[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.

[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.

[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.

[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.

[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.

[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.

[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.

[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.

[Interrelations between sympathetic adrenal and opioid systems--regulatory mechanism determining cardiac resistance to stress damage]. / Vzaimodeistvie simpatoadrenalovoi i opioidnoi sistem kak reguliatornyi mekhanizm, opredeliaiushchii ustoíchivost' serdtsa k povrezhdaiushchemu deistviiu stressa.

The present paper has analyzed relationship between sympatico-adrenal and opioid systems in the pathogenesis of stress heart damage. Based on the our own results and other investigator data the authors make a conclusion that namely relationship between opioid and sympatico-adrenal systems both on the level of the brain and on the periphery determines a degree of the heart resistance to the injury action of severe stress. Myocardial protection by opioids at stress was found to be mediated by the peripheral mu-opioid receptors and was associated with decrease in an activity of sympatico-adrenal system and a inhibition of its effector part. On contrary central opioid system activation leads to an increase in stress heart damage via an increase in sympathetical influence on the myocardium.

[Ligands of opioid and sigma receptors and correction of cardiac electrical instability in post-infarction cardiosclerosis]. / Ligandy opioidnykh retseptorov, sigma retseptorov i korrektsiia élektricheskoi inestabil'nosti serdtsa pri postinfarktnom kardioskleroze.

Peripheral administration of the mu- or kappa-receptor agonists or sigma-receptor antagonists produced a significant receptor-dependent increase in the ventricular fibrillation threshold in rats with postinfarction cardiosclerosis. The effect was not observed upon administration of the epsilon-receptor agonist beta-endorphin. The receptor and molecular mechanisms of the observed effects are discussed.

[Effects of emoxipine and histochrome on lipid peroxidation and activity of serum MB-creatine phosphokinase in patients with ischemic heart disease during aortocoronary shunting]. / Vliianie émoksipina i gistokhroma na protsess perekisnogo okisleniia lipidov i aktivnost' MB-kreatinfosfokinazy syvorotki krovi bol'nykh ishemicheskoi bolezn'iu serdtsa v dinamike operatsii aorto-koronarnogo shuntirovaniia.

Comparative study of the cardioprotective effect of antioxidants emoxipin and hystochrom was conducted in patients with chronic ICD during and after operation for aorto-coronary shunting. Both drugs effectively inhibited LPO activation and reduced the reperfusion damage to the myocardium recorded according to the release of MB-PCK into the blood. The new antioxidant hystochrom proved to be more effective. Its prevalent effect is associated with its higher antioxidant activity.

[Effect of amiodarone on the extrasystolic and post-extrasystolic contractions of the isolated myocardium of rats and of patients with chronic ischemic heart disease]. / Vliianie amiodarona na ékstrasistolicheskoe i postékstrasistolicheskoe sokrashchenie izolirovannogo miokarda krys i bol'nykh s khronicheskoi ishemicheskoi bolezn'iu serdtsa.

Peculiarities in the extrasystolic and post-extrasystolic contractility of the isolated myocardium of patients suffering from chronic ischemic heart disease (IHD), in comparison to that of intact rats, were studied in the presence of the antiarrhythmic drug amiodarone. The contractility was measured in an isometric mode at an electric stimulation frequency of 0.5 Hz, a temperature of 37 degrees C, and a perfusion rate of 10 ml/min. The extrasystolic action was produced by additional electric pulses generated 25 sec after the base stimulation signal. Amiodarone (1 microgram/ml) reduced the inotropic response of intact rat myocardium to the extrasystolic action, but increased the post-extrasystolic contractility. In the myocardium of IHD patients, the drug also suppressed manifestations of the spontaneous abnormal contractility, while not decreasing the inotropic response to the extrasystolic action. An increase in the post-extrasystolic contractility reached on the average 24% (against 6% in the control). The effect of amiodarone on the post-extrasystolic contractility can be related to a change in the functional state of sarcoplasmic reticulum (SR) and in the content of deposited Ca2+ ions. SR is an important factor of intracellular homeostasis of cardiomyocytes during IHD and can probably influence the antiarrhythmic efficacy of amidarone in IHD patients.

[Processes of protein biosynthesis in cardiac muscle and cardioprotective effect of mu-opiate receptor ligands in immobilization stress]. / Protsessy biosinteza belka v serdechnoi myshtse i kardioprotektornoe deistvie ligandov mu-opiatnykh retseptorov pri immobilizatsionnom stresse.

Immobilization stress leads to the increase of 99mTc-pyrophosphate accumulation in the heart that points to the cardiomyocyte damage. The stress-reaction was accompanied by a decrease of protein synthesis rate in the heart muscle and immunoreactive insulin level in blood plasma and increase of blood plasma cortisol and aldosteron. Pretreatment with agonists mu-opioid receptors DALDA and DAGO (0.1 mg/kg intraperitonealy (i.p.) twice during stress) completely prevented the stress-induction decrease of myocardial protein synthesis rate, heart damage and hormonal imbalance. Cycloheximide administration (0.3 mg/kg i.p.) increased rats myocardial membrane injury during immobilization and reduced cardioprotective effect of DALDA.

[Effect of enkephalins on biosynthesis of myocardial proteins during acute exposure to cold]. / Vliianie énkefalinov na biosintez miokardial'nykh belkov pri ostrom kholodovom vozdeistvii.

Acute cold exposure of organism (4 hours at -20 degrees C) inhibits myocardial protein synthesis and increases cortisol/insulin index in rat blood. Preliminary repeated administration in [D-Ala2, Leu5, Arg6]-enkephalin (dalargin) prevents the decrease of myocardial protein synthesis rate after cold stress and decreases cortisol/insulin ratio. Pretreatment with naloxone at dose of 0.2 mg/kg or 2 mg/kg doesn't eliminate "anabolic" effect of dalargin. "Anabolic" effect of dalargin is suggested to be connected with -opioid receptor stimulation and change in insulin and cortisol secretion.

[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.

[Do endogenous opioid peptides participate in the realization of the cardioprotective effect of adaptation?]. / Uchastvuiut li éndogennye opioidnye peptidy v realizatsii kardioprotektornogo éffekta adaptatsii?

Twenty-four-hour immobilization stress induced heart damage (SHD). The agonist of mu-opioid receptors (OR) DAGO potentiated SHD. The agonist of peripheral mu-OR DALDA prevented SHD. Naltrexone decreased SHD. The peripheral mu-OR inhibitor methylnaltrexone potentiated SHD. Other OR ligands did not affect SHD. Acetorphane increased SHD. Repeated immobilization decreased the magnitude of myocardial damage. Neither naltrexone, naloxone, nor DAGO changed myocardial 99mTc pyrophosphate accumulation in the adapted rats.

[Morphofunctional manifestations of cardioprotective effect of mu-opioid receptor stimulation in stress]. / Morfofunktsional'nye proiavleniia kardioprotektornogo éffekta stimuliatsii mu-opiatnykh retseptorov v usloviiakh stressa.

Activation of peripheral mu-opioid receptors contributes to an increase in stability of cardiomyocytes to stress damage manifesting with decreased accumulation of Tc-99m pyrophosphate in the heart muscle and contractures of the myocardium. As a principal mechanism of mu-receptor-dependent increase in resistance of the heart to stress damage, modulated influence of opioids on adrenergic pathogenetic links of heart stress damage is considered. In realization of the discovered cardioprotective effect associated with mu-receptor activation, opioidergic limitation of histamine release from mast cells in the myocardium and also mu-receptor-dependent intensification of coronary bloodstream in stressed animals may play a definite role.

[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.

[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.