PROBLEM OF HEART SALVATION DURING REPERFUSION. OPIOID RECEPTOR AGONISTS AS A POSSIBLE SOLUTION

Ischaemia/reperfusion cardiac injury contributes to morbidity and mortality during percutaneous coronary intervention, heart surgery and transplantation. Even when the recanalization of an infarct-related coronary artery is carried out successfully, there is still a risk of death due to reperfusion injury. Numerous pharmacological interventions have been found in experiments on animals. However, the translation of these interventions to clinical practice has been disappointing. None of the drug treatment has been able to improve in-hospital mortality of patients with acute myocardial infarction. The search for pharmacological agents able to salvage myocardium during reperfusion continues. Opioid receptor (OR) agonists represent one of the promising group of drugs for treatment of patients with myocardial infarction. It has been found that µ-, δ- and κ-OR agonists are able to attenuate heart injury when administered before or at the beginning of reperfusion. However, what kind of OR receptors need to be activated in order to protect the heart during reperfusion and the precise mechanism of this effect have yet to be elucidated.Ischaemia/reperfusion cardiac injury contributes to morbidity and mortality during percutaneous coronary intervention, heart surgery and transplantation. Even when the recanalization of an infarct-related coronary artery is carried out successfully, there is still a risk of death due to reperfusion injury. Numerous pharmacological interventions have been found in experiments on animals. However, the translation of these interventions to clinical practice has been disappointing. None of the drug treatment has been able to improve in-hospital mortality of patients with acute myocardial infarction. The search for pharmacological agents able to salvage myocardium during reperfusion continues. Opioid receptor (OR) agonists represent one of the promising group of drugs for treatment of patients with myocardial infarction. It has been found that µ-, δ- and κ-OR agonists are able to attenuate heart injury when administered before or at the beginning of reperfusion. However, what kind of OR receptors need to be activated in order to protect the heart during reperfusion and the precise mechanism of this effect have yet to be elucidated

ИШЕМИЧЕСКОЕ ПОСТКОНДИЦИОНИРОВАНИЕ СЕРДЦА. АНАЛИЗ ЭКСПЕРИМЕНТАЛЬНЫХ И КЛИНИЧЕСКИХ ДАННЫХ

Published data on the impact of the experimental atherosclerosis on the infarct-limiting effect of ischemic postconditioning (IPost) are controversial. The reviewed data indicate that aging eliminates or reduces the infarct-limiting effect of postconditioning but does not affect the antiarrhythmic effect of IPost. Most of the experimental data reported that streptozotocin-induced diabetes removes the infarct-limiting effect of IPost. Regarding the second type of diabetes, information is contradictory: some authors argue that this diabetes completely eliminates the cardioprotective effect of IPost, others say that it only weakens but does not eliminate the infarct-limiting effect of IPost. Postconditioning in rats with high blood pressure prevents the appearance of reperfusion contractile dysfunction of the heart and provides the infarct-limiting effect. Cardiac hypertrophy, post-infarction remodeling and dilated cardiomyopathy have no effect on the infarct-reducing and inotropic effect of postconditioning. The majority of publications indicates that IPost enhances the inotropic and cardioprotective effect of cardioplegia. Data on the effect of postconditioning on the tolerance of the human heart to ischemia/reperfusion are limited and do not allow to make an unambiguous conclusion about whether IPost prevents reperfusion myocardial injury in cardiac patients.Литературные данные о влиянии экспериментального атеросклероза на инфаркт-лимитирующий эффект ишемического посткондиционирования (ИПост) носят противоречивый характер. Представленные данные свидетельствуют о том, что старение устраняет или ослабляет инфаркт-лимитирующий эффект посткондиционирования, но не влияет на антиаритмический эффект ИПост. Большинство экспериментальных данных сообщают о том, что стрептозотоцин-индуцированный диабет устраняет инфаркт- лимитирующий эффект ИПост. Относительно сахарного диабета 2-го типа сведения носят противоречивый характер: одни авторы утверждают, что подобный диабет полностью нивелирует кардиопротекторный эффект ИПост, другие говорят о том, что он только ослабляет, но не устраняет инфаркт-лимитирующий эффект ИПост. Посткондиционирование у крыс с повышенным артериальным давлением предупреждает появление реперфузионной сократительной дисфункции сердца и оказывает инфаркт-лимитирующий эффект. Гипертрофия сердца, постинфарктное ремоделирование и дилатационная кардиомиопатия не влияют на инфаркт-лимитирующий и инотропный эффект посткондиционирования. Согласно большинству публикаций, ИПост усиливает инотропный и кардиопротекторный эффект кардиоплегии. Данные о влиянии посткондиционирования на толерантность сердца человека к действию ишемии-реперфузии носят ограниченный характер и не позволяют сделать однозначный вывод о том, может ли ИПост предупреждать реперфузионные повреждения миокарда у кардиологических пациентов

АДАПТИВНЫЙ ФЕНОМЕН ИШЕМИЧЕСКОГО ПОСТКОНДИЦИОНИРОВАНИЯ СЕРДЦА. ПЕРСПЕКТИВЫ КЛИНИЧЕСКОГО ПРИМЕНЕНИЯ

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.Анализ экспериментальных данных свидетельствует о том, что старение и метаболический синдром могут быть серьезными препятствиями для реализации кардиопротекторного эффекта посткондиционирования. Умеренная гиперхолестеринемия, постинфарктный кардиосклероз и гипертрофия сердца не устраняют защитный эффект посткондиционирования у экспериментальных животных. Вопрос о том, влияют ли экспериментальный сахарный диабет и артериальная гипертензия на эффективность посткондиционирования, является предметом дискуссии. Клинические исследования свидетельствуют о кардиопротекторном действии посткондиционирования у больных острым инфарктом миокарда и кардиохирургических пациентов. Вместе с тем, остается неясным, в какие сроки после появления коронарной окклюзии посткондиционирование оказывает кардиопротекторный эффект. Также остается неизвестным, как влияют старение, сахарный диабет, метаболический синдром, артериальная гипертензия, гипертрофия миокарда, постинфарктное ремоделирование сердца на эффективность посткондиционирования в клинической практике. Требуются дальнейшие клинические исследования, направленные на разработку фармакологических подходов к профилактике реперфузионных повреждений сердца

Anisotropic Behavior of Knight Shift in Superconducting State of Na_xCoO_2yH_2O

The Co Knight shift was measured in an aligned powder sample of Na_xCoO_2yH_2O, which shows superconductivity at T_c \sim 4.6 K. The Knight-shift components parallel (K_c) and perpendicular to the c-axis (along the ab plane K_{ab}) were measured in both the normal and superconducting (SC) states. The temperature dependences of K_{ab} and K_c are scaled with the bulk susceptibility, which shows that the microscopic susceptibility deduced from the Knight shift is related to Co-3d spins. In the SC state, the Knight shift shows an anisotropic temperature dependence: K_{ab} decreases below 5 K, whereas K_c does not decrease within experimental accuracy. This result raises the possibility that spin-triplet superconductivity with the spin component of the pairs directed along the c-axis is realized in Na_xCoO_2yH_2O.Comment: 5 pages, 5 figures, to be published in Journal of Physical Society of Japan vol. 75, No.

Approach to the metal-insulator transition in La(1-x)CaxMnO3 (0<x<.2): magnetic inhomogeneity and spin wave anomaly

We describe the evolution of the static and dynamic spin correlations of La$_{1-x}$Ca$_x$MnO$_3$, for x=0.1, 0.125 and 0.2, where the system evolves from the canted magnetic state towards the insulating ferromagnetic state, approaching the metallic transition (x=0.22). In the x=0.1 sample, the observation of two spin wave branches typical of two distinct types of magnetic coupling, and of a modulation in the elastic diffuse scattering characteristic of ferromagnetic inhomogeneities, confirms the static and dynamic inhomogeneous features previously observed at x$<$0.1. The anisotropic q-dependence of the intensity of the low-energy spin wave suggests a bidimensionnal character for the static inhomogeneities. At x=0.125, which corresponds to the occurence of a ferromagnetic and insulating state, the two spin wave branches reduce to a single one, but anisotropic. At this concentration, an anomaly appears at {\bf q$_0$}=(1.25,1.25,0), that could be related to an underlying periodicity, as arising from (1.5,1.5,0) superstructures. At x=0.2, the spin-wave branch is isotropic. In addition to the anomaly observed at q$_0$, extra magnetic excitations are observed at larger q, forming an optical branch. The two dispersion curves suggest an anti-crossing behavior at some {\bf q$_0$'} value, which could be explained by a folding due to an underlying perodicity involving four cubic lattice spacings

Hearts from Mice Fed a Non-Obesogenic High-Fat Diet Exhibit Changes in Their Oxidative State, Calcium and Mitochondria in Parallel with Increased Susceptibility to Reperfusion Injury

High-fat diet with obesity-associated co-morbidities triggers cardiac remodeling and renders the heart more vulnerable to ischemia/reperfusion injury. However, the effect of high-fat diet without obesity and associated co-morbidities is presently unknown.To characterize a non-obese mouse model of high-fat diet, assess the vulnerability of hearts to reperfusion injury and to investigate cardiac cellular remodeling in relation to the mechanism(s) underlying reperfusion injury.Feeding C57BL/6J male mice high-fat diet for 20 weeks did not induce obesity, diabetes, cardiac hypertrophy, cardiac dysfunction, atherosclerosis or cardiac apoptosis. However, isolated perfused hearts from mice fed high-fat diet were more vulnerable to reperfusion injury than those from mice fed normal diet. In isolated cardiomyocytes, high-fat diet was associated with higher diastolic intracellular Ca2+ concentration and greater damage to isolated cardiomyocytes following simulated ischemia/reperfusion. High-fat diet was also associated with changes in mitochondrial morphology and expression of some related proteins but not mitochondrial respiration or reactive oxygen species turnover rates. Proteomics, western blot and high-performance liquid chromatography techniques revealed that high-fat diet led to less cardiac oxidative stress, higher catalase expression and significant changes in expression of putative components of the mitochondrial permeability transition pore (mPTP). Inhibition of the mPTP conferred relatively more cardio-protection in the high-fat fed mice compared to normal diet.This study shows for the first time that high-fat diet, independent of obesity-induced co-morbidities, triggers changes in cardiac oxidative state, calcium handling and mitochondria which are likely to be responsible for increased vulnerability to cardiac insults