Effects of Deltorphin II and Its Retroenantio Analog on Cardiac Tolerance to Ischemia and Reperfusion.

Selective agonist of δ2-opioid receptors deltorphin II and its retroenantio analog (0.12 mg/kg intravenously) were preventively injected to male Wistar rats 15 min prior to 45-min coronary occlusion or 5 min before 120-min reperfusion. Administration of deltorphin II before artery occlusion and before reperfusion decreased the infarct size/area at risk ratio. Deltorphin II prevented the appearance of ischemia-provoked ventricular arrhythmias and exerted no effect on HR and BP (systolic and diastolic). The retroenantio analog of deltorphin II produced no antiarrhythmic or infarct-limiting effects, but reduced HR without affecting BP. Deltorphin II can be viewed as a promising prototype for a medicinal remedy to treat acute myocardial infarction.

Endomorphins and ß-Endorphin Do Not Affect Heart Tolerance to the Pathogenic Effect of Reperfusion.

Selective agonists of µ1- and µ2-opioid receptors endomorphin-2 and endomorphin-1 injected intravenously in a dose of 4500 nmol/kg in 5 min before coronary blood flow resumption had no effect on cardiac reperfusion damage. Consequently, µ1- and µ2-opioid receptors are not involved in the regulation of heart tolerance to reperfusion injury. Nonselective opioid receptor agonist ß-endorphin (100 nmol/kg) also did not affect heart tolerance to the pathogenic effect of reperfusion.

[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.

[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.

[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.

[Clinical effects of free transplanted pre-expanded scapular flap in reconstructing scar contracture deformity of neck].

Objective: To investigate the clinical effects of free transplanted pre-expanded scapular flap in reconstructing scar contracture deformity of neck. Methods: A retrospective observational study was conducted. From February 2010 to August 2020, 17 cervical scar deformity patients (9 males and 8 females, aged 8-42 years) who met the inclusion criteria were admitted to the First Affiliated Hospital of Air Force Medical University. The patients underwent skin and soft tissue expander (hereinafter referred to as expander) implantation in scapular region in stage Ⅰ procedures, and the free transplanted pre-expanded flaps were used to resurface the wounds followed by neck scar resection in the stage Ⅱ procedures. The wound size after neck scar release was 12.0 cm×6.0 cm-30.0 cm×24.0 cm, and the size of the flap ranged from 13.0 cm×7.5 cm to 31.5 cm×25.0 cm. The wounds in donor site of 15 patients were sutured directly, and the wounds in donor site of 2 patients were covered with full-thickness skin graft from abdominal area. The survival of flaps was observed after the operation of stage Ⅱ. Six months after stage Ⅱ surgery, Z plasty was performed to treat the incision scar contracture in 2 patients. For the 5 patients of overweight or bloating appearance in the 1/3 proximal flap underwent debulking procedures in 6-9 months after stage Ⅱsurgery. Before the stage Ⅰ surgery and six months after the last procedure (stage Ⅱ or stage Ⅲ), mental cervical angle (MCA) and cervical mandibular angle (CMA) were measured and the improvement of neck scar was evaluated by the angle values. The cervical motor function, skin color and texture in recipient areas, and scar in the donor sites assessed by Vancouver scar scale (VSS) were observed during follow-up. Data were statistically analyzed with paired sample t test. Results: After stage Ⅱ surgery, 15 patients' flaps survived well; venous crisis occurred in 2 flaps within 24 h after operation, and the flaps survived well after emergency exploration and thrombus removal+vascular re-anastomosis. Compared with the angle values of MCA of (126±12)° and CMA of (148±13)° of patients before the stage Ⅰ surgery, the angle values of MCA of (107±12)° and CMA of (123±11)° of patients in six months after the last procedure were significantly decreased (with t values of 10.68 and 6.54, respectively, P<0.05). After 2 years of follow-up, the patient's neck dorsiflexion, lateral bending, or other motor functions were not restricted; the color and texture of the flap in recipient site were close to those of the normal neck skin; the patient cases with VSS scores of scarring of 3, 4, 5, 6, and 7 were 1, 3, 7, 5, and 1 case, respectively. Conclusions: The free transplantation of the pre-expanded scapular flaps can provide sufficient tissue for wound coverage after the release of cervical scar contracture deformity; the expanded skin tissue is featured by thin soft tissue and good pliability, which is conducive to restore the neck appearance; the donor sites are relatively covert with less tension, therefore, the treatment is an effective method for correcting the contracture in the neck.

[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.

[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.

[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.

[PHENOMENON OF REMOTE PRECONDITIONING THE HEART AND ITS MAIN MANIFESTATIONS].

Remote ischemic preconditioning prevents reperfusion cardiomyocyte apoptosis and has the infarct-limiting effect which is maintained in the experiments on the isolated perfused heart. Remote preconditioning promotes to recovery the contractility of the heart during reperfusion, but did not affect the incidence of occlusion and reperfusion of ventricular arrhythmias. Remote preconditioning has a mild anti-inflammatory effect. Presented article is a review and formulated conclusions based on the published literature data.

[SIGNIFICANCE OF OPIOID RECEPTORS IN THE CYTOPROTECTIVE ACTION OF CHRONIC HYPOXIA DURING ANOXIA-REOXYGENATION OF CARDIOMYOCYTES].

It was investigated the role of δ-, µ- и κ-opioid receptors (ORs) in the development of cytoprotective effect of chronic normobaric hypoxia (CNH) using anoxia/reoxygenation of isolated cardiomyocytes. Adaptation to CNH was achieved by the maintenance of rats for 21 days at atmosphere containing 12% O2. Anoxia/reoxygenation of isolated cardiomyocytes of intact rats evoked a death of 23% cells and enhancement of lactate dehydrogenase (LDH) release from cells. Anoxia/reoxygenation of isolated cardiomyocytes of adapting rats induced a death of only 2.5% cells and LDH release decreased by 25%. Preliminary incubation of cells with the OR blocker naloxone (300 nM) or the δ-OR antagonist TIPP(ψ) (30 nM) or the selective δ2-OR antagonist naltriben (1 nM) or the µ-OR antagonist CTAP (100 nM) 25 min prior to anoxia abolished adaptive enhancement of cell survival and a decrease in LDH release. The blocking of δ1-OR by BNTX (1 nM) or κ-OR by nor-binaltorphimine (3 nM) not affected on the cytoprotection at CNH. Consequently, cardiac cell δ2- and µ-opioid receptors are involved in the cytoprotective effect of chronic normobaric hypoxia.

[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.

[PROBLEM OF END EFFECTOR OF ISCHEMIC POSTCONDITIONING OF THE HEART].

It is well known that cardiovascular disease and in particular acute myocardial infarction are a major cause of death among working-age population in Russia. Some of the patients die after successful recanalization of the infarct-related coronary artery as a result of ischemic and reperfusion injury of the heart. It is obvious that there is an urgent need to develop new approaches to prevention reoxygenation heart damages. In this regard the study of adaptive phenomenon postconditioning is of particular interest. This analysis of literature source preformed by authors of the article 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) mitoKATp 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 these 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 an adaptive phenomenon of postconditioning.

[Comparison of vasorelaxing actions of vasonatrin peptide, C-type natriuretic peptide and atrial natriuretic peptide].

The vasorelaxing effects of vasonatrin peptide (VNP), C-type natriuretic peptide (CNP) and atrial natriuretic peptide (ANP) on isolated rat pulmonary artery, abdominal aorta and celiac vein were measured by in vitro perfusion. The results showed that VNP, CNP and ANP caused concentration-dependent relaxation in isolated rat pulmonary artery, abdominal aorta and celiac vein with endothelium or without endothelium. The maximal responses (Rmax) of VNP were (76 +/- 17)%, (51 +/- 14)% and (62 +/- 14)% in pulmonary artery, abdominal aorta and celiac vein with endothelium respectively, whereas those of CNP were (31 +/- 8)%, (22 +/- 7)% and (41 +/- 8)%, and ANP (38 +/- 10)%, (41 +/- 10)% and (11 +/- 4)%. The median effective concentration (EC50) of VNP were 16 +/- 11, 35 +/- 18 and 12 +/- 8 nmol/L in pulmonary artery, abdominal aorta and celiac vein with endothelium respectively, while those of CNP were 148 +/- 112, 299 +/- 84 and 14 +/- 12 nmol/L, and ANP 66 +/- 47, 16 +/- 15 and 909 +/- 445 nmol/L. VNP were more effective than CNP and ANP, and the differences were statistically significant (P < 0.05-0.01). The potency of these peptides for relaxing the blood vessels can be summarized as: VNP > ANP > or = CNP for pulmonary artery; VNP > ANP > CNP for abdominal aorta; VNP > CNP > ANP for celiac vein. There was no significant difference between vessels with intact endothelium and those denuded of endothelium (P > 0.05).

[Effects of tetraethylammonium chloride and verapamil on the effective refractory period of ischemic myocardium in rabbits].

The effects of potassium ion channel blocker TEA and calcium ion channel blocker verapamil on effective refractory period (ERP) of ischemic ventricular muscle were studied in rabbits. The results showed that ERP of the ventricular muscle in central ischemic zone (CIZ) and border ischemic zone (BIZ) were shortened, respectively, at 10 min and 30 min after coronary occlusion (P < 0.01). The changes of ERP in TEA-treated and verapamil-treated rabbits after coronary occlusion were found to be significantly less than those in untreated rabbits. The results suggest that TEA and verapamil alleviated the degree of ERP shortening after coronary occlusion and may exhibit protective effects on the ischemic myocardium.

[The effect of batroxobin on coronary segmental resistance and coronary blood flow in acute myocardial ischemic dogs].

To study the effects of batroxobin on coronary circulation and cardiac performance in acute myocardial ischemia, Batroxobin was given intravenously to dogs with experimental coronary stenosis. A dose-dependent increase of coronary blood flow (CBF) was observed. Forty minutes after batroxobin (2 BU.kg-1 at infusion rate 0.1 BU.kg-1.min-1) administration, CBF increased by 12% (P < 0.05), small coronary resistance(RS) decreased from 4.1 +/- 0.5 to 3.2 +/- 0.5 mmHg.min.ml-1 (P < 0.01), while large coronary resistance(RL) changed insignificantly from 3.9 +/- 0.8 to 3.8 +/- 0.7 mmHg.min.ml-1 (P > 0.05). Two hours following drug administration, the changes in CBF, RS and RL still remained and RT decreased by 13% (P < 0.05). The + LV(dp/dt)max and -LV(dp/dt)max increased by 14% and 16% (P < 0.05) respectively compared with those in control group. It is concluded that batroxobin improves the ischemic canine coronary circulation and cardiac performance by way of lowering the small coronary resistance and thus increasing CBF. The data also suggest the benificial effect of batroxobin in acute myocardial ischemia.

[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.

[Preconditioning impact on coronary perfusion during ischemia and reperfusion of heart].

Recent studies have confirmed that ischemic preconditioning prevents appearance of reperfusion endothelial dysfunction. However, the issue of preconditioning impact on no-reflow phenomenon remains unresolved. The receptor mechanisms involved in the cardioprotective and vasoprotective effects of preconditioning are different. The ability of preconditioning in preventing reperfusion endothelial dysfunction is dependent upon bradykinin B2-receptor activation and not dependent upon adenosine receptor stimulation. The vasoprotective effect of preconditioning is mediated via mechanisms relying in part on activation of protein kinase C, NO-synthase, cyclooxygenase, mitochondrial K(ATP)-channel opening and an enhancement of antioxidative protection of the heart. The delayed preconditioning also exerts endothelium-protective effect. Peroxynitrite, NO* and O2* are the triggers of this effect but a possible end-effector involves endothelial NO-synthase.

[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.