Targeting myocardial ischaemic injury in the absence of reperfusion

Sudden myocardial ischaemia causes an acute coronary syndrome. In the case of ST-elevation myocardial infarction (STEMI), this is usually caused by the acute rupture of atherosclerotic plaque and obstruction of a coronary artery. Timely restoration of blood flow can reduce infarct size, but ischaemic regions of myocardium remain in up to two-thirds of patients due to microvascular obstruction (MVO). Experimentally, cardioprotective strategies can limit infarct size, but these are primarily intended to target reperfusion injury. Here, we address the question of whether it is possible to specifically prevent ischaemic injury, for example in models of chronic coronary artery occlusion. Two main types of intervention are identified: those that preserve ATP levels by reducing myocardial oxygen consumption, (e.g. hypothermia; cardiac unloading; a reduction in heart rate or contractility; or ischaemic preconditioning), and those that increase myocardial oxygen/blood supply (e.g. collateral vessel dilation). An important consideration in these studies is the method used to assess infarct size, which is not straightforward in the absence of reperfusion. After several hours, most of the ischaemic area is likely to become infarcted, unless it is supplied by pre-formed collateral vessels. Therefore, therapies that stimulate the formation of new collaterals can potentially limit injury during subsequent exposure to ischaemia. After a prolonged period of ischaemia, the heart undergoes a remodelling process. Interventions, such as those targeting inflammation, may prevent adverse remodelling. Finally, harnessing of the endogenous process of myocardial regeneration has the potential to restore cardiomyocytes lost during infarction

Main ways of improving the efficiency of fuel and energy resources utilization in energy production

The paper analyzes the main ways of improving the energy efficiency of boiler plants that provide thermal energy to industrial enterprises and housing and utilities sectors. The paper also presents the methodology for evaluating the effectiveness of energy-saving measures. The authors point out the main measures to save boiler and furnace fuel, heat and electric energy

ОБОСНОВАНИЕ ОСНОВНЫХ ПАРАМЕТРОВ ПЕРСПЕКТИВНЫХ УБОРОЧНЫХ МАШИН ФРЕЗЕРНОГО ТОРФА

Main directions of further modernization of УМПФ-type milling peat machines have been determined on the basis of complex analysis pertaining to application of these machines. Their modernization presupposes successful solution of national economy problem which is to increase a portion of local kinds of fuel in the power engineering balance of the Republic. One of the prospective peat machine diagram proposes to use a wheel propeller with a narrow back axle and front placement of removing and transporting element tool in relation to a bunker while applying a flight conveyer. Using this machine it is possible to obtain an improvement in indices of reliable operation of units, reduction in specific amount of metal per structure, reduction in power consumption in accomplishment of technological operation, higher productivity. First two directions of modernization provide for partial changes in some components of the machine and these tasks are successfully solved at repair and maintenance shops of peat enterprises. The third direction, that is development of milling peat machine of new generation, requires involvement of design organizations and machine-building plants. На основе комплексного анализа применения уборочных машин фрезерного торфа типа УМПФ определены основные пути их дальнейшей модернизации для успешного решения народнохозяйственной проблемы по увеличению доли местных видов топлива в энергетическом балансе республики. В одной из перспективных схем уборочной машины предлагается использовать колесный движитель с узкой задней осью, а также переднее расположение уборочно-транспортирующего рабочего органа по отношению к бункеру с использованием скребкового конвейера. При этом достигаются улучшение показателей надежности работы агрегатов, снижение металлоемкости конструкции и энергоемкости выполнения технологической операции, повышение производительности.Первые два пути модернизации предусматривают частичное изменении отдельных составных частей машины и успешно реализуются в ремонтно-механических мастерских торфопредприятий. Третье направление – разработка уборочной машины фрезерного торфа нового поколения – требует привлечения проектных организаций и машиностроительных заводов

Neural mechanisms in remote ischaemic conditioning in the heart and brain: mechanistic and translational aspects.

Remote ischaemic conditioning (RIC) is a promising method of cardioprotection, with numerous clinical studies having demonstrated its ability to reduce myocardial infarct size and improve prognosis. On the other hand, there are several clinical trials, in particular those conducted in the setting of elective cardiac surgery, that have failed to show any benefit of RIC. These contradictory data indicate that there is insufficient understanding of the mechanisms underlying RIC. RIC is now known to signal indiscriminately, protecting not only the heart, but also other organs. In particular, experimental studies have demonstrated that it is able to reduce infarct size in an acute ischaemic stroke model. However, the mechanisms underlying RIC-induced neuroprotection are even less well understood than for cardioprotection. The existence of bidirectional feedback interactions between the heart and the brain suggests that the mechanisms of RIC-induced neuroprotection and cardioprotection should be studied as a whole. This review, therefore, addresses the topic of the neural component of the RIC mechanism

Glucagon-Like Peptide-1 (GLP-1) Mediates Cardioprotection by Remote Ischaemic Conditioning

AIMS: Although the nature of the humoral factor which mediates cardioprotection established by remote ischaemic conditioning (RIc) remains unknown, parasympathetic (vagal) mechanisms appear to play a critical role. As the production and release of many gut hormones is modulated by the vagus nerve, here we tested the hypothesis that RIc cardioprotection is mediated by the actions of glucagon-like peptide-1 (GLP-1). METHODS AND RESULTS: A rat model of myocardial infarction (coronary artery occlusion followed by reperfusion) was used. Remote ischaemic pre- (RIPre) and perconditioning (RIPer) was induced by 15 min occlusion of femoral arteries applied prior to or during the myocardial ischaemia. The degree of RIPre and RIPer cardioprotection was determined in conditions of cervical or subdiaphragmatic vagotomy, or following blockade of GLP-1 receptors (GLP-1R) using specific antagonist Exendin(9-39). Phosphorylation of PI3K/AKT and STAT3 was assessed. RIPre and RIPer reduced infarct size by ~50%. In conditions of bilateral cervical or subdiaphragmatic vagotomy RIPer failed to establish cardioprotection. GLP-1R blockade abolished cardioprotection induced by either RIPre or RIPer. Exendin(9-39) also prevented RIPre-induced AKT phosphorylation. Cardioprotection induced by GLP-1R agonist Exendin-4 was preserved following cervical vagotomy, but was abolished in conditions of M3 muscarinic receptor blockade. CONCLUSIONS: These data strongly suggest that GLP-1 functions as a humoral factor of remote ischaemic conditioning cardioprotection. This phenomenon requires intact vagal innervation of the visceral organs and recruitment of GLP-1R-mediated signalling. Cardioprotection induced by GLP-1R agonism is mediated by a mechanism involving M3 muscarinic receptors

СПЕЦИФИКА И НАПРАВЛЕНИЯ УЛУЧШЕНИЯ ДИНАМИКИ ТОРМОЖЕНИЯ АКТИВНЫХ ТРАКТОРНЫХ ПОЕЗДОВ

The paper considers an important problem in improvement of  braking dynamics potential as part of the overall tractor train dynamics consisting of  an all-wheel drive tractor and heavy-duty trailers which are either locally manufactured or developed with the participation of the paper’s authors. The trailers have a mechanical drive for their wheels from the tractor engine. The trains are intended for transportation peat, organic fertilizers and various loads in  forest exploitation and under other complicated soil and climatic and road conditions where there is justified necessity to activate the trailer wheels.Methodological tools have been developed with the purpose to analyze an influence of the blocked inter-double-reduction axle drive of an active tractor train on distribution of braking forces in double-reduction axles with due account of the heavy-duty peat trailer specificity. Theoretical provisions for wheeled vehicles have been developed with regard to the braking application specificity of active tractor trains with mechanical multi-path drive for wheels of a multi-double-reduction axle propulsion device. The paper presents calculation and theoretical data in order to estimate  distribution of specific braking forces in the double-reduction axle links of the active tractor train when the blocked inter-double-reduction axle drive of the tractor and trailer wheels is switched on and also in the case when the tractor engine is involved in braking process and a clutch coupling is switched-on.Sequence of the calculation formula has been completely carried out in the paper. They represent clear design and operational parameters of the active tractor train. Such approach has made it possible to realize them in the form of a software application which is convenient for analysis of the braking process pertaining to the investigated objects in order to select means for improvement of braking dynamics, rational parameters of multi-path wheel drive and tire completing of the active tractor train under design. The proposed information has a theoretical and practical value for specialists who are involved in development of new machine-tractor units for transport application in peat extraction, forestry, and agriculture.Статья посвящена важной проблеме улучшения потенциала тормозной динамики как части общей динамики тракторных поездов в составе полноприводного трактора и выпущенных промышленностью или создаваемых с участием авторов большегрузных прицепов, имеющих механический привод на колеса прицепа от двигателя трактора. Они предназначены  для перевозки торфа, органических удобрений, различных грузов на лесоразработках и в других сложных почвенно-климатических и дорожных условиях, в которых оправдана активизация колес прицепов.Разработан методический инструментарий для анализа влияния блокированного межмостового привода колес активного тракторного поезда на распределение тормозных сил по мостам с учетом специфики большегрузных прицепов-торфовозов. При решении задачи развиты положения теории колесных машин применительно к специфике торможения активного тракторного поезда с механическим разветвленным приводом колес многомостового движителя. Получены расчетно-теоретические выражения для оценки распределения удельных тормозных сил по мостам звеньев активного тракторного поезда при включенном блокированном межмостовом приводе колес трактора и прицепа, а также в случае участия в тормозном процессе двигателя трактора при включенной муфте сцепления.В полной мере выполнена последовательность расчетных выражений, включающих в явном виде конструктивные и эксплуатационные параметры активного тракторного поезда. Это позволило реализовать их в виде программного приложения, удобного для анализа процесса торможения исследуемых объектов при выборе средств улучшения динамики торможения, рациональных параметров разветвленного привода колес  и комплектации шинами проектируемого активного тракторного поезда. Изложенный материал  имеет теоретическое значение и представляет практический интерес для разработчиков новых машинно-тракторных агрегатов транспортного назначения для торфоразработок, лесного и сельского хозяйства

Intracellular sodium elevation reprograms cardiac metabolism

Intracellular Na elevation in the heart is a hallmark of pathologies where both acute and chronic metabolic remodeling occurs. We assessed whether acute (75μM ouabain 100nM blebbistatin) and chronic myocardial Naiload (PLM3SA mouse) are causally linked to metabolic remodeling and whether the hypertrophied failing heart shares a common Na-mediated metabolic ‘fingerprint’. Control (PLMWT), transgenic (PLM3SA), ouabain treated and hypertrophied Langendorff-perfused mouse hearts were studied by 23Na, 31P, 13C NMR followed by 1H NMR metabolomic profiling. Elevated Nai leads to common adaptive metabolic alterations preceding energetic impairment: a switch from fatty acid to carbohydrate metabolism and changes in steady-state metabolite concentrations (glycolytic, anaplerotic, Krebs cycle intermediates). Inhibition of mitochondrial Na/Ca exchanger by CGP37157 ameliorated the metabolic changes. In silico modelling indicated altered metabolic fluxes (Krebs cycle, fatty acid, carbohydrate, amino acid metabolism). Prevention of Nai overload or inhibition of Na/Camitomay be a new approach to ameliorate metabolic dysregulation in heart failure

Glucagon-like peptide-1 (GLP-1) receptor activation dilates cerebral arterioles, increases cerebral blood flow, and mediates remote (pre)conditioning neuroprotection against ischaemic stroke.

Stroke remains one of the most common causes of death and disability worldwide. Several preclinical studies demonstrated that the brain can be effectively protected against ischaemic stroke by two seemingly distinct treatments: remote ischaemic conditioning (RIC), involving cycles of ischaemia/reperfusion applied to a peripheral organ or tissue, or by systemic administration of glucagon-like-peptide-1 (GLP-1) receptor (GLP-1R) agonists. The mechanisms underlying RIC- and GLP-1-induced neuroprotection are not completely understood. In this study, we tested the hypothesis that GLP-1 mediates neuroprotection induced by RIC and investigated the effect of GLP-1R activation on cerebral blood vessels, as a potential mechanism of GLP-1-induced protection against ischaemic stroke. A rat model of ischaemic stroke (90 min of middle cerebral artery occlusion followed by 24-h reperfusion) was used. RIC was induced by 4 cycles of 5 min left hind limb ischaemia interleaved with 5-min reperfusion periods. RIC markedly (by ~ 80%) reduced the cerebral infarct size and improved the neurological score. The neuroprotection established by RIC was abolished by systemic blockade of GLP-1R with a specific antagonist Exendin(9-39). In the cerebral cortex of GLP-1R reporter mice, ~ 70% of cortical arterioles displayed GLP-1R expression. In acute brain slices of the rat cerebral cortex, activation of GLP-1R with an agonist Exendin-4 had a strong dilatory effect on cortical arterioles and effectively reversed arteriolar constrictions induced by metabolite lactate or oxygen and glucose deprivation, as an ex vivo model of ischaemic stroke. In anaesthetised rats, Exendin-4 induced lasting increases in brain tissue PO2, indicative of increased cerebral blood flow. These results demonstrate that neuroprotection against ischaemic stroke established by remote ischaemic conditioning is mediated by a mechanism involving GLP-1R signalling. Potent dilatory effect of GLP-1R activation on cortical arterioles suggests that the neuroprotection in this model is mediated via modulation of cerebral blood flow and improved brain perfusion

Intracellular sodium elevation reprograms cardiac metabolism

Intracellular Na elevation in the heart is a hallmark of pathologies where both acute and chronic metabolic remodelling occurs. Here, we assess whether acute (75 μM ouabain 100 nM blebbistatin) or chronic myocardial Nai load (PLM3SA mouse) are causally linked to metabolic remodelling and whether the failing heart shares a common Na-mediated metabolic ‘fingerprint’. Control (PLMWT), transgenic (PLM3SA), ouabain-treated and hypertrophied Langendorff-perfused mouse hearts are studied by 23Na, 31P, 13C NMR followed by 1H-NMR metabolomic profiling. Elevated Nai leads to common adaptive metabolic alterations preceding energetic impairment: a switch from fatty acid to carbohydrate metabolism and changes in steady-state metabolite concentrations (glycolytic, anaplerotic, Krebs cycle intermediates). Inhibition of mitochondrial Na/Ca exchanger by CGP37157 ameliorates the metabolic changes. In silico modelling indicates altered metabolic fluxes (Krebs cycle, fatty acid, carbohydrate, amino acid metabolism). Prevention of Nai overload or inhibition of Na/Camito may be a new approach to ameliorate metabolic dysregulation in heart failure