rheological properties of the blood in the model of myocardial ischemia/reperfusion. Dibornol (100 mg/kg intraperitoneally for 3 days before and 5 days after ischemia/reperfusion) decreased blood viscosity by 9-25% in comparison with that in sham-operatedanimals by modulating cellular (erythrocyte deformability and aggregation) and plasma (plasma viscosity) rheological parameters. Normalization of blood rheology under the influence of dibornol increased the availability of oxygen to tissues at high shear rates by 9-18% after acute ischemia/reperfusion in rats.

Изучены эндотелийпротективные эффекты диборнола® (4-метил-2,5-диизоборнилфенола) – нового отечественного препарата из группы пространственно затрудненных фенолов в условиях острой ишемии/реперфузии миокарда у крыс. У диборнола в эксперименте выявлены антиоксидантный, антигипоксический, гемореологический виды фармакологической активности, что явилось основанием для изучения его эффектов, направленных на защиту эндотелия сосудистой стенки от повреждения при усилении перекисного окисления липидов, обусловленном ишемическими и реперфузионными процессами в миокарде. У крыс при модели острой ишемии/реперфузии миокарда отмечено существенное нарушение функциональной активности эндотелия сосудов, которое проявилось снижением его антиагрегантной и сосудорасширяющей активности. В этих условиях диборнол при его лечебно-профилактическом введении (100 мг/кг внутрижелудочно, в течение 3 дней до и 5 дней после воспроизведения модели ишемии/реперфузии миокарда) повышал антиагрегантную активность эндотелия сосудистой стенки крыс на 37 %, по сравнению с эффектом эндотелия сегмента брюшной аорты животных, не получавших лечения. Кроме того, диборнол уменьшал коэффициент эндотелиальной дисфункции на 43 %, по сравнению с показателем контрольной группы. Следовательно, диборнол в условиях модели ишемии/реперфузии миокарда оказывает эндотелийпротективное действие, о чем свидетельствует его способность повышать антиагрегантные свойства эндотелия и уменьшать коэффициент эндотелиальной дисфункции.

A Endothelial protective and antithrombogenic effects of Cimicifuga racemosa standardized extract (Klimadynon, Bionorica, Germany) in comparison with ethinylestradiol in experimental ovariectomy were investigated. Extract of Cimicifuga racemosa (klimadynon) contents phytoestrogens, that was the basis for studying of its effects in hypoestrogenic conditions for the purpose of prophylaxis and treatment of cardiovascular complications in climacteric syndrome as an alternatively of hormonal replacement therapy.The course administration of klimadynon (100 mg/kg p.o. daily during 14 days) decelerated the formation of intravascular thrombosis which was initiated by application of 10% FeCb solution on carotid artery. The ethinylestradiol in this conditions intensified prothrombogenic effect of application of 10% FeCh: blood flow in carotid artery stoped to 5 minutes of experiment and mass of the thrombus was on 28% more, than in control rats. For studying of possible mechanisms antithrombogenic action of klimadynon antiplatelet and vasodilator activity of endothelium were studied in rats after bilateral ovariectomy in comparison with effects of ethinylestradiol (25 µg/kg p.o. daily during 14 days). Treatment with klimadynon as well as ethinylestradiol increased the antiplatelet activity of endothelium, restoring its activity to level in sham-operated animals. The endothelium-dependent and endothelium-independence vasodilation by using of acetylcholine (5 µg/kg) and of sodium nitroprusside (30 µg/kg). respectively, were investigated. Coefficient of endothelium dysfunctions (CED) was estimated as ratio: area over curve of arterial pressure after sodium nitroprusside intravenous injection to value of this index after injection of acetylcholine. In rats after bilateral ovariectomy CED was increased by 66% in comparison with CED value in sharm-operated rats. The klimadynon and ethinylestradiol treatment decreased CED on 42% and 28% correspondingly in comparison with values of control group.In summary klimadynon has antytrombogenic and endothelial protective activities in the rats after ovariectomy. The ethinylestradiol decreases endothelial disfunction in ovariectomized rats, but unlike klimadynon demonstrates protrombogenic effect. The present findings suggest that klimadynon could be used as a therapeutic agent for menopausal vascular complication.

The effects of Maackia amurensis extract (200 mg/kg, p.o. during the 14 days) on the vasomotor and psychoemotional reactions in rats after ovariectomy were investigated. The Maackia amurensis extract did not change the blood level of sex hormones, showed anxiolytic activity with the models of anxious disorders, did not influence considerably on the motor activity in «open field» test. Maackia amurensis extract reduced the pathological vasomotor reactions, showing by the change in vessels reactions on vasoactive agents and «hot flushes».

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.

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).

The effects of Maackia amurensis extract (200 mg/kg, p.o. during the 14 days) on the vasomotor and psychoemotional reactions in rats after ovariectomy were investigated. The Maackia amurensis extract did not change the blood level of sex hormones, showed anxiolytic activity with the models of anxious disorders, did not influence considerably on the motor activity in «open field» test. Maackia amurensis extract reduced the pathological vasomotor reactions, showing by the change in vessels reactions on vasoactive agents and «hot flushes».

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 in rats induces the activation of lipid peroxidation processes, reduces total lipid content, and decreases the accumulation of lysophospholipids in erythrocyte membranes. The administration of Maackia amurensis extract (200 mg/kg, p.o., during 14 days) reduces the level of lipid peroxidation, prevents a decrease in the total lipid content, normalizes the proportion of lipids and proteins, and eliminates the accumulation of lysophospholipids in erythrocyte membranes in ovariectomized 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.

In experiments on rats with cerebral ischemia (30-min occlusion of carotid arteries), the novel calcium antagonist Cerebrocrast (0.4 microgram.kg-1.min-1 i.v. for 15 min) was found to provide the functional maintenance of the parietal cerebral bed in the postischemic period by improving cerebral hemodynamics, reducing the number of highly narrowed capillaries. The agent prevented the erythrocytic accumulation of lipid peroxidation (LPO) products (diene conjugates and Schiff bases) in the intra- and postischemic periods, promoted the maintenance of viscoelastic properties during LPO activation.