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Over the last decade, magnetic iron oxide nanoparticles (IONPs) have drawn much attention for their potential biomedical applications. However, serious in vitro and in vivo safety concerns continue to exist. In this study, the effects of uncoated, Fe m O n -SiO 2 composite flake-like, and SiO 2 -Fe m O n core-shell IONPs on cell viability, function, and morphology were tested 48 h postincubation in human umbilical vein endothelial cell culture. Cell viability and apoptosis/necrosis rate were determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and annexin V-phycoerythrin kit, respectively. Cell morphology was evaluated using bright-field microscopy and forward and lateral light scattering profiles obtained with flow cytometry analysis. All tested IONP types were used at three different doses, that is, 0.7, 7.0, and 70.0 μg. Dose-dependent changes in cell morphology, viability, and apoptosis rate were shown. At higher doses, all types of IONPs caused formation of binucleated cells suggesting impaired cytokinesis. Fe m O n -SiO 2 composite flake-like and SiO 2 -Fe m O n core-shell IONPs were characterized by similar profile of cytotoxicity, whereas bare IONPs were shown to be less toxic. The presence of either silica core or silica nanoflakes in composite IONPs can promote cytotoxic effects., Competing Interests: The authors report no conflicts of interest in this work.

Functional parameters and degree of myocardial damage by ischemia-reperfusion model of isolated heart were investigated during acute experiments on rats with an antibiotic-induced intestinal dysbiosis after administration of the probiotic strains of Enterococcus faecium L3. Administration of antimicrobial drugs has resulted in an increased heart rate and in an increase in coronary flow of isolated heart. Administration of enterococci after the global ischemia has caused rats to have a decrease in diastolic pressure, increased systolic and pulse pressure, and an increased intensity of coronary flow. The article presents data on changes in the composition of the intestinal microbiota and the immune system that was previously obtained in studies based on this experimental model.

Silicon-containing nanoparticles (NPs) are considered promising drug carriers for targeted drug delivery. In this study, we investigated the physical and chemical properties of silicon-containing NPs, including silica and organomodified silica NPs (SiO2NPs and OrSiO2NPs, respectively), with different surface modifications, with the aim of increasing drug-loading efficiency. In addition, we described the original synthesis methods of different sizes of OrSiO2NPs, as well as new hybrid OrSiO2NPs with a silica core (SiO2 + OrSiO2NPs). Animal experiments revealed that the silicon-containing NPs investigated were non-toxic, as evidenced by a lack of hemodynamic response after intravenous administration. Bioelimination studies showed rapid renal excretion of OrSiO2NPs. In drug release kinetics studies, adenosine was immobilized on SiO2NPs using three different approaches: physical adsorption, ionic, and covalent bonding. We observed that the rate of adenosine desorption critically depended on the type of immobilization; therefore, adenosine release kinetics can be adjusted by SiO2NP surface modification technique. Adsorption of adenosine on SiO2 + OrSiO2NPs resulted in a significant attenuation of adenosine-induced hypotension and bradycardia.

The unmet clinical need for myocardial salvage during ischaemia-reperfusion injury requires the development of new techniques for myocardial protection. In this study the protective effect of different local ischaemic preconditioning (LIPC) and remote ischaemic preconditioning (RIPC) protocols was compared in the rat model of myocardial ischaemia-reperfusion, using infarct size and ischaemic tachyarrhythmias as end-points. In addition, the hypothesis that there is involvement of reactive oxygen species (ROS) in the protective signalling by RIPC was tested, again in comparison with LIPC. The animals were subjected to 30-min coronary occlusion and 90-min reperfusion. RIPC protocol included either transient infrarenal aortic occlusion (for 5, 15 and 30 min followed by 15-min reperfusion) or 15-min mesenteric artery occlusion with 15-min reperfusion. Ventricular tachyarrhythmias during test ischaemia were quantified according to Lambeth Conventions. It was found that the infarct-limiting effect of RIPC critically depends on the duration of a single episode of remote ischaemia, which fails to protect the heart from infarction when it is too short or, instead, too prolonged. It was also shown that RIPC is ineffective in reducing the incidence and severity of ischaemia-induced ventricular tachyarrhythmias. According to our data, the infarct-limiting effect of LIPC could be partially eliminated by the administration of ROS scavenger N-2-mercaptopropionylglycine (90 mg/kg), whereas the same effect of RIPC seems to be independent of ROS signalling., (© 2016 The Authors. International Journal of Experimental Pathology © 2016 International Journal of Experimental Pathology.)

Objective: To evaluate cardioprotective effects of remote ischemic preconditioning (RIPC) in cardiac surgery patients undergoing aortic valve replacement depending on the type of anesthesia and investigate the level of myocardial protein kinase C epsilon (PKC-ε) expression after RIPC., Methods: In prospective randomized trial, forty eight patients aging from 50 to 75 years old (64 (56 ;69)) were included All patients were scheduled for aortic valve replacement using cardiopulmonary bypass (CPB). The patients were randomized into 4 groups: 1) RIPC applied during propofol anesthesia (RIPC prop, n = 12), 2) RIPC applied during sevoflurane anesthesia (RIPC sev, n = 12), 3) propofol anesthesia without RIPC (CONTROL prop, n = 12), 4) sevoflurane anesthesia without RIPC (CONTROL sev, n = 12). There was no difference found between the groups as to the baseline patient's data. RIPC protocol consisted of 3 simultaneous ischemic episodes of both lower limbs (5 minutes) with 5-min reperfusion intervals. PKC-ε expression in right atrial myocardium was assessed using Western blotting. Troponin I (cTnI) was estimated before anesthesia induction, after 30 min, 6, 12, 24, 48 hours after CPB completion. Also we calculated area under curve of cTnI (cTnI AUC). According to nonparametric distribution, data were assessed by the Mann-Whitney U-test and Newman-Keuls methodfor multigroup comparison. p < 0.05 was considered signifcant. The data are presented as median (25th; 75th percentile)., Results: Cardioprotective effects of RIPC were observed only after sevoflurane anesthesia: cTnI AUC was 134,8 (122,3; 232.4) ng/ml/48 h in CONTROL sev group and only 74.3 (64.7; 85.0) ng/ml/48 h in RIPC sev group (p < 0.05). RIPC applied during propofol anesthesia was not associated with cTnIAUC decrease: 93.8 (74.1; 246.8) ng/ml/48 h in CONTROL prop group and 122.5 (74.1; 185.0) ng/ml/48 h in RIPC prop group (p = 0.37). RIPC applied during sevoflurane anesthesia significantly increased PKC-ε expression: 1221 (921; 1438) U in CONTROL sev group vs 1882 (1564; 2131) U in RIPC sev group 6 (p < 0.05). RIPC implication during propofol anesthesia was not associated with any significant difference in PKC-ε expression in comparison with control group: 620 (436; 782) U in CONTROL prop group versus 788 (574;1063) U in RIPC prop group. In control groups, PKC-ε expression was significantly higher in sevoflurane anesthesia in comparison with propofol anesthesia., Conclusion: RIPC was only effective when it was applied during sevofiurane anesthesia. This was confirmed by PKC-ε expression increase and lower value of cTnI. There were no evidence of preconditioning and cardioprotection when MPG was initiated during propofol anesthesia.

Cardioprotective effects of necrostatin-1 (necroptosis inhibitor) and 3-methyladenine (autophagy inhibitor) were studied on the model of long-term cold preservation of rat heart. Addition of necrostatin-1 (490 nmol/liter) or 3-methyladenine (4.5 mmol/liter) to custodiol preserving solution reduced myocardial infarction size and improved left-ventricular function during reperfusion after 8-h preservation at 4°C. Inhibition of necroptosis and autophagy contributed to the cardioprotective effect under conditions of cold preservation of the donor heart.

Acute myocardial infarction remains to be one of the most important problems of health care. Cardiac cell therapy is a new therapeutic strategy focused on repair of the injured cardiac muscle. Mesenchymal stem cells (MSC) are considered as the most suitable candidates for cardiac cell therapy. MSC transplantation in the myocardium after ischemic injury has been shown to be cardioprotective in animal models and clinical trials. However, the beneficial effects of MSC in humans are limited because of both poor survival and impaired function of the cells in ischemic tissue. To address these issues, a number of approaches to the modification of MSCs with the aim to improve their survival and proliferation, reduce the immune reaction, enhance transdifferentiation, and optimize the profile of secreted paracrine factors have been tested. In this review, we provide detailed discussion of different methods of MSCs modification, including targeted gene overexpression, conditioning of MSCs using physical and chemical factors, and application of multicellular units for transplantation. The effectiveness of these strategies in preclinical studies is also discussed.

Using the cell model of regenerative cardiomyogenesis (formation of contracting cardiomyocyte colonies from resident stem cells), we found that the addition of cardiomyocyte-derived apoptotic bodies to the culture of neonatal myocardial cells stimulated proliferation and differentiation of cardiomyocyte precursors and the frequency of their contraction was 1.5-fold higher than in the control. Systemic administration of cardiomyocyte-derived apoptotic bodies to Wistar rats with chronic postinfarction heart failure during the early period of myocardial remodeling considerably improved the contractile function of the heart.

The methods of donor heart preservation are aimed at minimizing graft dysfunction caused by ischaemia-reperfusion injury (IRI) which inevitably occurs during the ex vivo transport interval. At present, the standard technique of heart preservation is cardiac arrest followed by static cold storage in a crystalloid heart preservation solution (HPS). This technique ensures an acceptable level of heart protection against IRI for <6 h. In clinical trials, comparable levels of myocardial protection against IRI were provided by various HPSs. The growing shortage of donor hearts is one of the major factors stimulating the development of new techniques of heart preservation. Here, we summarize new HPS formulations and provide a focus for optimization of the composition of existing HPSs. Such methods of donor heart preservation as machine perfusion, preservation at sub-zero temperature and oxygen persufflation are also discussed. Furthermore, we review experimental data showing that pre- and post-conditioning of the cardiac graft can improve its function when used in combination with cold storage. The evidence on the feasibility of cardiac donation after circulatory death, as well as the techniques of heart reconditioning after a period of warm ischaemia, is presented. The implementation of new techniques of donor heart preservation may contribute to the use of hearts from extended criteria donors, thereby expanding the total donor pool., (© The Author 2014. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Background: Several studies have demonstrated that local ischemic preconditioning can reduce myocardial ischemia-reperfusion injury in cardiac surgery patients; however, preconditioning has not become a standard cardioprotective intervention, primarily because of the increased risk of atheroembolism during repetitive aortic cross-clamping. In the present study, we aimed to describe and validate a novel technique of preconditioning induction., Methods: Patients undergoing coronary artery bypass grafting (12 women and 78 men; mean age, 56 ± 11 years) were randomized into 3 groups: (1) Controls (n = 30), (2) Perfusion (n = 30), and (3) Preconditioning (n = 30). All patients were operated under cardiopulmonary bypass using normothermic blood cardioplegia. Preconditioning was induced by subjecting the hemodynamically unloaded heart to 2 cycles of 3 min of ischemia and 3 min of reperfusion with normokalemic blood prior to cardioplegia. In the Perfusion group, the heart perfusion remained unaffected for 12 min. Troponin I (TnI) levels were analyzed before surgery, and 12, 24, 48 h, and 7 days after surgery. The secondary endpoints included the cardiac index, plasma natriuretic peptide level, and postoperative use of inotropes., Results: Preconditioning resulted in a significant reduction in the TnI level on the 7th postoperative day only (0.10 ± 0.05 and 0.33 ± 0.88 ng/ml in Preconditioning and Perfusion groups, respectively, P < 0.05). In addition, cardiac index was significantly higher in the Preconditioning group than in the Control and Perfusion groups just after weaning from cardiopulmonary bypass. The number of patients requiring inotropic support with ≥ 2 agents after surgery was significantly lower in the Preconditioning and Perfusion group than in the Control group (P < 0.05). No complications of the procedure were recorded in the Preconditioning group., Conclusions: The preconditioning procedure described can be performed safely in cardiac surgery patients. The application of this technique of preconditioning was associated with certain benefits, including improved left ventricular function after weaning from cardiopulmonary bypass and a reduced need for inotropic support. However, the infarct-limiting effect of preconditioning in the early postoperative period was not evident. The procedure does not involve repetitive aortic cross-clamping, thus avoiding possible embolic complications.

One of the effective methods of fertility preservation is an autologous transplantation of cryopreserved ovarian tissue. Currently, according to the world literature, after orthotopic autotransplantation of ovarian tissue 37 healthy children were born. In 2014 at the North-West Federal Medical Research Center it was established Cryobank of ovarian tissue, which is now kept 50 samples of ovarian tissue of man. Cryoconservation is performed by standard slow freezing. Autotransplantation of cryopreserved ovarian tissue has unique advantages over other methods of fertility preservation. This method does not lead to the postponement of anticancer therapy, safe for hormone-dependent cancer and can be performed regardless of the day of menstrual cycle and it is the only option for fertility preservation in prepubertal girls. The use of this method in clinical practice leads to restoration of endocrine function of the ovaries as well as of fertility in the future.

Bcl-2 protein expression was studied in hippocampal CA1, CA2, CA3 and CA4 pyramidal neurons in Mongolian gerbils (Meriones unguiculatus), of the in in the early (Day 2) and late (Day 7) reperfusion period after a 7-minute forebrain ischemia and following ischemic postconditioning (IPostC), as well as in sham-operated animals (n=60). In the latter, the highest level, of Bcl-2-expression was found in CA4 neurons, while the lowest--in-CA1 neurons (P<0.01). Reversible ischemic brain damage led to the increasing deficit of morphologically unchanged hippocampal neurons with the increasing duration of reperfusion period. This was accompanied by a significant decrease in expression of Bcl-2 in the early reperfusion period, but in the late reperfu- sion period this decrease largely disappeared. IPostC, applied as three episodes of ischemia-reperfusion lasting 15/15 seconds, contributed to significant increase in the number of morphologically unchanged CA1 and CA3 neurons in the early reperfusion period, while the expression of Bel-2 was increased in morphologically unchanged neurons in all the hippocampal areas. In the late reperfusion period after IPostC, the number of unchanged neurons was increased in hippocampal areas CA1, CA3 and CA4 (P<0.05), while a significant increase in Bcl-2 expression (by 12.7%, P<0.01) was detected only in CA1 neurons. The results suggest that the cytoprotective effect of IPostC in hippocampal CA1 area is realized through a mechanism leading to increased expression of Bcl-2 protein, i.e., by blocking apoptosis.

Purpose of the Study: To evaluate the effects of remote ischemic preconditioning (RIPC) on the perioperative period in elective aortic valve replacement (AVR) along different anaesthesia techniques., Materials and Methods: 48 patients aged 50 to 75 years (64 (56;69)) which were scheduled for AVR due to aortic valve stenosis were included into the prospective, randomized study. Four groups were formed after randomization: 1) RIPC applied during propofol anesthesia (RIPCprop, n = 12), 2) RIPC applied during sevoflurane anesthesia (RIPCsevo, n = 12), 3) propofol anesthesia without RIPC (CONTROLprop, n = 12), 4) sevoflurane anesthesia without RIPC (CONTROLsevo, n = 12). Groups were similar in baseline data of patients. RIPC protocol: three five-minutes episodes of simultaneous both lower limbs ischemia with five-minutes reperfusion intervals. Troponin I (cTrI), interleukin-6 (IL-6), Interleukin-8 (IL-8) and C-reactive protein (CRP) levels were assessed prior to induction of anesthesia, at 30 min, 6, 12, 24 and 48 hours after the cessation of CPB. Significant differences were assessed by the nonparametric Mann-Whitney and Fisher's exact tests. Data are presented as: median (25th percentile, 75th percentile)., Results: . Significant differences in cTnI were found between RIPCsevo and CONTROLsevo groups at 6, 12 and 24 hours: 1.68 (1.28, 2.09) ng/ml vs 3.66 (2.07, 4.49) ng/ml, respectively at 6 hours (p = 0.04); 1.89 (1.59, 2.36) ng/ml vs 3.66 (2.91, 5.64) ng/ml, respectively at 12 hours (p = 0.001); 1.68 (1.55; 2.23) ng/ml vs 3.32 (2.10; 5.46) ng/ml, respectively at 24 hours (p = 0.01). There were no differences found in cTnI between RIPCprop and CONTROLprop groups during the whole study. There were no significant differences found in the levels of IL-6 and CRP between RIPC and control groups during the whole study Unexpectedly significant excess concentrations of IL-8 at 24 h were found when RIPC applied during sevoflurane anesthesia: 12.3 (10.6, 14.4) pg/mL in RIPCsevo group vs 6.2 (4.8, 11.1) pg/ml in CONTROLsevo group (p = 0.02). There was no paroxysmal atrial fibrillation (AF) after RIPC, and 5 cases were registered in the control groups (p = 0.02). No other significant differences in the clinical course of the postoperative period were found., Conclusions: Cardioprotective effect of RIPC and its effect on systemic inflammatory response should be assessed in the selected anesthesia groups. RIPC on the background of sevoflurane anesthesia reduces myocardial injury during AVR. RIPC does not reduce the severity of the systemic inflammatory response after AVR. RIPC reduces the risk of AF after AVR.

Cerebral venous drainage is generally believed to be regulated primarily by hydrodynamic forces. To gain further insight into the regulation of this process, we investigated the response of blood flow velocity and cross-sectional area (CSA) of the internal jugular veins (IJVs) to local hemodynamic shifts. All procedures and assessments were performed on patients (n = 30) undergoing embolization of brain arteriovenous malformations (AVMs). The procedure efficiency was verified by the postembolization reduction in time-averaged maximum blood flow velocities, as well as the elevation of pulsatility index and resistance index in the arterial feeders. In cerebral veins, the dominant IJV pressure remained unchanged during the procedure. At the same time, AVM embolization caused a significant reduction in maximal CSA (84 ± 7.6 to 68 ± 7.7 mm(2), P < 0.05) and minimal CSA (68 ± 7.0 to 51 ± 7.0 mm(2), P < 0.01) of the IJV located ipsilateral to the AVM, while the maximal linear blood flow velocity in the IJV remained unchanged (71 ± 4.9 and 85 ± 8.4 cm/s, P = 0.098). Consistent with previously published studies, the data obtained provide further evidence of active regulation of the venous outflow, probably mediated by certain neurogenic and/or endothelium-dependent mechanisms.

The effect of metformin on myocardial sensitivity to ischemia in rats with neonatal streptozotocin T2DM was investigated using the model of global ischemia-reperfusion in the isolated perfused heart. Metformin administration had no effect on infarct size. At the same time, infarct size in T2DM was significantly lower than in controls, which is indicative of the phenomenon of metabolic preconditioning in T2DM. The protocol of metformin administration used in this study had not afforded a significant cardioprotective effect in animals with T2DM.

Introduction: The present study tested the hypothesis that long-term effects of baroreceptor activation might contribute to the prevention of persistent arterial blood pressure (BP) increase in the rat model of renovascular hypertension (HTN)., Methods: Repetitive arterial baroreflex (BR) testing was performed in normo- and hypertensive rats. The relationship between initial arterial BR sensitivity and severity of subsequently induced two-kidney one-clip (2K1C) renovascular HTN was studied in Wistar rats. Additionally, the time course of changes in systolic BP (SBP) and cardiac beat-to-beat (RR) interval was studied for 8 weeks after the induction of 2K1C renovascular HTN in the rats with and without sinoaortic denervation (SAD). In a separate experimental series, cervical sympathetic nerve activity (cSNA) was assessed in controls, 2K1C rats, WKY rats, and SHR., Results: The inverse correlation between arterial BR sensitivity and BP was observed in the hypertensive rats during repetitive arterial BR testing. The animals with greater initial arterial BR sensitivity developed lower BP values after renal artery clipping than those with lower initial arterial BR sensitivity. BP elevation during the first 8 weeks of renal artery clipping in 2K1C rats was associated with decreased sensitivity of arterial BR. Although SAD itself resulted only in greater BP variability but not in persistent BP rise, the subsequent renal artery clipping invariably resulted in the development of sustained HTN. The time to onset of HTN was found to be shorter in the rats with SAD than in those with intact baroreceptors. cSNA was significantly greater in the 2K1C rats than in controls., Conclusions: Arterial BR appears to be an important mechanism of long-term regulation of BP, and is believed to be involved in the prevention of BP rise in the rat model of renovascular HTN.

This study aimed to investigate the effect of bone marrow- and adipose tissue-derived mesenchymal stem cell (BM-MSC and AD-MSC respectively) transplantation on left ventricular function and infarct area (IA) in the rat model of ischaemic heart failure. In anaesthetized Wistar rats, the left coronary artery (LCA) was occluded for 40 min with subsequent reperfusion for 7 days. Seven days following surgery, the animals with LCA occlusion/reperfusion were randomized into three groups: (i) Controls received intramyocardial injection of vehicle at three different locations within the peri-infarct zone, (ii) BM-MSC: cells were injected in the same way as in previous group (10(6) ), (iii) AD-MSC: using the same protocol as used in the BM-MSC group. In addition there was also a sham-treated group that had no injection. Two weeks following MSC transplantation, the hearts were isolated and perfused according to the Langendorff method followed by 30-min global ischaemia and 90-min reperfusion. After this IA was determined histologically. During Langendorff perfusion initial and postischaemic LV functions were the same in all groups although LV pressure at the 10th minute of reperfusion was higher in the AD-MSC group compared to controls. However, LV pressure during 30-min global ischaemia was significantly higher in BM-MSC as compared to controls and AD-MSC. The sham treated animals showed the same results as those seen with BM-MSC. Thus, BM-MSC transplantation, in contrast to transplantation of AD-MSC, resulted in better preservation of the LV ability to contract during ischaemia. Furthermore, IA was significantly smaller in BM-MSC group as compared to the controls and the AD-MSC groups. Thus this study has demonstrated that treatment with BM-MSC both ameliorates LV function and reduces histological scar size., (© 2013 The Authors. International Journal of Experimental Pathology © 2013 International Journal of Experimental Pathology.)

The cardioprotective effects of necroptosis inhibitors necrostatin-1 and necrostatin-5 were studied on the isolated heart model in rats. Intraperitoneal injection of necrostatin-1 (1.65 mg/kg) or necrostatin-5 (2.46 mg/kg) 60 min before reperfusion of the isolated heart reduced the infarction zone caused by 30-min global ischemia and 120-min reperfusion. Intracoronary injection of necrostatin-1 (44.5 μmol/liter) caused an increase of left-ventricular systolic pressure, that is produced a positive inotropic effect, but did not reduce the infarction zone.

We analyzed changes in activity of SDH, one of the most important enzymes of the Krebs cycle, in the cytoplasm of hippocampal and cortical neurons of Mongolian gerbils (Meriones unguiculatus) at the early and delayed reperfusion period after global brain ischemia. The data indicate that SDH activity in pyramidal neurons of various hippocampal areas and in neurons of II, III and V layers of cerebral cortex after 7-min forebrain ischemia depends on both the localization of these neurons and duration of the postischemic reperfusion. SDH activity in neurons significantly increased on days 2 and 7 after reperfusion.

Background: The Krebs-Henseleit buffer is the best perfusion solution for isolated mammalian hearts. We hypothesized that a Krebs-Henseleit buffer-based cardioplegic solution might provide better myocardial protection than well-known crystalloid cardioplegic solutions because of its optimal electrolyte and glucose levels, presence of buffer systems, and mild hyperosmolarity., Methods: Isolated Langendorff-perfused rat hearts were subjected to either global ischemia without cardioplegia (controls) or cardioplegic arrest for either 60 or 180 min, followed by 120 min of reperfusion. The modified Krebs-Henseleit buffer-based cardioplegic solution (mKHB) and St. Thomas' Hospital solution No. 2 (STH2) were studied. During global ischemia, the temperatures of the heart and the cardioplegic solutions were maintained at either 37°C (60 min of ischemia) or 22°C (moderate hypothermia, 180 min of ischemia). Hemodynamic parameters were registered throughout the experiments. The infarct size was determined through histochemical examination., Results: Cardioplegia with the mKHB solution at moderate hypothermia resulted in a minimal infarct size (5 ± 3%) compared to that in the controls and STH2 solution (35 ± 7% and 19 ± 9%, respectively; P < 0.001, for both groups vs. the mKHB group). In contrast to the control and STH2-treated hearts, no ischemic contracture was registered in the mKHB group during the 180-min global ischemia. At normothermia, the infarct sizes were 4 ± 3%, 72 ± 6%, and 70 ± 12% in the mKHB, controls, and STH2 groups, respectively (P < 0.0001). In addition, cardioplegia with mKHB at normothermia prevented ischemic contracture and improved the postischemic functional recovery of the left ventricle (P < 0.001, vs. STH2)., Conclusions: The data suggest that the Krebs-Henseleit buffer-based cardioplegic might be superior to the standard crystalloid solution (STH2).

The aim of this study was to determine the effect of ischemic postconditioning (IP) on the viability of neurons in various hippocampal areas as well as on cytoplasmic activity of succinatedehydrogenase (SDH) in these cells in 30 male Mongolian gerbils (Meriones unguiculatus). Ischemic brain injury was induced by bilateral common carotid artery occlusion for 7 min. IP protocol comprised 3 cycles of 15 s of reperfusion/15 s of ischemia. After reperfusion for 48 h, the morphometric analysis was conducted, and SDH cytoplasmic activity was assessed using quantitative histochemistry in the pyramidal neurons of the hippocampal areas CA1, CA2, CA3, CA4. The experiment has demonstrated that 7-minute-long ischemia resulted in a significant decrease in the number of viable neurons in CA1 area (up to 24%) and in the CA3 (to 56%) of the hippocampus; besides, it lead to the elevation of SDH activity in the cytoplasm of the neurons in all the hippocampal areas as compared to that in sham-operated animals. The application of IP significantly increased the number of viable neurons in CA1 (up to 52.9%, P<0,01) and in CA3 areas of the hippocampus(up to 88%, P<0,05), and it was accompanied by reduction of SDH activity in surviving neurons in all the hippocampal areas.

The objective of the present work was to expose the universal general biological significance of the protective pre- and postconditioning phenomena and to provide an insight into the possibility of application of therapeutic modalities based on these effects in current otorhinolaryngological practice. Pre- and postconditioning phenomena (Pre-C and Post-C respectively) began to be studied as protective physiological mechanisms since the 1980s, first in cardiology and thereafter in other fields of experimental medicine. At the same time, their protective properties had been known and intuitively used much earlier among the established human cultural and social stereotypes, psychophysical training techniques, and methods of traditional and empirical medicine. The widespread application of these phenomena gives evidence of their universal biological nature as factors involved in the interactions between the organism and pathogens (including co-morbidity), the process leading to the enhancement of non-specific resistance, mechanisms underlying realization of pharmacodynamic effects of a number of pharmaceutical products,etc. The understanding of the protective potential of PreC and PostC dictates the necessity to revise and further elaborate the present-day strategy of prophylaxis and treatment of the most serious chronic ENT diseases.

Cardioprotective properties of dimethyl sulfoxide (DMSO) were studied in the isolated rat heart model. Intraperitoneal administration of DMSO to animals for 3 days before the experiment, but not addition of DMSO to the perfusate, reduced infarction size. Both intraperitoneal and intracoronary administration of DMSO reduced the severity of postischemic left-ventricular dysfunction.

Experiments performed on mice C57Bl/6 with the use of GFP technology showed that activation of apoptosis is a potent physiological stimulus for targeted migration of mesenchymal stem cell from the blood to tissues. The effect of apoptosis-induced targeted migration of stem cells can be used in cell therapy of damaged organs and tissues in various pathological states.

A new rat model of global cerebral ischemia-reperfusion was proposed via reversible occlusion of the major vessels originating from the aortic arch and supplying the brain. This technique can be used for the search and study of exogenous (pharmacological) and endogenous methods of brain protection from ischemia-reperfusion injury.

Cerebral ischemia results in severe derangements of energy metabolism in the nervous tissue including activation of glycolytic pathway. Activity of cytosolic lactate dehydrogenase (LDH) in the specific brain structures remains unclear. The recent study was aimed at investigation into the LDH activity in the cytoplasm of both hippocampal and cortical neurons in Mongolian gerbils (Meriones unguiculatus) at different durations of reperfusion after global ischemia. Analysis showed that the activity of LDH in pyramidal neurons of various hippocampal areas and neurons of II, III and V cortical layers after 7-minute forebrain ischemia depended on both localization of the neurons and duration ofreperfusion. In general, the changes in postischemic cytosolic LDH activity include significant decrease in the LDH activity 2 days after reperfusion with varying degree of recovery on day 7 of reperfusion.

The objective of this publication is to summarize "classical" and modern concepts of pathogenesis, clinical features of cisplatin ototoxicity, its screening, and prophylaxis. It is argued that pathogenesis of a cisplatin-induced injury to the inner ear shares common features with the ototoxic mechanisms of action of other pharmaceuticals even though it is characterized by certain important differences. The authors consider the mechanisms of ototropicity, specific cytochemical aspects of cisplatin cytotoxicity that aggravate risk factors, and genetic predisposition to the development of iatrogenic problems. The data are presented on monitoring and experimental aspects of otoprotection for the prevention of cisplatin-induced damage to the auditory analyzer.

In the first part of this review molecular mechanisms of ischemic tolerance emerging as a result ofpreconditioning of the brain are discussed. Data on inductors, sensors, transducers and effectors of early and delayed ischemic tolerance are presented.

The aim of this study was to determine the effect of ischemic postconditioning on hippocampal CA1 neuronal survival and cytoplasmic activity of lactate dehydrogenase (LDH) in the gerbil model of cerebral ischemia-reperfusion injury. Ischemia was induced by bilateral common carotid artery occlusion (for 7 min) in male Mongolian gerbils (Meriones unguiculatus). Ischemic postconditioning protocol comprised 3 cycles of 15 s reperfusion/15 s ischemia. After 48 h of reperfusion, CA1 neuronal death was detected by Nissl staining and the cytoplasmic LDH was demonstrated histochemically in CA1 area of the hippocampus with a quantitative cytophotometric assessment of the enzyme activity. The results have shown that 7 min ischemia resulted in a significant decrease in the number of viable neurons (up to 24%) in the CA1 area of hippocampus; in addition, it reduced the activity of LDH in these neurons (from 0.260 +/- 0.009 to 0.190 +/- 0.006 relative units). The application of ischemic postconditioning significantly increased the number of viable neurons (up to 52.9%, P < 0.01) in the CA1 area of hippocampus, and it was accompanied by an increase in the activity of LDH (0.240 +/- 0.008 relative units, P < 0.001).

In the 2nd part the authors describe in details the main aspects of protective effect of preconditioning of the brain: inhibition of programmed cell death, weakening of phenomenon of excitotoxicity, activation of endogenous antioxidant systems, anti-inflammatory effects, modulation of glial cell function, changes in regional blood flow and vascular reactivity. In addition, data analysis on the impact of preconditioning on brain neurogenesis, the state of the blood-brain barrier, ion homeostasis and metabolism of neurons is presented. Review emphasizes the role of microRNAs in mechanisms of ischemic tolerance of brain. Profound understanding of molecular mechanisms of increased tolerance of brain to ischemic and reperfusion injury requires the implementation of this phenomenon in clinical practice.

Silica nanoparticles as carriers for targeted drug delivery to the heart were studied. Studies of hemodynamic parameters of rats after intravenous infusion of silica nanoparticles showed no acute toxicity. Intravenous infusion of silica nanoparticles to animals with ischemia-reperfusion of the myocardium led to accumulation of the nanoparticles in the focus of injury, which attests to possibility of passive targeted drug delivery to the myocardium.

The aim of this study was to evaluate the role of nitric oxide (NO) in the mechanisms of arterial distensibility and intravascular pressure stability in normotensive and spontaneously hypertensive rats. The experiments were performed on the anesthetized male Wistar, Wistar-Kyoto (WKY), and spontaneously hypertensive rats (SHR). The abdominal aorta was cannulated and perfused with variable blood flow rates with subsequent determination of major characteristics of regional vascular function. The blockade of nitric oxide (NO) synthase resulted in the increase in hydraulic resistance of the hindlimb vascular bed in all series of the experiments. It was associated with the decrease in the intravascular pressure stability. The obtained results provide further evidence for an important role of NO in the formation of conductivity and stability of the arterial pressure both in normo- and hypertensive rats. However, the involvement of NO in the phenomenon of flow-dependent vasodilation in SHR is unlikely. The major difference between SHR and normotensive rats involved the ability of the resistive arteries of SHR to enhance vascular conductivity in response to blood flow enhancement. Presumably, there are some unidentified additional factors that are involved in the flow-dependent vasodilation in SHR.

The clinical outcome of patients with ischemic heart disease can be significantly improved with the implementation of targeted drug delivery into the ischemic myocardium. In this paper, we present our original findings relevant to the problem of therapeutic heart targeting with use of nanoparticles. Experimental approaches included fabrication of carbon and silica nanoparticles, their characterization and surface modification. The acute hemodynamic effects of nanoparticle formulation as well as nanoparticle biodistribution were studied in male Wistar rats. Carbon and silica nanoparticles are nontoxic materials that can be used as carriers for heart-targeted drug delivery. Concepts of passive and active targeting can be applied to the development of targeted drug delivery to the ischemic myocardial cells. Provided that ischemic heart-targeted drug delivery can be proved to be safe and efficient, the results of this research may contribute to the development of new technologies in the pharmaceutical industry.

Improvement of myocardial protection against global ischemia-reperfusion injury during cardiopulmonary bypass remains to be of primary importance for cardiac surgery. In the present study, the effectiveness of new Krebs-Henseleit buffer-based cardioplegic solution was investigated in an isolated rat heart preparation in normo- and hypothermic states. Use of this crystalloid cardioplegic solution in the normothermic mode (37 degrees C) resulted in better myocardial protection in comparison to standard cardioplegic solutions as evidenced from both infarct size data and the patterns of left ventricular postischemic recovery. The data obtained indicate that Krebs-Henseleit buffer-based cardioplegic solution might be recommended for further preclinical testing.

It was shown previously that ethylmethylhydroxypyridine succinate (EMHPS) can produce metabolic cardioprotective action due to its antihypoxant and antioxidant properties. In the present study, the cardioprotective effects of EMHPS administered in doses 50 and 100 mg/kg alone and in combination with ischemic preconditioning have been studied on the model of ischemic-reperfusive myocardial infarction in rats. It is established that both the administration of EMHPS in a dose 50 mg/kg and the ischemic preconditioning produce significant limitation of the infarction size. A combined use of EMHPS in a dose of 50 mg/kg and ischemic preconditioning also provided significant protection, although the effect was not further potentiated. In contrast, EMHPS administered in a dose 100 mg/kg did not ensure reliable protection against infarction, while a combination of this drug dose with the ischemic preconditioning even partially eliminated the infarction-limiting effect of the latter.

The effects of mexicor (ethylmethylhydroxypyridine succinate) at doses of 50 and 100 mg/kg on myocardial infarct size, serum levels of myocardial markers, and severity of ischemia- and reperfusion-induced arrhythmias were studied in the rat model of myocardial ischemia-reperfusion injury. It was shown that pre-ischemic intravenous infusion of mexicor at a dose of 50 mg/kg resulted in significant reduction of myocardial infarct size and troponin I level. When the dose of mexicor was increased up to 100 mg/kg the infarct-limiting effect was reversed. Both doses of mexicor tested in this study failed to protect the heart from ischemic tachyarrhythmias but decreased the occurrence of persistent reperfusion-induced ventricular fibrillation.

It has been shown that exposure of the isolated rat heart perfused according to Langendorff to therapeutic ultrasound (210 kHz and 0.5-1.5 W/cm2 ) induces a cardioprotective response similar to ischemic preconditioning. This reduces the infarct size and improves the postischemic systolic and diastolic function. The ATP-sensitive K+ channel blocker glybenclamide abolished the protection afforded by ultrasound; in contrast, the free radical scavenger N-2-MPG did not influence the ultrasound-induced cardioprotective response.

Traditionally infarction size reduction by ischemic preconditioning is estimated in duration of test ischemia. This approach limits the understanding of real antiischemic efficacy of ischemic preconditioning. Present study was performed in the in vivo rat model of regional myocardial ischemia-reperfusion and showed that protective effect afforded by ischemic preconditioning progressively decreased with prolongation of test ischemia. There were no statistically significant differences in infarction size between control and preconditioned animals when the duration of test ischemia was increased up to 1 hour. Preconditioning ensured maximal infarction-limiting effect in duration of test ischemia varying from 20 to 40 minutes.

Reduction of infarct size as well as alleviation of other ischemia- and reperfusion-associated injuries are the goals of primary importance in cardiology. One of the remedies is considered to be myocardial preconditioning (PreCon) referred usually to as an increased myocardial tolerance to prolonged ischemia following brief ischemic or non-ischemic challenge. In this review, PreCon stimuli tested to date are considered including a number of mildly noxious factors applied either locally to the myocardium or systemically. Recently, one more mode of heart protection against reperfusion injury termed postconditioning (PostCon) has been developed. On the basis of ample evidence published, along with our findings, a detailed comparative analysis of PreCon and PostCon is presented, with special emphasis on the cellular, molecular, and pharmacological aspects of the topic as well as clinical applications, both implemented and awaiting practical approval.

Present study was aimed at investigation into the role of sodium-calcium exchanger (NCX) in myocardial ischemia-reperfusion injury and ischemic preconditioning (IPC). Experiments were performed in vivo rat model of regional myocardial ischemia-reperfusion. It was shown that inhibition of reverse mode of NCX with selective blocker KB-R7943 at a dose of 10 mg/kg resulted in significant decrease in occurrence and severity of ischemic ventricular tachyarrhythmias. Furthermore, administration of KB-R7943 caused potentiation of the antiarrhythmic effect exerted by single episode of IPC. However, KB-R7943 exerted no effect on myocardial infarction size nor affected infarction size limitation by IPC. In conclusion, inhibition of reverse mode of NCX conferred significant antiarrhythmic effect against ischemic rhythm disorders but it was ineffective in terms of infarction size limitation.

Data on the influences of diabetes mellitus on the severity of ischemic damage to the myocardium are contradictory. We report here experiments using a model based on in vivo myocardial infarcts resulting from coronary occlusion to study the resistance of the myocardium in rats with alloxan-induced insulin-dependent diabetes mellitus to prolonged ischemia, along with studies of the infarct-limiting efficacy of ischemic preconditioning. The results showed that after diabetes mellitus for six weeks, the relative size of infarcts was significantly less than in controls (39.8 +/- 8.8 and 62.3 +/- 6.6% of the size of the anatomical risk zone respectively, p < 0.01). In addition, animals with diabetes mellitus developed ischemic ventricular tachyarrhythmia significantly less often than controls. A single episode of ischemic preconditioning in animals with diabetes mellitus had a less marked infarct-limiting effect than the same procedure in controls. Thus, these data support the existence of an endogenous cardioprotective phenotype (metabolic preconditioning) in experimental diabetes. On the other hand, the efficacy of ischemic preconditioning was sharply decreased in diabetes.

Ischemic preconditioning (IPC) is one of the most effective means of myocardial protection against ischemic injury and involves two main types, local and remote. The aim of the present study was to investigate antiarrhythmic effects of local and remote IPC against early ischemic ventricular tachyarrhythmias (VTA) in a rat model of myocardial infarction. In contrast to local mode, remote IPC did not decrease the incidence and severity of ischemic VTA. The potential mechanisms of the antiarrhythmic effect of local IPC are discussed in the article together with prospects of clinical IPC application.

Low-frequency ultrasound transmission through a musculoskeletal fragment of thoracic cage was studied in vitro. The degree of ultrasound attenuation during noninvasive transthoracic application was estimated. The mean coefficient of ultrasound attenuation in thoracic cage was determined for the low-frequency region (210 kHz). The temperature effects of ultrasound application were also studied.

Data on myocardial tolerance of ischemia in the animals with experimental diabetes are controversial. In our study, myocardial sensitivity to ischemia and infarction-limiting effect of ischemic preconditioning have been investigated in the in vivo rat model of myocardial infarction in alloxan-induced insulin-dependent diabetes mellitus. It has been shown that in 6 weeks after alloxan injection in the diabetic rats infarction size as determined by TTC staining was significantly smaller than in healthy controls (39.8 +/- 8.8 and 62.3 +/- 6.6%, respectively, p < 0.01). Also, occurrence of ischemic tachyarrhythmias was more rare in diabetic rats than in controls. A single episode of ischemic preconditioning in diabetic rats showed a much lesser protection against infarction than in controls. Therefore, the data obtained support the existence of endogenous protective myocardial phenotype in diabetes, although the effectiveness of ischemic preconditioning in diabetes is reduced.

The phenomenon of ischemic preconditioning consists in increase in myocardial tolerance to ischemia after short periods of ischemia and reperfusion of the myocardium (local preconditioning) or a distant organ (distant preconditioning). This study is dedicated to the role of oxygen free radicals (OFR) in the mechanisms of preconditioning; pharmacological inhibition of OFR with N-2-mercaptopropionylglycin, a synthetic anti-oxidant, was used. Mouse experiments demonstrated a reduction in the infarction-limiting effect of local preconditioning as a result of OFR inhibiting. This confirms the hypothesis according to which OFR play an important role in the mechanisms of launching and mediating the protective effect of local preconditioning. On the contrary, application of the same dose of N2-mercaptopropionylglycin does not lead to a significant weakening of the infarction-limiting effect of distant preconditioning caused by 20 min of ischemia and 15 min of reperfusion of the small intestine. Thus, it is unlikely that OFR participate in the realization of the effect of distant preconditioning caused by small intestinal ischemia. The authors discuss hypothetic molecular mechanisms of distant myocardial preconditioning.

Aim: To examine effects of ischemic postconditioning on persistent ventricular fibrillation (VF) induced by reperfusion on the model of isolated rat heart., Material and Methods: Isolated by Langendorf hearts (n = 46) were ischemized for 30 min with following reperfusion. Hearts with persisting VF (n = 11) persisting to reperfusion minute 15 were randomized into two groups: control (n = 6)--reperfusion without interventions, study group on postconditioning (n = 5)--2 min global ischemia followed by reperfusion. Left ventricular pressure, heart rate, coronary blood flow were registered continuously., Results: VF converted to a regular rhythm in all the hearts exposed to postconditioning. Regular contractions were made by all the postconditioned hearts in the course of further reperfusion. None of the control hearts had normal rhythm in the end of the experiment. In the end of reperfusion pulse left ventricular pressure of the postconditioned hearts was lower than that in hearts without persistent VF., Conclusion: Ischemic postconditioining exerts an arrhythmic effect in relation to persistent reperfusion ventricular tachyarrhythmias. Postconditioning may serve a new strategy for myocardial protection.

Phenomenon of ischemic post-conditioning of the myocardium (attenuation of myocardial damage during reperfusion resulting from interruption of early reperfusion period by repetitive short episodes of ischemia) was discovered in 2003. This paper contains presentation of protective effects of ischemic post-conditioning during ischemia-reperfusion of the myocardium, data on antiarrhythmic effects of post-conditioning in relation to persistent tachyarrhythmias during reperfusion, analysis of possible mechanisms of infarct-limiting effect of post-conditioning, and perspectives of its clinical application.

Brief episodes of myocardial ischemia-reperfusion were shown to be protective against reperfusion injury when used during early reperfusion after a prolonged ischemic episode. This phenomenon has been termed myocardial ischemic postconditioning. In this study, an effect of ischemic postconditioning on persistent reperfusion-induced ventricular fibrillation was studied in the rat isolated heart. 2 minutes of global ischemia on the 15th minute of reperfusion after 30 minutes of regional ischemia effectively abolished the persistent ventricular fibrillation. In non-postconditioned hearts, the ventricular fibrillation continued to the end of reperfusion. The ischemic postconditioning seems to exert a strong antiarrhythmic effect protecting the heart against persistent reperfusion-induced ventricular tachyarrhythmias.

The experiments with low-intensity ultrasound stimulation of isolated rat heart revealed frequency-dependent effects of ultrasound in a frequency range of 45-298 kHz on cardiac activity.

Stimulation of the isolated heart with low-intensity low-frequency ultrasound produced a positive inotropic effect (at certain ultrasound intensity). This effect manifested in increased systolic and pulse intraventricular pressures and persisted for tens of minutes after the end of sonication.