[The phenomenon of ischaemic postconditioning of the heart. Analysis of clinical data]. / Fenomen ishemicheskogo postkonditsionirovaniia serdtsa. Analiz klinicheskikh dannykh.

Data concerning the effectiveness of ischaemic postconditioning (IPost) in treatment of acute ST-segment elevation myocardial infarction (STEMI) are controversial. The authors of the majority of studies have reported an anti-apoptotic and infarct reducing effect of IPost. There is evidence that IPost reduces the microvascular obstruction zone, increases coronary flow reserve, and improves the pumping functions of the heart. At the same time, there are publications reporting that IPost does not influence the course of acute STEMI. It was established that IPost protects the heart from reperfusion injury occurring after cold cardioplegia in patients with tetralogy of Fallot.

[Ischaemic postconditioning of the heart. Analysis of experimental findings]. / Ishemicheskoe postkonditsionirovanie serdtsa. Analiz eksperimental'nykh dannykh.

The data of publications regarding the influence of experimental atherosclerosis on the infarct-limiting effect of ischaemic postconditioning (IPost) are controversial. The presented information is suggestive that ageing removes or attenuates the infarct-limiting effect of postconditioning but does not influence the antiarrhythmic effect of IPost. The majority of experimental data report that streptozotocin-induced diabetes removes the infarct-limiting effect of IPost. The data concerning type 2 diabetes mellitus are controversial: some authors state that such diabetes completely levels the cardioprotecting effect of IPost; others tell that it only attenuates but does not remove the infarct-limiting effect of IPost. Postconditioning in rats with elevated arterial pressure prevents the appearance of reperfusion cardiac contractility dysfunction and exerts an infarct-limiting effect. Cardiac hypertrophy, postinfarction remodelling and dilatation cardiomyopathy do not influence the infarct-limiting and inotropic effect of postconditioning. According to the majority of publications, IPost enhances the inotropic and cardioprotecting effect of cardioplegia. The data of literature sources regarding the effect of gender on efficacy of IPost are limited.

CB-Receptor Agonist HU-210 Mimics the Postconditioning Phenomenon of Isolated Heart.

CB receptor agonist HU-210 exhibits an infarction-limiting effect during in vitro reperfusion of the heart after focal ischemia. This effect is paralleled by a decrease in left-ventricular developed pressure and double product. In addition, HU-210 reduces end-diastolic pressure during the reperfusion period, which indirectly attests to reduced Ca2+ overload of cardiomyocytes.

[CHRONIC CONTINUOUS NOR-MOBARIC HYPOXIA AUGMENTS CELL TOLERANCE TO ANOXIA(REOXYGE-NATION: THE ROLE OF PROTEIN KINASES].

The study evaluated the role of protein kinase C, PI3-kinase and tyrosine kinases in the cardi-oprotective effect of the chronic continuous normobaric hypoxia (CCNH). Adaptation to CCNH was provided by placing the rats in an atmosphere with a low content of O2 (12 %) during 21 days. Anoxia-reoxygenation of isolated cardiomyocytes of intact rats caused the deaths of 16.5 % of the cells and the lactate dehydrogenase (LDH) release of them. A similar effect on isolated cardiomyocytes of adapted rats caused the death of only 6.8 % of the cells and less pronounced increase in LDH release. Preincubation of cells for 25 minutes with one of the protein kinases inhibitors: che-lerythrine (10 |mM/l); rottlerin (1 |j.M/l); genistein (50 |mM/l) eliminated the adaptive increase in cell survival and reduction of LDH release. Incubation of cells with PI3-kinase blocker wortman-nin (100 nM/l) had no effect on the percentage of cell death of adapted animals and LDH release from them after anoxia-reoxygenation. The authors believe that the cytoprotective effect of chronic normobaric hypoxia is realized through activation of protein kinase C-5 and tyrosine kinases. Kinase PI3 - is not involved in the implementation of protective actions CCNH.

[PROSPECTS OF USING ADENOSINE, OPIOID AND BRADYKININ RECEPTOR AGONISTS FOR PHARMACOLOGICAL IMITATION OF HEART POSTCONDITIONING PHENOMENON.]

It is known that agonists of adenosine, opioid, and bradykinin receptors mimic the phenomenon of ischemic postconditioning. There is no commonly accepted notion of what adenosine receptor subtypes must be activated to increase cardiac resistance to reperfusion injury. Intravenous infusion of adenosine or intracoronary administration of adenosine produce infarct-limiting effect and contribute to a more complete restoration of coronary blood flow after recanalization of the infarct-related coronary artery. It was confirmed that opioids mimic the phenomenon of postconditioning. According to obtained data, the most promising compounds for the prevention of reperfusion injury of the heart are κ(1)- and δ(2)-opioid receptor agonists, as they produce the infarct-limiting effect, while not reducing the arterial pressure.

[MIMICKING ISCHEMIC PRECONDITIONING PHENOMENON THROUGH THE IMPACT ON THE CANNABINOID RECEPTORS: ROLE OF PROTEIN KINASE AND NO-SYNTHASE].

It was established that CB 1-receptors stimulation mimic preconditioning phenomena. Since the cardioprotective effect of cannabinoid HU-210 is occurred both in the experiments in vivo and in the experiments in vitro there are reasons to believe that the protective effect of HU-210 is me- diated via an activation of cardiac CB1-receptors. It is established that the cardioprotective effect of cannabinoid HU-2 10 is depends upon a stimulation ofprotein kinase C whereas NO-synthase is not involved in protective impact of CB1-receptor stimulation.

Role of MEK, PI3, p38, Tyrosine, and mTOR Kinases in Regulation of Heart Resistance to the Arrhythmogenic Action of Short-Term Ischemia and Reperfusion.

MEK, PI3, p38, tyrosine, and mTOR kinases are not involved in the regulation of heart resistance to the arrhythmogenic action of short-term ischemia/reperfusion in non-adapted rats.

Comparative analysis of early and delayed cardioprotective and antiarrhythmic efficacy of hypoxic preconditioning.

Hypoxic preconditioning produces an infarct-limiting effect both in the early and delayed periods. The increase in heart resistance to ischemia-repefusion was more pronounced after early preconditioning. Hypoxic preconditioning did not change heart resistance to the arrhythmogenic effect of coronary occlusion and reperfusion.

[Role of thyroid system in adaptation to cold].

Adaptation to cold promotes an increase in blood T3 and T4 levels in men and animals. The long-term cold exposure can induce a decrease in concentration of serum total and free T3 in human due to an enhancement of this hormone clearance. Endogenous catecholamines during adaptation to cold raise iodothyronine deiodinase D2 activity in brown fat due to α1-adrenergic receptor stimulation. Triiodothyronine is an inductor of iodothyronine deiodinase expression in brown fat, liver and kidney. Iodothyronine deiodinase D2 plays an important role in adaptation of organism to cold contributing to the high adrenergic reactivity of brown fat. At adaptation to cold T3 interacts with T3Rß, it is formed T3Rß-RXR complex, which binds to DNA with following transcription of UCP-1 and UCP-3 genes and UCP-1 and UCP-3 protein synthesis and uncoupling oxidative phosphorylation and an increase in heat production, where T3Rß is T3-receptor-ß, RXR is retinoid X-receptor, UCP is uncoupling protein. Triiodothyronine contributes to normal response to adrenergic agents of brown fat due to T3Rα activation. Sympatho-adrenomedullary and thyroid systems act as synergists in adaptation to cold.

[Perspective of use of agonists of adenosine and opioid receptors for prevention of reperfusion damages of heart. Analysis of experimental and clinical data].

In Russia inhospital lethality after acute myocardial infarction is 16.5-16.7%. The part of patients perishes even after recanalisation of infarct-related coronary artery as a result of reperfusion cardiac injury. Experimental data indicate that adenosine receptor agonists and opioids can prevent reperfusion damages of heart that is mimic postconditioning phenomena. Data of clinical observation show that adenosine during intravenous infusion or intracoronary administration during thrombolysis or percutaneous coronary intervention exert infarct reducing effect and eliminate manifestation of of "no-reflow" phenomenon. Clinical data indicate that morphine is able to prevent cardiac reperfusion injury in human. Thus, analysis of published data testifies that adenosine and opioid receptor agonists can be prototype for development of drugs for prophylaxis of reperfusion heart injury.

[Adaptive phenomenon of ischemic postconditioning of the heart. Perspectives of clinical use].

Analysis of experimental data indicates that aging, metabolic syndrome may be serious obstacle against realization of cardioprotective effect of postconditioning. The moderate hypercholesterolemia, postinfarction cardiosclerosis and cardiac hypertrophy do not abolish protective effect of postconditioning in experimental animals. The issue whether diabetes mellitus and arterial hypertension affect an efficacy of postconditioning is a subject of discussion. Clinical investigations testify on cardioprotective impact of postconditioning in patients with acute myocardial infarction and cardiosurgery patients. At the same time, it is remained unclear when after coronary artery occlusion postconditioning exhibits cardioprotective effect. It is remained unknown how do affect aging, diabetes mellitus, metabolic syndrome, arterial hypertension, myocardial hypertrophy, cardiac postinfarction remodeling and efficacy postconditioning in clinical praxis. It is required a further clinical investigations turning the development pharmacological approaches to prophylaxis of reperfusion injury of the heart.

[Problem of end-effector of ischemic postconditioning of the heart].

Analysis of literature source indicates that main pretenders to the role of end-effectors of ischemic postconditioning of the heart are: 1) Ca(2+)-dependent K+ channel of BK-type (big conductance K+ channel), 2) mitoK(ATP) channel (mitochondrial ATP-sensitive K(+)-channel), 3) MPT pore (mitochondrial permeability transition pore). At the same time, some investigators consider that mitoK(ATP) channel is only an intermediate link in the series of signaling events ensured an increase in cardiac tolerance to impact of ischemia-reperfusion. The most likely end-effector of the three structures is MPT pore. Alternatively, it is possible, that unique molecular complex appearing a single end-effector of postconditioning does not exist. Perhaps, that there are several effectors ensured cardioprotective effect of adaptive phenomenon of postconditioning.

[Neuroprotective and cardioprotective effects of hypothermic preconditioning].

The literature data testify the there is an early and delayed hypothermic preconditioning of brain. Neuroprotective effect of early hypothermic preconditioning is a result of activation of adenosine A1 receptors, KATP-channels. Ras protein and predetermined by a decrease in the synthesis of NO*. The infarct-sparing effect of delayed hypothermic preconditioning of brain is depended upon protein synthesis de novo. The presented data demonstrate that hypothermic preconditioning prevents cardiomyocyte necrosis in response to ischemia-reperfusion, improves pump function of the heart during reperfusion period, exerts an antiarrhythmic effect. The hypothermic preconditioning exerts more pronounced cardioprotective effect than ischemic preconditioning. The protective impact of hypothermic preconditioning is depended upon activation of protein kinase C, AMP-activated protein kinase (AMPK) and inhibition of MPT pore. The reactive oxygen species are triggers and mediators of hypothermic preconditioning of heart.

[Hypoxic preconditioning as novel approach to prophylaxis of ischemic and reperfusion damage of brain and 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.

[Uncoupling proteins and their role in the regulation of brain and heart tolerance to impact of ischemia and reperfusion].

Experimental data indicate that moderate uncoupling oxidative phosphorylation induces reduction in production of reactive oxygen species (ROS) and promotes an increase in survival of neurons and cardiomyocytes under hypoxia and re-oxygenation conditions. Uncoupling proteins (UCP) are expressed by cardiomyocytes and neurons. These proteins are involved in the thermogenesis, inhibit ROS generation by mitochondria, reduce deltaphi, elevate respiration rate of these organelles. It was established that UCP contributed to the elevation of cardiomyocyte and neuron tolerance of an impact of hypoxia and re-oxygenation. They also promote cell resistance to oxidative stress. Experimental data indicate the important role of the UCP in the neuroprotective and cardioprotective effects of ischemic preconditioning. At the same time, real contribution of the UCP in preconditioning is still to be verified.

[Signalling mechanisms of cardioprotective effect of hypothermic preconditioning].

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.

[Role of heat shock proteins in the mechanism of cardioprotective effect of transient hyperthermia and delayed preconditioning].

This review article focuses on discussing the role of the heat shock proteins (HSP) in myocardial protection against ischemia-reperfusion injury. In the present time, it has also been recognized that HSP may responsible for the increase in cardiac tolerance to ischemia-reperfusion after heat shock or after delayed ischemic preconditioning. The enhancement of the HSP expression in transgenic mice promotes an elevation of cardiac resistance to ischemia-reperfusion. The same effect is induced by transfection of the HSP genes. It has been established that deletion of the HSP70.1 and HSP70.3 genes abolishes a cardioprotective effect of delayed preconditioning. The mechanism by which HSP protect the heart against ischemia-reperfusion remains obscure. It has been proposed that HSP protect the heart via refolding proteins, an increase in 5'-nucleotidase activity, an improvement of Ca(2+)-pump function in sarcoplasmic reticulum during ischemia-reperfusion.

[Role of heat shock proteins, aldose reductase, Bcl-2 protein and microRNA in the mechanism of delayed preconditioning of heart].

Analysis of published data allows affirming that heat shock proteins (HSP) play an important role in the mechanism of cardioprotective effect of delayed preconditioning. However, HSP in all probability are non-end effectors but mediators of preconditioning because a peak of their levels in myocardium does not concur with maximal elevation of cardiac tolerance to impact of ischemia and reperfusion. There are bases to think that aldose reductase and Bcl-2 protein are claimants to the role of end-effectors of delayed preconditioning but microRNAs serve as mediators of forming increased cardiac tolerance to ischemia-reperfusion.

[Problem of end effector of delayed ischemic preconditioning of the heart].

Analysis of published data on the problem of end effector of delayed ischemic preconditioning of the heart presented evidence that NO-synthase, superoxide dismutase, cyclooxygenase-2, heme oxygenase-1 are the main pretenders to the role of end effector of delayed ischemic preconditioning.

[Hypoxic preconditioning is a phenomenon increasing tolerance of cardiomyocytes to hypoxia-reoxygenation].

The work covers the problem of hypoxic preconditioning (HP) carried out in isolated cardiomyocytes. Papers on delayed HP in vivo are comparatively few, and only some single works are devoted to early preconditioning in vivo. It has been established that the HP limits necrosis and apoptosis of cardiomyocytes and improves contractility of the isolated heart after ischemia (hypoxia) and reperfusion (reoxygenation). It was found that adenosine was a trigger of iP in vitro. It was proved that NO* was a trigger of HP both in vitro and in vivo. It was shown that reactive oxygen species also were triggers of hypoxic preconditioning. It was shown that ERK1/2 and p38 kinase played important role in delayed HP in vitro.