[Protein kinases role in adaptive phenomenon of heart ischemic postconditioning development].

Authors submitted an analysis of papers given up an involvement of protein kinases in heart ischemic postconditioning. This analysis of literature source allowed to authors affirms that signaling system of postconditioning can involve kinases: PKC, PI3K, Akt, MEKl/2, ERK1/2, MTOR, p70s6K, GSK3b, PKG and also eNOS, NO, GC, motoKATP channel, ROS, MPT pore. At the same time it is unclear a real contributions of kinases mTOR, p70s6, AMPK and GSK3b in the mechanism of infarct limiting impact of postconditioning. It is required a further study of the chain of signaling events following JAK2 and p38 kinase activation. The knowledge of Ras and Raf-1 role in postconditioning has hypothetical character. The tyrosine kinase significance in postcondi-tioning is unclear, particular Src kinase, which plays an important role in the regulation of cardiac tolerance to an impact of ischemia and reperfusion.

[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.

[Role of receptor transactivation in the cardioprotective effects of preconditioning and postconditioning].

Analysis of published data indicates that the activity of receptors for adenosine, opioids, bradykinin, calcitonin-gene related peptides (CGRP) and epidermal growth factor (EGF) play important role in triggering the cardioprotective effects of ischemic preconditioning. Cannabinoids mimic the infarct-sparing effects of preconditioning. Endogenous adenosine, opioids, bradykinin and CGRP have also been implicated in infarct-reduction with ischemic postconditioning. Again, cannabinoids also mimic the protective effect of postconditioning. Recent works support heterodimerization of G-protein coupled receptors (GPCRs), and GPCR transactivation of EGF receptors. It was found that cross-talk between delta(j)-opioid receptors and adenosine A(1)-receptors is essential to cardiac protection. Furthermore, evidence implicates EGF receptor transactivation in cardioprotective effect of multiple GPCrs including adenosine, acetylcholine, bradykinin, and opioid receptors. Such findings support a convergent pathway in which multiple GPCRs may interact (or function independently) to transactivate EGF receptor-dependent kinase signaling and cytoprotection.

[Trigger mechanism of adaptive phenomenon of ischemic heart postconditioning].

Analysis of published data indicates on trigger role of protons, adenosine, opioids, bradykinin, calcitonin gene-related peptide, nitric oxide, epoxyeicosatrienoic acid, reactive oxygen species, hydrogen sulfide in ischemic heart postconditioning. It is shown that B-type natriuretic peptide, transforming growth factor-beta1, cardiotrophin-1, urocortin, acetylcholine, insulin and carbon monoxide can mimic postconditioning phenomenon.

[Significance of opioid receptors in regulation of cardiac tolerance in pathogenic impact of long-term ischemia-reperfusion in vivo].

The study aimed at investigation of the role of opioid receptor (OR) in regulation of cardiac tolerance to ischemia-reperfusion. Opioid receptor ligands and inhibitors were administered in vivo prior to coronary artery occlusion (45 min) and reperfusion (2 hrs). Occurring infraction size/area at risk (IS/AAR) ratio was determined. Pretreatment with the micro-OR agonists DAMGO and dermorphin H exerted no effect on the IS/AAR ratio. Activation of delta 1-OR by DPDPE did not alter cardiac tolerance in ischemia-reperfusion either. Pretreatment with the delta 2-OR agonists deltorphin D and deltorphin E or ORL1 receptor agonist nociceptin exerted no effect on the IS/AAR ratio. Stimulation of K-OR by selective agonists did not modify cardiac tolerance to ischemia-reperfusion. The delta 2-OR agonist deltorphin II significantly reduced the IS/AAR index. This effect was prevented by treatment with naltrexone, naloxone methiodide and the delta 2-OR antagonist naltriben but not by the delta 1-OR antagonist BNTX. The infarction-limiting effect of deltorphin II was also abolished by inhibition of protein kinase C (PKC) and mitochondrial Katp channels. Thus, the agonists of micro, delta 1, kappa, and ORL1 receptors in used doses did not affect cardiac tolerance in ischemia-reperfusion injury in vivo. The peripheral delta 2-OR activation induces infarction size reduction. Its infarction-reducing effect of deltorphin II is mediated via PKC activation and mitochondrial Katp, channel opening.

[Role of kappa-opioid receptors in the regulation of cardiac resistance to arrhythmogenic effects of ischemia and reperfusion].

It was found that pretreatment of rats with selective agonist of kappa1-opioid receptors (OR) (-)--U--50.488 decreased the incidence of ischemic (10 min) and reperfusion (10 min) ventricular arrhythmias. The selective kappa2-OR agonist GR-89696 had no effect on the incidence of ventricular arrhythmias during a 10-min coronary artery occlusion and following reperfusion in anesthetized rats. The effect of (-)--U-50.488 was abolished by the selective kappa1-OR antagonist of non-binaltorphimine and the non-selective peripheral OR antagonist naloxone methiodide. Perfusion of isolated rat heart with (-)--U-50.488 did not affect arrhythmias during ischemia and reperfusion. The authors suggest that stimulation of kappa1-opioid receptors located outside the central nervous system increases heart resistance against arrhythmogenic action of ischemia/reperfusion, antiarrhythmic action of (-)--U-50.488 being mediated through extracardiac opioid receptors.

[The antiarrhythmic effect of (-)-U-50,488 in rats with acute ischemia and reperfusion of heart is mediated by kappa1-opioid receptor activation].

Pretreatment with a selective kappa1 opioid receptor (OR) agonist (-)-U-50,488 (1 mg/kg, i.v.) prevented the development of arrhythmias induced by occlusion (10 min) and reperfusion (10 min) in ketamine anesthetized rats, while the treatment with a less active enantiomer (+)-U-50,488 in the same dose produced no such effects. Preliminary intravenous administration of a selective kappa1 OR antagonist norbinaltorphimine (9 mg/kg) fully abolished the antiarrhythmic effect of (-)-U-50,488, while the kappa2 OR antagonist quadazocine (3 mg/kg) did not eliminate this effect. The injections of norbinaltorphimine or quadazocine alone did not influence the incidence of model arrhythmias caused by the occlusion and reperfusion. It was concluded that kappa1 OR stimulation favors an increase in cardiac tolerance to the arrhythmogenic action of occlusion and reperfusion.

[Comparative study of the antiarrhythmic activity of mu- and delta-opioid receptor agonists during acute cardiac ischemia and reperfusion models in rats].

It has been established that pretreatment with the selective mu-opioid receptor (OR) agonist DALDA (0.1 mg/kg, i.v.) or the selective delta1-OR agonists DPDPE (0.09 mg/kg) and/or (-)-TAN-67 (0.08 mg/kg) has no effect on the incidence of ventricular arrhythmias induced by a 10-min coronary artery occlusion and a 10-min reperfusion in ketamine-anesthetized rats. In contrast, the pretreatment with the selective delta2-OR agonist deltorphin II (0.12 mg/kg) and the proposed delta2-OR agonists deltorphin D (0.3 mg/kg) and/or dermorphin H (0.23 mg/kg) increases cardiac resistance to the arrhythmogenic action of acute ischemia and reperfusion. Administration of the mixed mu- and delta-OR agonist dalargin (0.12 mg/kg) 15 min before the coronary artery ligation abolished only the reperfusive ventricular fibrillation. It is concluded that peptidergic stimulation of delta2-ORs can be used as a new means of increasing cardiac tolerance to the arrhythmogenic effects of acute ischemia and reperfusion.

[The effect of K(ATP)-channel activation on the electrical stability of myocardium in rats with postinfarction cardiosclerosis]. / Vliianie aktivatsii K(ATP)-kanalov na élektricheskuiu stabil'nost' miokarda pri postinfarktnom kardioskleroze.

Opening of the ATP-dependent K-channels (K(ATP) channels) upon intravenous administration of the cardioselective activator BMS 180448 (3 mg/kg) decreased the ventricular fibrillation threshold (VFT) in rats with postinfarction cardiosclerosis (PIC). Preliminary injection of the selective K(ATP) channel blocker glibenclamide (0.3 mg/kg, i.v.) completely abolished the profibrillatory effect of BMS 180448. At the same time, the mitochondrial K(ATP) channel blocker 5-hydroxydecanoic acid (5 mg/kg) did not influence the proarrhythmogen activity of BMS 180448. Simultaneous administration of the sarcoK(ATP) channel inhibitor HMR 1098 (3 mg/kg) and BMS 180448 increased the VFT up to a level in intact animals. Administration of the mitoK(ATP) channel activator diazoxide (5 mg/kg) after preliminary treatment with guanethidine (50 mg/kg) increased the VFT in rats with PIC. It is concluded that opening of the mitoK(ATP) channels increases the cardiac electrical stability in rats with PIC.

[Changes in cardiac resistance to arrhythmogenic effects during ATP-dependent K+ channel activation]. / Izmenenie ustoichivosti serdtsa k aritmogennym vozdeistviiam v usloviiakh aktivatsii ATF-zavisimykh K+ kanalov.

It has been found that pretreatment with ATP-dependent potassium channel (KATP-channel) opener, BMS 180448 (3 mg/kg, intravenously), increases cardiac resistance against arrhythmogenic action of coronary artery occlusion and reperfusion in anaesthetized rats. However, BMS 180448 induced a decrease in ventricular fibrillation threshold in rats postinfarction cardiac fibrosis. This effect was completely abolished by administration of the KATP-channel inhibitor, glibenclamide. By contrast, coadministration of BMS 180448 and selective sarcolemmal KATP-channel inhibitor, HMR 1098, promoted an increase in ventricular fibrillation threshold in rats with postinfarction cardiac fibrosis before normal value. The selective mitochondrial KATP-channel opener, diazoxide, also exacerbated a decrease in ventricular fibrillation threshold induced by postinfarction cardiac sclerosis. But after depletion of endogenous catecholamine storage by pretreatment with guanthidine, diazoxide, on the contrary, elevated the ventricular fibrillation threshold. It has been suggested that stimulation of mitochondrial ATP-sensitive potassium channels promotes an elevation in electrical stability of the heart, whereas opening of sarcolemmal KATP-channel increases a possibility of ventricular arrhythmias.

[Interactions of peripheral mu-opioid receptors and K(ATP)-channels in regulation of cardiac electrical stability in ischemia, reperfusion, and postinfarction cardiosclerosis]. / Vzaimodeistvie perifericheskikh mu-opiatnykh retseptorov i K(ATF)-kanalov v reguliatsii élektricheskoi stabil'nosti serdtsa pri ishemii, reperfuzii i postinfarktnom kardioskleroze.

It has been shown that mu-opioid receptor stimulation by intravenous administration of the selective mu receptor agonist DALDA in a dose of 0.1 mg/kg prevented ischemic and reperfusion arrhythmias in rats subjected to coronary artery occlusion (10 min) and reperfusion (10 min), and also increased the ventricular fibrillation threshold in rats with postinfarction cardiac fibrosis. These effects were abolished by pre-treatment with the selective mu receptor antagonist CTAP in a dose of 0.5 mg/kg or by prior injection of the opioid receptor antagonist naloxone methiodide (2 mg/kg) which does not penetrate the blood-braib barrier. Both antagonists by themselves had no effect on the incidence of occlusion or reperfusion-induced arrhythmias or on the ventricular fibrillation threshold. Pre-treatment with ATP-sensitive K+ channel (KATP channel) blocker glibenclamide in a dose of 0.3 mg/kg completely abolished the antiarrhythmic effect of DALDA. We believe that DALDA prevents occurrence of electrical instability during ischemia and reperfusion and increases the ventricular fibrillation threshold in rats with postinfarction cardiac fibrosis via stimulation of peripheral mu-opioid receptor which appear to be coupled to the KATP channel.

[Myocardial tolerance to arrhythmogenic exposure and pharmacological activation of K(ATP)-channels in rats]. / Tolerantnost' serdtsa krys k aritmogennym vozdeistviiam v usloviiakh farmakologicheskoi aktivatsii K(ATP)-kanalov.

The cardioselective KATP channel activator BMS 180448 (3 mg/kg) administered intravenously 15 min before the coronary artery occlusion (10 min) decreased the incidence of ischemic and reperfusion arrhythmias in rats. A similar antiarrhythmic effect was observed when BMS 180448 was infused 2 min before reperfusion. Pretreatment with BMS 180448 also prevented the occurrence of CsCl induced arrhythmias, but but did not affect the incidence of epinephrine induced arrhythmias. On the contrary, BMS 180448 potentiated the arrhythmogenic action of CaCl2. The mechanism of the antiarrhythmic activity of BMS 180448 is discussed.

[Stimulation of peripheral delta1-opioid receptors as a method of preventing ischemic and reperfusion arrhythmia: role of K(ATP)-channels]. / Stimuliatsiia perifericheskikh delta(1)-opioidnykh retseptorov kak sposob profilaktiki ishemicheskikh i reperfuzionnykh aritmii: rol' K(ATP)-kanalov.

Preliminary administration of the delta 1-opioid receptor (delta 1-OR) peptide agonist DPDPE (0.5 mg/kg, i.v.) decreased the incidence of occlusion (10 min) and reperfusion (10 min) arrhythmias in rats. The delta 2-OR agonist DSLET did not affect arrhythmias upon the coronary artery occlusion and reperfusion. Pretreatment with the selective delta-antagonists ICI 174,864 (2.5 mg/kg) or TIPP[psi] (0.5 mg/kg) completely eliminated the antiarrhythmic effect of DPDPE. Uncapable of crossing the blood brain barrier, the nonselective OR antagonist naloxone methiodide (5 mg/kg) also abolished this effect. At the same time, hexametonium (10 mg/kg) did not antagonize the antiarrhythmic effect of DPDPE. Pretreatment with the KATP channel blocker glibenclamide (0.3 mg/kg) completely eliminated the protective effect of the delta 1-OR stimulation. It was concluded that the delta 1-OR stimulation prevents the ischemic and reperfusion arrhythmias by means of the KATP channel activation.

[Participation of K(ATP)-channels in cardioprotective effect of mu-opioid receptor agonists in acute ischemia and reperfusion of the isolated heart]. / Rol' K(ATP)-kanalov v realizatsii kardioprotektornogo deistviia agonistov miu-opioidnykh retseptorov pri ostroi ishemii i reperfuzii izolirovannogo serdtsa.

Preliminary administration of the mu-opioid receptor (mu-OR) agonist DAMGO (0.1 mg/kg) 15 min before heart isolation led to attenuation of the postischemic systolic and diastolic contractility dysfunction in isolated perfused rat heart. In addition, the mu-OR decreased creatine kinase (CK) release from the heart during the postischemic period, which was indicative of an increase in the sarcolemma tolerance to reperfusion injury. This protective effects are mediated by KATP channel activation. These data show that the mu-OR stimulation in vivo increases, by means of the KATP channel activation, the cardiac tolerance to the ischemia and reperfusion injury in vitro. Pretreatment with mu-OR agonists DAMGO or DALDA in vitro (0.5 mg/liter, 15 min prior to ischemia) exacerbated the postischemic contractility dysfunction of myocardium and did not affect the CK release. It is concluded that the protective effect of mu-OR simulation in vivo is mediated by the activation of these receptors localized outside the heart, probably with an unknown circulating humoral factor.