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

Cardioprotection of Immature Heart by Simultaneous Activation of PKA and Epac: A Role for the Mitochondrial Permeability Transition Pore

Metabolic and ionic changes during ischaemia predispose the heart to the damaging effects of reperfusion. Such changes and the resulting injury differ between immature and adult hearts. Therefore, cardioprotective strategies for adults must be tested in immature hearts. We have recently shown that the simultaneous activation of protein kinase A (PKA) and exchange protein activated by cAMP (Epac) confers marked cardioprotection in adult hearts. The aim of this study is to investigate the efficacy of this intervention in immature hearts and determine whether the mitochondrial permeability transition pore (MPTP) is involved. Isolated perfused Langendorff hearts from both adult and immature rats were exposed to global ischaemia and reperfusion injury (I/R) following control perfusion or perfusion after an equilibration period with activators of PKA and/or Epac. Functional outcome and reperfusion injury were measured and in parallel, mitochondria were isolated following 5 min of reperfusion to determine whether cardioprotective interventions involved changes in MPTP opening behaviour. Perfusion for 5 min preceding ischaemia of injury-matched adult and immature hearts with 5 µM 8-Br (8-Br-cAMP-AM), an activator of both PKA and Epac, led to significant reduction in post-reperfusion CK release and infarct size. Perfusion with this agent also led to a reduction in MPTP opening propensity in both adult and immature hearts. These data show that immature hearts are innately more resistant to I/R injury than adults, and that this is due to a reduced tendency of MPTP opening following reperfusion. Furthermore, simultaneous stimulation of PKA and Epac causes cardioprotection, which is additive to the innate resistance

Preconditioning or postconditioning with 8-Br-cAMP-AM protects the heart against regional ischemia and reperfusion:a role for mitochondrial permeability transition

The cAMP analogue 8-Br-cAMP-AM (8-Br) confers marked protection against global ischaemia/reperfusion of isolated perfused heart. We tested the hypothesis that 8-Br is also protective under clinically relevant conditions (regional ischaemia) when applied either before ischemia or at the beginning of reperfusion, and this effect is associated with the mitochondrial permeability transition pore (MPTP). 8-Br (10 μM) was administered to Langendorff-perfused rat hearts for 5 min either before or at the end of 30 min regional ischaemia. Ca2+-induced mitochondria swelling (a measure of MPTP opening) and binding of hexokinase II (HKII) to mitochondria were assessed following the drug treatment at preischaemia. Haemodynamic function and ventricular arrhythmias were monitored during ischaemia and 2 h reperfusion. Infarct size was evaluated at the end of reperfusion. 8-Br administered before ischaemia attenuated ventricular arrhythmias, improved haemodynamic function, and reduced infarct size during ischaemia/reperfusion. Application of 8-Br at the end of ischaemia protected the heart during reperfusion. 8-Br promoted binding of HKII to the mitochondria and reduced Ca2+-induced mitochondria swelling. Thus, 8-Br protects the heart when administered before regional ischaemia or at the beginning of reperfusion. This effect is associated with inhibition of MPTP via binding of HKII to mitochondria, which may underlie the protective mechanism

Functional and cardioprotective effects of simultaneous and individual activation of protein kinase A and Epac

BACKGROUND AND PURPOSE: Myocardial cAMP elevation confers cardioprotection against ischaemia/reperfusion (I/R) injury. cAMP activates two independent signalling pathways, PKA and Epac. This study investigated the cardiac effects of activating PKA and/or Epac and their involvement in cardioprotection against I/R. EXPERIMENTAL APPROACH: Hearts from male rats were used either for determination of PKA and PKC activation or perfused in the Langendorff mode for either cardiomyocyte isolation or used to monitor functional activity at basal levels and after 30 min global ischaemia and 2 h reperfusion. Functional recovery and myocardial injury during reperfusion (LDH release and infarct size) were evaluated. Activation of PKA and/or Epac in perfused hearts was induced using cell permeable cAMP analogues in the presence or absence of inhibitors of PKA, Epac and PKC. H9C2 cells and cardiomyocytes were used to assess activation of Epac and effect on Ca(2+) transients. KEY RESULTS: Selective activation of either PKA or Epac was found to trigger a positive inotropic effect, which was considerably enhanced when both pathways were simultaneously activated. Only combined activation of PKA and Epac induced marked cardioprotection against I/R injury. This was accompanied by PKCε activation and repressed by inhibitors of PKA, Epac or PKC. CONCLUSION AND IMPLICATIONS: Simultaneous activation of both PKA and Epac induces an additive inotropic effect and confers optimal and marked cardioprotection against I/R injury. The latter effect is mediated by PKCε activation. This work has introduced a new therapeutic approach and targets to protect the heart against cardiac insults

Prospects for Creation of Cardioprotective Drugs Based on Cannabinoid Receptor Agonists

Cannabinoids can mimic the infarct-reducing effect of early ischemic preconditioning, delayed ischemic preconditioning, and ischemic postconditioning against myocardial ischemia/reperfusion. They do this primarily through both CB1 and CB2 receptors. Cannabinoids are also involved in remote preconditioning of the heart. The cannabinoid receptor ligands also exhibit an antiapoptotic effect during ischemia/reperfusion of the heart. The acute cardioprotective effect of cannabinoids is mediated by activation of protein kinase C, extracellular signal-regulated kinase, and p38 kinase. The delayed cardioprotective effect of cannabinoid anandamide is mediated via stimulation of phosphatidylinositol-3-kinase-Akt signaling pathway and enhancement of heat shock protein 72 expression. The delayed cardioprotective effect of another cannabinoid, Δ9-tetrahydrocannabinol, is associated with augmentation of nitric oxide (NO) synthase expression, but data on the involvement of NO synthase in the acute cardioprotective effect of cannabinoids are contradictory. The adenosine triphosphate-sensitive K+ channel is involved in the synthetic cannabinoid HU-210-induced cardiac resistance to ischemia/reperfusion injury. Cannabinoids inhibit Na+/Ca2+ exchange via peripheral cannabinoid receptor (CB2) activation that may also be related to the antiapoptotic and cardioprotective effects of cannabinoids. The cannabinoid receptor agonists should be considered as prospective group of compounds for creation of drugs that are able to protect the heart against ischemia–reperfusion injury in the clinical setting. </jats:p

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.

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