[Chronic exposure to cold is adaptation without stress ].

It has been established that prolonged continuous cold exposure (+4°C for 24 hours/day, four weeks) causes an increase in brown fat weight, hypertrophy of the adrenal gland, spleen and did not affect cortisol and corticosterone levels in the blood serum in rats. Gastric ulcers were not observed in the rats. Chronic intermittent exposure to cold (+4°C, 8 hours/day, 4 weeks) promoted an increase in the weight of brown fat, spleen, kidneys and heart, stomach ulcers and an alteration of cortisol and corticosterone levels were did observed. Short-term intermittent exposure to cold (+4°C, 1.5 hours/day, 4 weeks) did not affect the weight of brown fat, but promoted an increases in the weight of body, spleen, kidneys and heart, stomach ulcers were not found, cortisol and corticosterone levels was not changed.

[IMPACT OF LONG-TERM ADAPTATION TO COLD ON THE STATE OF CARDIOVASCULAR SYSTEM].

The inhabitancy in Far North increases a probability of development of coronary heart disease, acute myocardial infarction and arterial hypertension. Catecholamines and NO deficiency play a substantial role in the development of cold hypertension but are not involved in acclimatization cardiac hypertrophy. Data of in vivo experiments indicate in favor of an involvement of α-adrenergic receptors (ARs) in the mechanism of an appearance of cold hypertension. Cold acclimatization promotes an elevation of ß3-AR density and decrease in ß1-AR and ß2-AR quantity on sarcolemma of cardiomyocytes. Experimental data indicate about the important role of aldosterone and angiotensin-II in the development of acclimatization hypertension. Catecholamines, aldosterone and angiotensin-II are not involved in cold hypertrophy of heart. Experimental data say on the important role of endothelin ETA-receptor in the formation of cold hypertrophy of heart and cardiofibrosis. Thyroid hormones play substantial role in the development of cold hypertension and cardiac hypertrophy.

[Role of Bradikynin in the Mechanism of Ischemic Preconditioning of the Heart. Prospects of Bradykinin Application in Cardiosurgical Praxis].

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.

[Reactive oxygen species are triggers and mediators of an increase in cardiac tolerance to impact of ischemia-reperfusion].

Reactive oxygen species (ROS) are triggers of ischemic preconditioning (IP). On the role of intracellular messengers of such cardioprotective effect of preconditioning claim: O2*, H2O2, OH*. However, we cannot exclude the possibility that other reactive oxygen metabolites also involved in the IP. Presented data suggest that IP enhances the production of ROS. The source of ROS may be mitochondrial respiratory chain and NADPH oxidase. Exogenous reactive oxygen species (O2*, H2O2) mimic the cardioprotective effect of preconditioning. Preconditioning prevents free radical damage of the heart during ischemia-reperfusion. The protective effect of IP is the consequence of reducing the production of ROS or the result of increased formation of endogenous antioxidants. Antioxidant enzymes are not involved in the protective effect of IP. Cardioprotective effect of many compounds (bradykinin, opioids, acetylcholine, phenylephrine, tumor necrosis factor-α, volatile anesthetics, protonophores, diazoxide, angiotensin II) depends on the increased production of ROS.

[Opioids--triggers of adaptive phenomenon of ischemic preconditioning of heart].

It was established that short-term ischemia/reperfusion evokes an increase in myocardial tissue of enkephalin levels. A blockade of delta-opioid receptors abolishes the cardioprotective effect of ischemic preconditioning both in vivo and in vitro. An inhibition of kappa-opioid receptors abolishes the cardioprotective effect of ischemic preconditioning only in vitro. Agonists of mu-, delta1- delta- and kappa1-opioid receptors mimic the cardioprotective effect of preconditioning. Consequently, it can be argued that endogenous opioid peptides are triggers of ischemic preconditioning.

[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.

[Signaling mechanism of cardioprotective effects of opioids].

It has been established that G(i/o)-proteins are an intermediate link that provides intracellular signaling between opioid receptors and protein kinases. Our investigations have shown that protein kinase C is involved in realization of the anti-necrotic and anti-apoptotic effects of opioids. PI3 and Akt kinases are involved in the cardioprotective effect of opioids. MEK1/2, ERK1/2, Src and JAK2 kinases play an important role in the cardioprotective effect of opioids. Further study of the participation of JNK, p70s6K and GRK2 in the opioid-induced increase of cardiac tolerance to ischemia and reperfusion is required. NO-synthase plays an important role in the cardioprotective action of opioids. Transactivation of opioid and adenosine receptors is an important element in the development of cardiac tolerance to ischemia and reperfusion. Opioid transactivation of EGF receptor is a connecting link between opioid receptors and ERK1/2 and PI3 kinase cascades.

[Receptor and signalling mechanisms of antiarrhythmic effects of ischemic pre-conditioning].

It has been established that ischemic preconditioning (IP) exerts significant antiarrhythmic effects, as revealed in experiments both in vivo and in vitro. Consequently, processes arising within the myocardium play a key role in adaptive tolerance to ischemia/reperfusion. Preconditioning enhances cardiac electrical stability both in animals and humans. The antiarrhythmic effect of preconditioning is transient, with enhanced tolerance to ischemia-reperfusion triggered arrhythmogenesis dissipating 2-3 after the IP stimulus. The basis of the antiarrhythmic and cardioprotective effects of IP may differ. Preconditioning improves conduction of the cardiac electrical impulse, thereby preventing occurrence of re-entrant arrhythmias. NO-synthase and peroxynitrite play an important role in evolution of the antiarrhythmic effects of IP. Furthermore, intracellular Ca2+ may be a trigger of improved cardiac electrical stability after IP. It has been established that G(i/o)-protein coupled receptors are not involved in antiarrhythmic effects of IP, whereas bradykinin B2 and alpha1 adrenergic receptor activities are involved in IP-dependent improvements in cardiac electrical stability. Adenosine receptors contribute only partially to these effects. In terms of signalling mechanisms, protein kinase C appears essential to the antiarrhythmic effects of IP, whereas PI3-kinase and cyclooxygenase do not appear to be significantly involved. It has also been established that cardiac mast cells are involved in IP effects. Some data indicate that increased cardiac electrical stability with preconditioning depends upon mitoK(ATP) channel opening. Other data provide evidence that antiarrhythmic effects of preconditioning depends upon sarcK(ATP) channel opening. Some data indicate that an increase in electrical stability of heart after preconditioning depends upon mitoK(ATP) channel opening. Other data are evidence that antiarrhythmic effect of preconditioning depends upon sarCK(ATP) channel opening. Further work is needed to fully delineate the mechanistic basis of antiarrhythmic effects of IP.

[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.

[Perspective of creation of drugs on basis of opioids increasing cardiac tolerance to pathogenic impact of ischemia reperfusion].

It was established that delta- and kappa1-opioid receptor (OR) stimulation both in vivo and in vitro promotes a decrease of infarct size/area at risk (IS/AAR) ratio during ischemia and reperfusion of heart. mu-OR activation increases a tolerance of isolated perfused heart to impact of ischemia and reperfusion but has no effect on IS/AAR index in vivo. The ORL1-receptor agonist nociceptin does not exert IS/AAR ratio in vivo. Delta- and kappa1-OR stimulation prevents cardiomyocyte apoptosis during ischemia and reperfusion of heart. The delta- and kappa1-OR agonists mimic infarct-reducing effect of postconditioning. The OR inhibition does not impact IS/AAR index both in vivo and in vitro. The delta1-, delta2- and kappa1-OR agonists are the most perspective group of opioids for creation of drugs increasing cardiac tolerance to pathogenic impact of ischemia and reperfusion.

[Phenomenon of heart ischemic postconditioning].

Authors of review analyzed papers on problem of heart ischemic postconditioning. In the review, it was demonstrated that postconditioning decreased an infarct size, prevented cardiomyocytes apoptosis, improved cardiac contractility in reperfusion period, augmented cardiac tolerance to arrhythmogenic impact ofreperfusion, prevented neutrophil invasion into the reperfused heart, abolished reperfusion endothelial dysfunction and suppressed reperfusion oxidative stress in myocardium.

[Endogenous opioid system as a mediator of acute and long-term adaptation to stress. Prospects for clinical use of opioid peptides].

It has been well established that opioid peptides (OPs) affect various hormonal systems. Opioids exhibit stress-limiting and gastro-protective effects in stressed animals, acting via mu- and delta-opioid receptors (OR). Peripheral mu-OR stimulation by endogenous and exogenous opioids increases cardiac tolerance to pathological consequences of stress. Enhancement ofprostacyclin synthesis, decrease of thromboxane production as well as suppression of lipid peroxidation can be directly responsible for cardioprotective effects of OPs in stressed animals. Adaptive responses are accompanied by increased OP levels in blood and tissues. Reduction of ventricular arrhythmias induced by repeated short-term immobilization stress is mediated via mu-OR stimulation by endogenous opioids, while delta-OR account for an antiarrhythmic effect of adaptation to chronic intermittent hypobaric hypoxia. The mechanism of infarct size-limiting effect of continuous normobaric hypoxia involves both mu- and delta-OR stimulation. Peptide OR agonists can be considered in future clinical practice for treatment of withdrawal syndrome, stress-related cardiac disease or myocardial injury caused by ischemia-reperfusion insult.

[Intracellular mechanisms of cardioprotection during adaptation to hypoxia. Triggers and kinase cascades].

Adaptation to chronic hypoxia increases myocardial ischemic tolerance to injury caused by acute ischemia-reperfusion. In this article, we provide a brief overview of current literary data dealing with signalling mechanisms that can play a certain role in chronic hypoxia-induced cardioprotection. It has been shown that reactive oxygen species are major contributors to induction of the protective cardiac phenotype. In this context, we discuss the role of cytochromes, NADPH oxidase, heme oxygenase-1, mitochondrial monoamme oxidase, and prolyl 4-hydroxylase in triggering adaptive responses resulting in myocardial salvage. Moreover, we point to other cytoprotective proteins that can be involved in the protection from chronic hypoxia, such as protein kinase C, mitogen-activated protein kinases, 5'AMP-activated protein kinase, NO-synthases, mitochondrial ATP-sensitive K+ channels, Ca(2+)-activated large-conductance K+ channels, and MPT pore. Understanding the molecular mechanism of this long-lasting form of cardioprotection may help in providing basis for development of future therapeutic strategies to protect ischemic heart.

[The role of sarcolemmal and mitochondrial K(ATP)-channels in realization of the cardioprotection and antiarrhythmic effect of different regimens of hypobaric adaptation].

The aim of study was an investigation of the role of different types of K(ATP)-channels in the increased tolerance to the rat heart to ischemic and reperfusion arrhythmias after the different regimes ofhypoxic adaptation. Wistar rats were exposed to an intermittent hypoxia in two different regimens: 5000 m, 6 h/day during 6 weeks or 7000 m, 8 h/day during 7 weeks. It has been found that both types of adaptation increase cardiac tolerance to arrhythmogenic impact of acute ischemia, but only training at 7000 m induces cardioprotective effect. Inhibition of mitK(ATP)-channels by pretreatment with 5-hydroxydecanoate (5 mg/kg) or MCC-134 (3 mg/kg) completely abolishes cardioprotection and antiarrhythmic effect of adaptation in the 7000 m regimen. Antiarrhythmic effect of adaptation in the 5000 m regimen is eliminated by injection of glibenclamide (0.3 mg/kg), an inhibitor of sarcolemmal and mitochondrial K(ATP)-channels. It has been proposed that in cardioprotection of adaptation in the 7000 m regimen mitK(ATP)-channels play a considerable role, whereas in the 5000 m regimen sarcK(ATP)-channels are involved. Antiarrhythmic effect and cardioprotectio has not been found during experiments on the isolated perfused rat heart.

[Significance of ATP-sensitive K(+)-channel in the mechanism of antiarrhythmic and cardioprotective effect of adaptation to intermittent hypobaric hypoxia].

Adult male Wistar rats were exposed to intermittent hypobaric hypoxia (5000 m, 6 h/day, 6 weeks). It has been found that such mode of adaptation increased cardiac tolerance to arrhythmogenic action of a 45-min coronary artery occlusion but did not change an infarct size/area at risk (IS/AAR) ratio. In a separate series, rats were exposed to stronger intermittent hypobaric hypoxia (7000 m, 8 h/day, 6 weeks) and subjected to 20-min coronary artery occlusion and 3-h reperfusion on the day after the last hypoxic exposure. It has been established that in this case adaptation decreased the IS/AAR ratio, increased cardiac tolerance to arrhythmogenic action of reperfusion but had no effect on the incidence of ventricular arrhythmias occurred during ischemic period. We found that cardioprotective and antiarrhythmic effect of adaptation to the "altitudes" of 7000 m and antiarrhythmic effect of adaptation to the "altitude" of 5000 m is mediated via K(ATP)-channel activation.

[The complex adaptogenic drug tonizid attenuates myocardial contractile dysfunction and prevents irreversible cardiomyocytic damages in ischemia and reperfusion of the isolated heart].

A course administration of the complex plant adaptogenic drug tonizid was ascertained to increase murine exercise tolerance. In addition, the drug increased murine survival during hypobaric hypoxia (at an altitude of 10,500 m upon 20-min exposure). A model of total 35-min ischemia and that of 30-min reperfusion of the rat isolated heart were used by the Langendorff technique. The course administration of tonizid attenuated a reperfusion decrease in the left ventricular pressure and in the rate of contraction. However, tonizid did not prevent a reperfusion reduction in heart rate, a decrease in the rate of relaxation and an elevation of end diastolic pressure. Tonizid lowered the level of creatine kinase in the venous effluent from the isolated rat heart during reperfusion. At the same time, the plant adaptogen exerted no effect on the incidence of ventricular arrhythmias and coronary flow. It has been suggested that tonizid is an adaptogenic drug that attenuates contractile dysfunction and prevents irreversible cardiomyocytic damage during ischemia and reperfusion of the isolated heart.

[Endogenic opioid peptides and antiarrhythmic effect of adaptation to stress]. / Endogennye opioidnye peptidy i antiaritmicheskii éffekt adaptatsii k stressu.

Adaptation of rats to repeated short-term immobilization increases cardiac resistance to an arrhythmogenic action of coronary artery occlusion (10 min) and reperfusion (10 min) in rats anesthetized with ketamine and artificially ventilated. We examined the role of opioid receptors and endogenous opioid peptides in the development of this antiarrhythmic effect produced in response to repeated periods of immobilization stress. We found that repeated daily stress during a 15-day period resulted in an increase of leu-enkephalin in blood plasma, in the suprarenal gland and myocardium. Adaptation to stress also resulted in an increase in beta-endorphinl-31 in blood plasma, the hypophysis, hypothalamus and midbrain. Pretreatment with selective mu, delta and cappa opioid receptor (OR) antagonists had no effect on the incidence of occlusion and reperfusion-induced arrhythmias in non-adapted control rats. However, pretreatment with the selective muOR antagonist CTAP (0.5 mg/kg) intravenously completely abrogated the antiarrhythmic effect of adaptation. Selective delta and cappa receptor antagonists did not affect the antiarrhythmic effect of adaptation. Prior administration of the selective muOR agonist DALDA (0.1 mg/kg) decreased the incidence of occlusion and reperfusion-evoked arrhythmias in non-adapted rats. This effect was abolished by pretreatment with the selective muOR antagonist CTAP (0.5 mg/kg). These data suggest that mu opioid receptors and endogenous opioid peptides play an important role in the antiarrhythmic effect of adaptation to stress in rats.

[The opiatergic link between the antiarrhythmic effect of adaptation and hypoxia in the model of ischemia and reperfusion in vivo]. / Opiatergicheskoe zveno antiaritmicheskogo éffekta adaptatsii k gipoksii na modeli ishemii i reperfuzii in vitro.

Rat adaptation to repeated periods of hypobaric hypoxia has been found to prevent the occurrence of ischemic and reperfusion ventricular arrhythmias on a 10-minte coronary artery occlusion model. Inhibition of delta-opioid receptors by intravenous administration of the selective delta-opioid antagonist TIPP (psi) in a dose of 0.5 mg/kg, intravenously (i.v.), completely abolished the antiarrhythmic effect of adaptation to hypoxia. Inhibition of mu-opioid receptors by CTAP (0.5 mg/kg, i.v.) or kappa-receptors by nor-binaltorphimine (9 mg/kg i.v.) had no effect on the incidence cardiac rhythm disturbances in adapted rats during coronary artery occlusion and reperfusion. Therefore, these findings suggest that delta-opioid receptors play an important role in inhibiting arrhythmia formation in this model.

[The role of opiate receptors and ATP-dependent potassium channels of mitochondria in the formation of myocardial adaptive resistance to the arrhythmogenic effect of ischemia and reperfusion]. / Rol' opiatnykh retseptorov i ATF-zavisimykh kalievykh kanalov mitokhondrii v formirovanii adaptatsionnoi ustoichivosti miokarda k aritmogennomu deistviiu ishemii i reperfuzii.

Preliminary stimulation of opiate receptors (ORs) by intravenous administration of mu agonist DALDA (0.5 mg/kg), delta 1 agonist DPDPE (0.5 mg/kg), and kappa agonist (-)-U-50.488 (1 mg/kg) increases rat myocardial resistance to arrhythmogenic effect of coronary occlusion (10 min) and reperfusion (10 min). Activation of delta 2 ORs (DSLET, 0.5 mg/kg) has no effect on the incidence rate of ischemic and reperfusion arrhythmias. Preliminary administration of glibenclamide (0.3 mg/kg), an inhibitor of KATP channels, blocks the antiarrhythmic effect of DALDA and DPDPE. Repeated short-term exposures of rats to immobilization within two weeks increases the heart tolerance to the arrhythmogenic effect of coronary occlusion and reperfusion. This effect disappears after administration of CTAP (0.5 mg/kg), a mu antagonist, or injection of 5-hydroxydecanoate (5 mg/kg), an inhibitor of mitochondrial KATP channels. The selective antagonists of delta and kappa ORs have no effect on cardiac adaptation-induced resistance to the arrhythmogenic effect of ischemia and reperfusion. We believe that stimulation of mu, delta, and kappa ORs increases myocardial tolerance to the arrhythmogenic effect of ischemia and reperfusion through activation of KATP channels. The antiarrhythmic effect of the adaptation is mediated by stimulation of mu ORs and mitochondrial KATP channels.