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Renal ischemic and reperfusion injury resulting in acute renal failure is a multidisciplinary problem at the junction of pathophysiology, transplantology, urology, nephrology, cardiac surgery and pharmacology. One of renal protection strategies is using the phenomenon of preconditioning. Preconditioning is one of the ways to adopt a tissue to repeated short-term effects of damaging factors to induce an enhanced tolerance to the long period of hypoxia and/or ischemia. There are multiple cellular and molecular mechanisms of the renal protective effects of preconditioning stimuli, but the key effectors and signaling molecules are ATP-dependent potassium channels, nitric oxide synthase, nitric oxide, and mitochondrial pore. Contradictory data on the protective effect of ischemic preconditioning allow searching for approaches to pharmacological correction of ischemic and reperfusion injuries. The article provides data on possible ways of using erythropoietin, darbepoetin and phosphodiesterase 5 inhibitors.

Objective: To assess the efficacy of pharmacological preconditioning with actovegin in carotid endarterectomy., Material and Methods: The study was based on the results of surgical treatment of 80 patients with hemodynamically significant uni- and bilateral lesions of carotid arteries. Half of the patients was operated immediately and others after pharmacological preconditioning with actovegin in dose of 1200 mg/daily during 1,5 months., Results: Pharmacological preconditioning with actovegin increased the cerebral perfusion determined with one-photon emission computed tomography that improved significantly results of the surgery. There were significant changes in patient's state 7 days and 6 months after surgery. The improvement was correlated with the less number of asymptotic post-surgery ischemic strokes in different brain areas., Conclusion: A positive role of pharmacological preconditioning with actovegin in surgical treatment of carotid artery stenosis has been demonstrated.

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.

Purpose: To examine the efficacy of renal preconditioning effect of dalargin and lithium ions by observing the model of gentamycin-induced acute renalfailure., Materials and Methods: The experiments were performed on white rats, male. The influence of dalargin and lithium ions on the development of gentamycin-induced acute renalfailure was studied in vivo. On the first 24 hours after dalargin injections were terminated, the rats were euthanized humanly. After this we took the blood for a biochemistry study and a renal culture for biochemical test and also for the test of gsk-3β activity. Concentrations of creatinine and urea were studied in serum. The culture samples of renal tubular epithelium before insertion of gentamycin were incubated in dalargin or lithium ions in different concentrations. After that the substratum was immediately changed to gentamycin in different concentrations also and the incubated for 24 hours. After all the standards MTT-test was performed (based on the ability of living cells to reduce the unpainted form by 3-4,5-dimethylthiazol-2-yl-2,5-difenilterarazola to blue crystalline farmazan)., Results: Lithium precondition leads to the 250% increase of gsk-3β concentration (p = 0.035). The same results were observed after injection of dalargin in 50 mcg/kg concentration. Concentration of creatinine was 44% lower in the dalargin group than in the control group (p = 0.022). Concentration of creatinine was 32% lower in the lithium group than in the control group (p = 0.030). Concentration of urea was 27% lower in the lithium group than in the control group (p = 0.049). Morphological inflammatory changes in the control group were more significant also. In vitro studies showed the maximum efficacy in the lithium group. The most effective dalargin concentration was 5 mg/ml., Conclusion: Lithium and dalargine preconditioning lowers the signs of gentamycine induced acute renal failure and damage rate of renal parenchyma in vivo and in vitro.

Introduction: Remote ischemic preconditioning has gained clinicians' attention as a technique to protect the heart in patients undergoing cardiac surgery under cardiopulmonary bypass. While experimental data report neuroprotective properties of remote ischemic preconditioning, we failed to find any clinical studies investigating its effects on neurologic outcome in cardiac surgery., Purpose of the Study: This prospective randomized placebo-controlled study was undertaken with the aim of elucidating the role of remote ischemic preconditioning for neuroprotection in cardiac surgery., Patients and Methods: 88 patients with coronary heart disease scheduled for on-pump coronary bypass grafting surgery were randomized to receive either remote ischemic preconditioning or control. We studied S100B peptide and neuron-specific enolase to assess neurological damage. Psychophysiological tests were employed to investigate cognitive function after surgery., Results: The perioperative dynamics of S100B and neuron-specific enolase followed similar patterns in both groups throughout the observation period. At the end of surgery, level of S100B was significantly higher in the preconditioning group as compared to controls--0.58 (0.33-0.65) vs. 0.34 (0.23-0.42) mcg/l, p

Bradykinin level is increased in myocardium in response to short-term ischemia/reperfusion that is one of the evidences of its trigger role in ischemic preconditioning (IP). Pharmacological induced increase of endogenous bradykinin and kallidin-like peptide levels in myocardium enhances cardiac tolerance to impact of ischemia/reperfusion. Experiments with genetically modified mice indicate that kinins are involved in preconditioning but they are not the only trigger of IP. The B2-receptor blocking abolishes antiarrhythmic, infarct reducing effects ofpreconditioning, eliminates IP-induced cardiac tolerance to oxidative stress. Exogenous bradykinin mimics inotropic and cardioprotective effects of IP but does not mimic antiarrhythmic effect of preconditioning. The intracoronary or intravenous bradykinin infusion enhances human heart resistance to ischemia/reperfusion. Implementation of the cardioprotective effect of IP is provided by the activation of multiple signaling pathways that involve: B2-receptor, calcitonin gene-related peptide, NO-synthase, guanylyl cyclase, cGMP, protein kinase G, mitochondrial KATP channels, reactive oxygen species, kinases C, ERK andAkt. To increase of the human heart tolerance to ischemia/reperfusion is necessary to develop B2-receptor agonists devoid hypotensive and pro-inflammatory properties.

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.

Experimental and clinical studies of the last ten years gave evidence of successful application of the protective effect of hypoxia in clinical practice. The view of hypoxia as an exclusively injurious factor has undergone significant changes. A promising approach to solving the problem of heart adaptation to ischemic injury is the use of cellular mechanisms realized through myocardial ischemic preconditioning (IP). Modern understanding of the mechanisms of IP protective effect takes into consideration the processes underlying the development of adaptation to hypoxia related to the changes in intracellular metabolism and accompanied by a stronger activation of the systems responsible for adaptation. All this provides a real opportunity for studying intracellular functional and metabolic mechanisms of adaptation to hypoxia and ischemia, formation of adaptive syndromes in clinical practice, development and implementation of new evidence-based medical technologies for diagnostics, prevention, and rehabilitative treatment of heart pathology.

The optimal regimen of preliminary ischemic preparation, in which the vessels occlusion causes minimal pathohistological hepatic changes without inhibition of its regeneration capacities, was studied in experiment. The ischemic-reperfusional damage of liver, using hepatoduodenal ligament crossclamping in various regimens, was modeled on 40 rabbits in a randomized experimental investigation. Morphological investigations of the animals liver fragments, taken immediately after ligament crossclamping and on the third postoperative day, were performed. There was established, that severity and reversibility of the hepatic tissue affection have differed, depending on the ischemia duration and reperfusion period. The vessels occlusion regimen with preliminary ischemic preparation was the most safe for hepatic tissue, without rude structural injuries and functional disorders, permitting to recommend it for clinical application as the optimal one while performance of hepatic resection in combination with afferent vascular exclusion.

Hypoxic postconditioning using episodes of mild hypobaric hypoxia is a new neuroprotective technique. We compared the neuroprotective efficacy of hypoxic postconditioning and cerebrolysin in a model of posthypoxic pathology in rats. Animals that survived the severe hypoxia (180 Torr, 3 h) were exposed to hypoxic postconditioning or received cerebrolysin. Postconditioning prevented the injury and loss of hippocampal (fields CA1, CA4) and neocortical neurons whereas cerebrolysin was protective only for CA4 and the neocortex. Besides that, postconditioning, unlike cerebrolysin, led to the complete functional rehabilitation from the severe hypoxia by normalizing the level of anxiety and the pituitary-adrenal axis activity. The findings demonstrate that the elaborated postconditioning technique might provide useful tool for therapy of posthypoxic pathology and stroke.

Adaptation of the brain and myocardium to ischemia by short shutdowns of the regional circulation (preconditioning) is an interesting and important subject. Nowadays it is discussed with animation in the scientific literature. However this problem is very complicated and contains a lot of contradictions. We tried to examine these contradictions and tofind the reasons for this phenomenon.

During the last decade, stem cell research has developed at an accelerated pace. Various types of stem cells have been tested for myocardial infarction therapy. Despite the preclinical benefits of cell therapy success in clinical trials remains modest. The main obstacles to regeneration of the infarcted heart using stem cells are: 1) not every stem cell type can differentiate into cardiomyocytes; and 2) low survival rates of transplanted cells, due to the harsh environment of the infarcted myocardium. Hypoxic preconditioning (HP) has been shown to improve transplantation efficacy of mesenchymal stem cells and cardiac progenitor cells in animal models of myocardial infarction. It has also been shown that transplantation of preconditioned cells decreases infarct size, prevents postinfarction remodeling of the heart, and positively modulates development of ischemic cardiomyopathy. Hypoxic preconditioning also prevents extensive death of transplanted cells due to necrosis and apoptosis during long-term hypoxia or oxidative stress. The protective effect of HP is based on three main processes: (1) modification of cell phenotypes to help survival during hypoxia (enhancement of HIF-1alpha expression, ERK1/2 and Akt activation, enhancement of erythropoietin receptor expression and erythropoietin production, and an elevation in levels of antiapoptotic proteins Bcl-2 and Bcl-xL); (2) upregulation of various secretable factors including the vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF), and expression of VEGF-2 and HGF-receptors; (3) enhancement in the formation of CXCR4 and CXCR7 receptors, which play an important role in mobilization and homing of stem cells in the ischemic region.

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.

This article is dedicated to diagnostics, prevention and surgical treatment of vascular complications of diabetes mellitus, particularly prevention of ischemic strokes and treatment of critical ischemia of lower limbs. The main tendency in treatment of brachiocephalic artery lesions nowadays is a surgical intervention in the latent stage of the disease. X-ray endovascular surgical techniques are being increasingly used to treat lesions of lower limbs arteries. Limb preservation is impossible without cooperation of many specialists. It's essential to perform careful out-patient follow up of the patient after vascular reconstructive surgery.

The present work was aimed at assessing safety and efficacy of hypoxic preconditioning of the brain as a method of protecting the central nervous system during operations on the internal carotid artery in patients presenting with atherosclerotic lesions of the carotid arteries. The study included a total of 72 patients who underwent carotid endarterectomy for haemodynamically significant atherosclerosis of carotid arteries. Based on the obtained findings, a conclusion was made on a possibility of using intraoperative hypoxic preconditioning for prevention of ischaemic complications from the development in the perioperative period.

The presented data demonstrate that hypothermic preconditioning prevents cardiomyocyte necrosis in response to ischemia-reperfusion, improves pump function of the heart during reperfusion period, and exerts an antiarrhythmic effect. The hypothermic preconditioning exerts more pronounced cardioprotective effect than ischemic preconditioning. The protective impact of hypothermic preconditioning depends upon 3-adrenergic receptor stimulation, an increase in cAMP levels, activation of protein kinase A and protein kinase C, AMP-activated protein kinase (AMPK) and mitochondrial permeability transition pore blocking. The hypothermic preconditioning had no effect on the phosphorylation of GSK-3J3 (glycogen synthase kinase-3beta) and Akt-kinase. The reactive oxygen species end endogenous catecholamines are triggers or mediators of hypothermic preconditioning of heart.

Analysis of published data indicates that delayed hypoxic preconditioning essentially increases a cardiac and brain tolerance to ischemia-reperfusion. There are no experimental data in the literature on the neuroprotective effect of early hypoxic preconditioning in vivo. Clinical observations indicated that early hypoxic preconditioning exerts cardioprotective and neuroprotective effects. The single works testify that cardioprotective effect of delayed hypoxic preconditioning depend on the activation of inducible NO-synthase, KATP-channels and KCa-channels. Neuroprotective effect of hypoxic preconditioning is a consequence: (1) erythropoietin receptor stimulation and (2) an elevation of activity of PI3-Akt and ERK1/2 kinases. The supposed end effector of brain hypoxic preconditioning is MPT-pore.

Objective: Using renal scintigraphy to assess the nephroprotective efficacy of hypoxic preconditioning (HP) during myocardial revascularization under the conditions of artificial circulation (AC)., Materials and Methods: We examined a total of forty-seven patients with CAD (mean age 52.81 +/- 1.40 years) who endured coronary artery bypass grafting (CABG) under AC. All patients were randomly divided into 2 groups:patients (n = 16) who during CABG underwent HP (study group) and those (n = 31) without renal protection (comparison group). HP was performed in the mode of one cycle of 10-minute hypoxemia followed by a 5-minute period of reoxygenation. Dynamic radionuclide renal scintigraphy with 99mTc-DTPA was carried out before and 6-7 days after surgical treatment with calculating the parameters of the filtrating and excreting renal function., Results: The comparison-group patients after CABG were found to have negative dynamics of the parameters of the renal filtration activity. Thus there was a significant decrease in the mean values of total and individually for each kidney glomerular filtration rate (GFR) combined with deceleration of the blood clearance. Besides patients of this group showed a significant increase in the mean value of the half-period of excretion of the indicator from the pelvicalyceal system of the left kidney and the parenchyma of the both kidneys. The study group patients showed no alterations in the values of the filtration activity of the kidneys as compared with the baseline measures, with the exception of the GFR of the right kidney. Thus a decrease in the filtration function of either one kidney or both kidneys under the influence of non-pulsating blood flow was observed only in three (19%) patients and was not pronounced. Alterations in the indices reflecting the excretory renal function in the study group were also insignificant., Conclusion: Radionuclide renal scintigraphy makes it possible to objectively and with a high level of the informative value to determine the degree and pattern of the effect of open-heart surgery on renal functional activity. HPC exerts a nephroprotective effect action on the renal functional activity in patients with endured open-heart surgery in the conditions of assisted circulation.

It has been systematized modern data on the preconditioning at a distance and a tolerance of a heart, a brain and other organs to ischemia-reperfusion injury. It has been performed an analysis of the published works on the role of autonomic nervous system and humoral factors in the development of resistance to pathogenic action of ischemia and reperfusion. It has been shown that adenosine, bradykinin, opioid peptides, calcitonin gene-related peptide and also signaling cascade involved nitric oxide, free radicals, protein kinases, mitochondrial ATP-sensitive K+ -channel, mitochondrial permeability transition pore play an important role in the mechanism of cardioprotective action of remote preconditioning.

Different types of hypoxia, including several new models, protect the brain against complete global ischemia. Hypoxic (stay in hermetic chamber without or with consumption of CO2 and H2O exhaled), circulatory (bleeding), hematic (injections of NaNO2, CoCl2, NiCl2) and tissue (histotoxic) hypoxia (K2-malonate injection) increases cerebral ischemic tolerance in early terms (in hours). Intracerebroventricular injections of NaNO2, CoCl2, NiCl2 and K2-malonate in nontoxic doses have weak effects. These substances act by peripheral mechanisms. Increased ischemic tolerance is accompanied by pronounced hypothermia which closely correlates with a neuroprotective effect. This shows using tolerant strategy.

Ischemic tolerance (preconditioning) is taken to mean a short ischemic episode subfatal to cells that activates the protective endogenous mechanisms that ensure tolerance of further longer and more severe episodes of ischemia by the organ (tissue). The present review attempts to analyze information on ischemic preconditioning in the light of the possible use for brain protection. Experimental models, temporal aspects, crossed tolerance, genomic reaction, and mechanisms are considered. There is evidence for human ischemic preconditioning.

The protective effect of hypoxic preconditioning on the development of depressive states in rat experimental models has been studied. Three-trial preconditioning by repetitive hypobaric hypoxia (360 mm Hg, 2h) prevented triggering of behavioral depression, pituitary-adrenal axis hyperactivity and impairment of negative feedback in dexamethasone test in rats following inescapable aversive stress in the model of endogenous depression. Anxyolytic and antidepressant-like effect of the hypoxic preconditioning was not less than that of tetracyclic antidepressant ludiomil. The findings reveal that the preconditioning by intermittent hypobaric hypoxia increases tolerance to psychoemotional stress, possesses potent anxiolytic and antidepressant-like effects and might be applied for prevention of depressive episodes.

Though the mechanisms of hypoxic-ischemic preconditioning are under investigation, it is considered that nitric oxide can play a critical role in the formation of this phenomenon. Experiments on white rats for study of cerebral hemisphere masses were carried out on 22-nd day after 3-hours hypoxic-ischemic exposure: (a) on 7-day-old rats, (b) on 7-day-old rats but 30 minutes before this exposure animals 3-times underwent short lasting (5 minutes) hypoxic-ischemic impacts (preconditioning), (c) same as previous experimental condition, but 15 minutes before beginning of preconditioning, animals were intraperitoneally injected either by non selective nitric oxide synthase (NOS) inhibitor (L-NAME) or (d) inducible NO synthase (iNOS) selective inhibitor--aminoguanidine. Received results showed that 3-times preconditioning efficiently protect brain from three hours hypoxic-ischemic exposure. It is evident that nitric oxide play a critical role in this protection--it completely eliminated morphological manifestation of hypoxic-ischemic preconditioning while aminoguanidine--just partially decreased the volume of brain hypoxic-ischemic ischemic damage.

Three pathways to increase tolerance to global cerebral ischemia have been worked out: (1) the use of inhibitory neurotransmitters and their analogues; (2) injection of neuroleptics; (3) hypoxic preconditioning. We revealed the importance of receptors, K(ATP) channels and induction of hypothermia in neuroprotective mechanisms of these influences.

Aim: To assess effect of dipyridamole on ischemic preconditioning (IP) in patients with coronary artery disease by paired bicycle ergometer exercise tests (BETs)., Material and Methods: Patients (men, n=12, age 51.7+/-2.5 years) with class II-III stable angina pectoris underwent paired BETs (tests 1 and 2 at 15 min intervals). Test 1 was regarded as baseline and test 2 as the preconditioning one. In 72 hours another pair of BETs was carried out (tests 3 and 4) with same time interval in between. Before second pair of tests the patients received 75 mg of dipyridamole orally., Results: Significant improvements of several parameters of ECG were observed during repeat BETs (increased exercise duration, maximal heart rate and double product, decreased maximal ST-depression and number of ECG leads with >1 mm ST depression). These data suggested the presence of IP phenomenon in both paired BETs. However only test after dipyridamole was associated with significant increase of work load (from 82.4+/-10.5 to 96.4+/-10.1 W, p=0.033), shortening of ST-depression recovery time (from 367+/-45 to 254+30 s, p=0.032) and increase of increment of exercise duration (from 34+/-15 to 81+/-17 s, p=0.034). Number of ECG leads on with segment ST depression >0,1 mv was significantly less during test 4 compared with test 2 (2.6+/-0.4 and 3.4+/-0.5; p=0.045). This data reflected increase of ischemic threshold during test 4., Conclusion: Dipyridamole (75 mg orally) augmented IP in patients with coronary artery disease during repeated BETs.

Brief periods of ischemia and reperfusion are able to protect the heart from irreversible injury induced by consequent prolonged ischemia and reperfusion stress. This phenomenon called ischemic preconditioning (IP) may limit infarct size, enhance postischemic recovery of cardiac function, reduce reperfusion arrhythmias and vascular dysfunction. Mechanisms of IP are tightly related to alterations of efficiency of metabolic pathways and maintenance of ion homeostasis in ischemic cardiac myocytes. They may be initiated by formation of various triggers (adenosine, bradykinin, NO, free oxygen radicals etc.) that interact with receptors of cardiomyocytes and vascular endothelium or directly alter activity of enzymes. These interactions lead to activation of different pathways of intracellular signal conduction involving contribution of mediators and complex of the secondary messengers of IP. The most typical of them are e-isoform of protein kinase C and the ATP-dependent potassium channels. Biochemical pathways of molecular signaling in the preconditioned myocardium may be different, but always have same final effectors -- intracellular metabolism and ion homeostasis. As a rule, successfully preconditioned myocardium exhibits improved energy state of ischemic cardiomyocytes, reduced Ca(+) overload and attenuated damage of the sarcolemma and mitochondrial membranes. These beneficial changes provide myocardial salvage under conditions of deficient supply of cardiomyocytes with energy substrates and oxygen. Stimulation of adaptative mechanisms of IP is possible with specific receptor agonists or activation of secondary messenger pathways without causing ischemia. At present study of such pharmacological approaches to treating ischemia is a high priority task. In clinical practice selective openers of ATP-dependent potassium channels, A(1) and A(2) adenosine receptor agonists and Na(+)/H(+) exchange inhibitors are used to affect the final effectors of signaling pathways. These pharmacological agents are explored in transluminal coronary angioplasty, cardiac surgery and organ transplantation.