The aim of the study was to examine the potential role of mitochondrial permeability transition pore (mPTP) in the cardioprotective effect of chronic continuous hypoxia (CH) against acute myocardial ischemia/reperfusion (I/R) injury. Adult male Wistar rats were adapted to CH for 3 weeks, while their controls were kept under normoxic conditions. Subsequently, they were subjected to I/R insult while being administered with mPTP inhibitor, cyclosporin A (CsA). Infarct size and incidence of ischemic and reperfusion arrhythmias were determined. Our results showed that adaptation to CH as well as CsA administration reduced myocardial infarct size in comparison to the corresponding control groups. However, administration of CsA did not amplify the beneficial effect of CH, suggesting that inhibition of mPTP opening contributes to the protective character of CH.

• MeSH
• chronická nemoc MeSH
• cyklosporin * farmakologie   MeSH
• hypoxie * metabolismus   MeSH
• infarkt myokardu metabolismus   patologie   prevence a kontrola   MeSH
• krysa rodu rattus MeSH
• potkani Wistar * MeSH
• přechodový pór mitochondriální permeability * metabolismus   MeSH
• reperfuzní poškození myokardu * metabolismus   prevence a kontrola   patologie   MeSH
• srdeční mitochondrie metabolismus   účinky léků   patologie   MeSH
• transportní proteiny mitochondriální membrány metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

The cardioprotective effect of ischemic preconditioning (IPC) and ischemic postconditioning (IPoC) in adult hearts is mediated by nitric oxide (NO). During the early developmental period, rat hearts exhibit higher resistance to ischemia-reperfusion (I/R) injury, contain higher levels of serum nitrates, and their resistance cannot be further increased by IPC or IPoC. NOS blocker (L-NAME) lowers their high resistance. Wistar rat hearts (postnatal Days 1 and 10) were perfused according to Langendorff and exposed to 40 min of global ischemia followed by reperfusion with or without IPoC. NO and reactive oxygen species donors (DEA-NONO, SIN-1) and L-NAME were administered. Tolerance to ischemia decreased between Days 1 and 10. DEA-NONO (low concentrations) significantly increased tolerance to I/R injury on both Days 1 and 10. SIN-1 increased tolerance to I/R injury on Day 10, but not on Day 1. L-NAME significantly reduced resistance to I/R injury on Day 1, but actually increased resistance to I/R injury on Day 10. Cardioprotection by IPoC on Day 10 was not affected by either NO donors or L-NAME. It can be concluded that resistance of the neonatal heart to I/R injury is NO dependent, but unlike in adult hearts, cardioprotective interventions, such as IPoC, are most likely NO independent.

• MeSH
• donory oxidu dusnatého farmakologie   MeSH
• ischemické přivykání metody   MeSH
• ischemický postconditioning * metody   MeSH
• krysa rodu rattus MeSH
• molsidomin farmakologie   analogy a deriváty   MeSH
• myokard metabolismus   MeSH
• NG-nitroargininmethylester * farmakologie   MeSH
• novorozená zvířata * MeSH
• oxid dusnatý * metabolismus   MeSH
• potkani Wistar * MeSH
• reperfuzní poškození myokardu * prevence a kontrola   metabolismus   MeSH
• srdce účinky léků   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

While 3-N-butylphthalide (NBP) has demonstrated notable cardioprotective effects, its precise role in mitigating myocardial arrhythmia following ischemia/reperfusion (IR) injury in diabetes remains unclear. This study aimed to explore the potential mechanisms through which NBP mitigates reperfusion-induced myocardial arrhythmia in diabetic rats, with a particular focus on mitochondrial function and biogenesis, endoplasmic reticulum (ER) stress, and oxidative/inflammatory responses. Sixty Sprague-Dawley rats were divided into non-diabetic and diabetic groups, subjected to in-vivo myocardial IR injury, and treated with NBP (100 mg/kg, intraperitoneally) through different modalities: preconditioning, postconditioning, or a combination of both. Electrocardiography (ECG) was employed to assess the incidence and severity of arrhythmia. Fluorometric, Western blotting and ELISA analyses were utilized to measure the mitochondrial, ER stress, and cellular outcomes. Treatment of non-diabetic rats with NBP in preconditioned, postconditioned, and combined approaches significantly reduced cardiotroponin-I and the frequency and severity of arrhythmias induced by IR injury. However, only the combined preconditioning plus postconditioning approach of NBP had protective and antiarrhythmic effects in diabetic rats, in an additive manner. Moreover, the NBP combined approach improved mitochondrial function and upregulated the expression of PGC-1?, Sirt1, and glutathione while concurrently downregulating ER stress and oxidative and pro-inflammatory-related proteins in diabetic rats. In conclusion, the combined approach of NBP treatment was effective in mitigating myocardial arrhythmia in diabetic rats. This approach coordinates interactions within the mitochondria-endoplasmic reticulum network and inhibits oxidative and inflammatory mediators, offering a promising strategy for managing myocardial arrhythmia in diabetic patients. Key words: Myocardial Infarction, Mitochondria, Arrhythmia, Reperfusion, Diabetes, Ischemia.

• MeSH
• antiarytmika farmakologie   terapeutické užití   MeSH
• benzofurany * farmakologie   terapeutické užití   MeSH
• experimentální diabetes mellitus * metabolismus   farmakoterapie   komplikace   MeSH
• krysa rodu rattus MeSH
• oxidační stres * účinky léků   MeSH
• potkani Sprague-Dawley * MeSH
• reperfuzní poškození myokardu * metabolismus   farmakoterapie   prevence a kontrola   MeSH
• srdeční arytmie * etiologie   prevence a kontrola   metabolismus   farmakoterapie   MeSH
• srdeční mitochondrie metabolismus   účinky léků   MeSH
• stres endoplazmatického retikula * účinky léků   MeSH
• zánět metabolismus   farmakoterapie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Increased level of C-reactive protein (CRP) is a risk factor for cardiovascular diseases, including myocardial infarction and hypertension. Here, we analyzed the effects of CRP overexpression on cardiac susceptibility to ischemia/reperfusion (I/R) injury in adult spontaneously hypertensive rats (SHR) expressing human CRP transgene (SHR-CRP). Using an in vivo model of coronary artery occlusion, we found that transgenic expression of CRP predisposed SHR-CRP to repeated and prolonged ventricular tachyarrhythmias. Excessive ischemic arrhythmias in SHR-CRP led to a significant reduction in infarct size (IS) compared with SHR. The proarrhythmic phenotype in SHR-CRP was associated with altered heart and plasma eicosanoids, myocardial composition of fatty acids (FAs) in phospholipids, and autonomic nervous system imbalance before ischemia. To explain unexpected IS-limiting effect in SHR-CRP, we performed metabolomic analysis of plasma before and after ischemia. We also determined cardiac ischemic tolerance in hearts subjected to remote ischemic perconditioning (RIPer) and in hearts ex vivo. Acute ischemia in SHR-CRP markedly increased plasma levels of multiple potent cardioprotective molecules that could reduce IS at reperfusion. RIPer provided IS-limiting effect in SHR that was comparable with myocardial infarction observed in naïve SHR-CRP. In hearts ex vivo, IS did not differ between the strains, suggesting that extra-cardiac factors play a crucial role in protection. Our study shows that transgenic expression of human CRP predisposes SHR-CRP to excess ischemic ventricular tachyarrhythmias associated with a drop of pump function that triggers myocardial salvage against lethal I/R injury likely mediated by protective substances released to blood from hypoxic organs and tissue at reperfusion.

• MeSH
• akční potenciály MeSH
• C-reaktivní protein genetika   metabolismus   MeSH
• fibrilace komor etiologie   metabolismus   patofyziologie   MeSH
• hypertenze komplikace   metabolismus   patofyziologie   MeSH
• komorová tachykardie etiologie   metabolismus   patofyziologie   MeSH
• krevní tlak MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• myokard metabolismus   patologie   MeSH
• potkani inbrední SHR MeSH
• potkani transgenní MeSH
• reperfuzní poškození myokardu etiologie   metabolismus   patofyziologie   prevence a kontrola   MeSH
• srdeční frekvence MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Cangrelor je jediným nitrožilním inhibitorem destičkového receptoru pro adenosindifosfát typu P2Y12 s klinicky prokázanou účinností pro snížení ischemických komplikací koronární angioplastiky (percutaneous coronary intervention, PCI). Přestože doporučenou indikací pro jeho použití je každá PCI u pacientů neléčených perorálními inhibitory P2Y12, v klinické praxi je používán dominantně pro rizikové výkony při akutním koronárním syndromu. Hlavní výhodou jeho podání při léčbě infarktu myokardu PCI je jeho rychlý a dobře předvídatelný protidestičkový účinek, nicméně experimentální studie ukazují navíc významný vliv cangreloru na ochranu myokardu před reperfuzním poškozením. Slibné teoretické výhody cangreloru pro použití při léčbě infarktu myokardu čekají na potvrzení v klinických studiích.

Cangrelor is the only intravenous platelet P2Y12 receptor inhibitor that has proven clinical efficacy in reducing coronary angioplasty (percutaneous coronary intervention, PCI) - related ischemic complications. Despite being recommended to all P2Y12-naive patients, cangrelor is preferentially used in routine clinical practice for high-risk PCI's in acute coronary syndrome. The fast and predictable antiplatelet action creates the optimal conditions for PCI treatment of myocardial infarction, but in addition, cangrelor offers a cardioprotective effect against reperfusion injury in many animal models. The promising position of cangrelor in treating myocardial infarction needs to be confirmed by large randomized clinical trials.

• Klíčová slova
• Kangrelor,
• MeSH
• adenosinmonofosfát analogy a deriváty   MeSH
• antagonisté purinergních receptorů P2Y * farmakologie   terapeutické užití   MeSH
• infarkt myokardu * farmakoterapie   MeSH
• inhibitory agregace trombocytů farmakologie   terapeutické užití   MeSH
• koronární angioplastika metody   MeSH
• lidé MeSH
• reperfuze myokardu metody   MeSH
• reperfuzní poškození myokardu prevence a kontrola   MeSH
• ticagrelor terapeutické užití   MeSH
• Check Tag
• lidé MeSH

The role of opioid kappa1 and kappa2 receptors in reperfusion cardiac injury was studied. Male Wistar rats were subjected to a 45-min coronary artery occlusion followed by a 120-min reperfusion. Opioid kappa receptor agonists were administered intravenously 5 min before the onset of reperfusion, while opioid receptor antagonists were given 10 min before reperfusion. The average value of the infarct size/area at risk (IS/AAR) ratio was 43 - 48% in untreated rats. Administration of the opioid kappa1 receptor agonist (-)-U-50,488 (1 mg/kg) limited the IS/AAR ratio by 42%. Administration of the opioid kappa receptor agonist ICI 199,441 (0.1 mg/kg) limited the IS/AAR ratio by 41%. The non-selective opioid kappa receptor agonist (+)-U-50,488 (1 mg/kg) with low affinity for opioid kappa receptor, the peripherally acting opioid kappa2 receptor agonist ICI 204,448 (4 mg/kg) and the selective opioid ?2 receptor agonist GR89696 (0.1 mg/kg) had no effect on the IS/AAR ratio. Pretreatment with naltrexone, the peripherally acting opioid receptor antagonist naloxone methiodide, or the selective opioid kappa2 receptor antagonist nor-binaltorphimine completely abolished the infarct-reducing effect of (-)-U-50,488 and ICI 199,441. Pretreatment with the selective opioid ? receptor antagonist TIPP[psi] and the selective opioid μ receptor antagonist CTAP did not alter the infarct reducing effect of (-)-U-50,488 and ICI 199,441. Our study is the first to demonstrate the following: (a) the activation of opioid kappa2 receptor has no effect on cardiac tolerance to reperfusion; (b) peripheral opioid kappa1 receptor stimulation prevents reperfusion cardiac injury; (c) ICI 199,441 administration resulted in an infarct-reducing effect at reperfusion; (e) bradycardia induced by opioid kappa receptor antagonists is not dependent on the occupancy of opioid kappa receptor.

• MeSH
• 3,4-dichlor-N-methyl-N-(2-(1-pyrrolidinyl)-cyklohexyl)-benzenacetamid, (trans)-isomer aplikace a dávkování   toxicita   MeSH
• infarkt myokardu metabolismus   patologie   prevence a kontrola   MeSH
• intravenózní podání MeSH
• kardiomyocyty účinky léků   metabolismus   patologie   MeSH
• modely nemocí na zvířatech MeSH
• narkotika - antagonisté aplikace a dávkování   MeSH
• opioidní analgetika aplikace a dávkování   toxicita   MeSH
• piperaziny aplikace a dávkování   MeSH
• potkani Wistar MeSH
• pyrrolidiny aplikace a dávkování   toxicita   MeSH
• receptory opiátové kappa agonisté   metabolismus   MeSH
• reperfuzní poškození myokardu metabolismus   patologie   prevence a kontrola   MeSH
• signální transdukce MeSH
• srdeční arytmie chemicky indukované   patofyziologie   MeSH
• srdeční frekvence účinky léků   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH

Chronic continuous normobaric hypoxia (CNH) increases cardiac tolerance to ischemia/reperfusion injury in vivo and this effect is mediated via µ and delta2 opioid receptors (ORs) activation. CNH has also been shown to be cardioprotective in isolated rat heart. In this study, we hypothesize that this cardioprotective effect of CNH is mediated by activation of µ and delta2 ORs and preservation of mitochondrial function. Hearts from rats adapted to CNH (12 % oxygen) for 3 weeks were extracted, perfused in the Langendorff mode and subjected to 45 min of global ischemia and 30 min of reperfusion. Intervention groups were pretreated for 10 min with antagonists for different OR types: naloxone (300 nmol/l), the selective delta OR antagonist TIPP(psi) (30 nmol/l), the selective delta1 OR antagonist BNTX (1 nmol/l), the selective delta2 OR antagonist naltriben (1 nmol/l), the selective peptide µ OR antagonist CTAP (100 nmol/l) and the selective delta OR antagonist nor-binaltorphimine (3 nmol/l). Creatine kinase activity in coronary effluent and cardiac contractile function were monitored to assess cardiac injury and functional impairment. Additionally, cardiac tissue was collected to measure ATP and to isolate mitochondria to measure respiration rate and calcium retention capacity. Adaptation to CNH decreased myocardial creatine kinase release during reperfusion and improved the postischemic recovery of contractile function. Additionally, CNH improved mitochondrial state 3 and uncoupled respiration rates, ADP/O, mitochondrial transmembrane potential and calcium retention capacity and myocardial ATP level during reperfusion compared to the normoxic group. These protective effects were completely abolished by naloxone, TIPP(psi), naltriben, CTAP but not BNTX or nor-binaltorphimine. These results suggest that cardioprotection associated with adaptation to CNH is mediated by µ and delta2 opioid receptors activation and preservation of mitochondrial function.

• MeSH
• hypoxie patofyziologie   MeSH
• krysa rodu rattus MeSH
• narkotika - antagonisté farmakologie   MeSH
• orgánové kultury - kultivační techniky MeSH
• potkani Wistar MeSH
• receptory opiátové delta antagonisté a inhibitory   fyziologie   MeSH
• receptory opiátové mu antagonisté a inhibitory   fyziologie   MeSH
• reperfuzní poškození myokardu patofyziologie   prevence a kontrola   MeSH
• srdeční mitochondrie účinky léků   fyziologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Cardioprotective effect of ischemic preconditioning (IPC) and ischemic postconditioning (IPoC) in adult hearts is mediated by mitochondrial-K-ATP channels and nitric oxide (NO). During early developmental period, rat hearts exhibit higher resistance to ischemia-reperfusion (I/R) injury and their resistance cannot be further increased by IPC or IPoC. Therefore, we have speculated, whether mechanisms responsible for high resistance of neonatal heart may be similar to those of IPC and IPoC. To test this hypothesis, rat hearts isolated on days 1, 4, 7, and 10 of postnatal life were perfused according to Langendorff. Developed force (DF) of contraction was measured. Hearts were exposed to 40 min of global ischemia followed by reperfusion up to the maximum recovery of DF. IPoC was induced by 5 cycles of 10-s ischemia. Mito-K-ATP blocker (5-HD) was administered 5 min before ischemia and during first 20 min of reperfusion. Another group of hearts was isolated for biochemical analysis of 3-nitrotyrosine, and serum samples were taken to measure nitrate levels. Tolerance to ischemia did not change from day 1 to day 4 but decreased on days 7 and 10. 5-HD had no effect either on neonatal resistance to I/R injury or on cardioprotective effect of IPoC on day 10. Significant difference was found in serum nitrate levels between days 1 and 10 but not in tissue 3-nitrotyrosine content. It can be concluded that while there appears to be significant difference of NO production, mito-K-ATP and ROS probably do not play role in the high neonatal resistance to I/R injury.

• MeSH
• draslíkové kanály metabolismus   MeSH
• ischemický postconditioning * MeSH
• krysa rodu rattus MeSH
• novorozená zvířata MeSH
• oxid dusnatý metabolismus   MeSH
• potkani Wistar MeSH
• reperfuzní poškození myokardu metabolismus   patofyziologie   prevence a kontrola   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Epoxyeicosatrienoic acids (EETs) decrease cardiac ischemia-reperfusion injury; however, the mechanism of their protective effect remains elusive. Here, we investigated the cardioprotective action of a novel EET analog, EET-B, in reperfusion and the role of hypoxia-inducible factor (HIF)-1α in such action of EET-B. Adult male rats were subjected to 30 min of left coronary artery occlusion followed by 2 h of reperfusion. Administration of 14,15-EET (2.5 mg/kg) or EET-B (2.5 mg/kg) 5 min before reperfusion reduced infarct size expressed as a percentage of the area at risk from 64.3 ± 1.3% in control to 42.6 ± 1.9% and 46.0 ± 1.6%, respectively, and their coadministration did not provide any stronger effect. The 14,15-EET antagonist 14,15-epoxyeicosa-5( Z)-enoic acid (2.5 mg/kg) inhibited the infarct size-limiting effect of EET-B (62.5 ± 1.1%). Similarly, the HIF-1α inhibitors 2-methoxyestradiol (2.5 mg/kg) and acriflavine (2 mg/kg) completely abolished the cardioprotective effect of EET-B. In a separate set of experiments, the immunoreactivity of HIF-1α and its degrading enzyme prolyl hydroxylase domain protein 3 (PHD3) were analyzed in the ischemic areas and nonischemic septa. At the end of ischemia, the HIF-1α immunogenic signal markedly increased in the ischemic area compared with the septum (10.31 ± 0.78% vs. 0.34 ± 0.08%). After 20 min and 2 h of reperfusion, HIF-1α immunoreactivity decreased to 2.40 ± 0.48% and 1.85 ± 0.43%, respectively, in the controls. EET-B blunted the decrease of HIF-1α immunoreactivity (7.80 ± 0.69% and 6.44 ± 1.37%, respectively) and significantly reduced PHD3 immunogenic signal in ischemic tissue after reperfusion. In conclusion, EET-B provides an infarct size-limiting effect at reperfusion that is mediated by HIF-1α and downregulation of its degrading enzyme PHD3. NEW & NOTEWORTHY The present study shows that EET-B is an effective agonistic 14,15-epoxyeicosatrienoic acid analog, and its administration before reperfusion markedly reduced myocardial infarction in rats. Most importantly, we demonstrate that increased hypoxia-inducible factor-1α levels play a role in cardioprotection mediated by EET-B in reperfusion likely by mechanisms including downregulation of the hypoxia-inducible factor -1α-degrading enzyme prolyl hydroxylase domain protein 3.

• MeSH
• down regulace MeSH
• faktor 1 indukovatelný hypoxií - podjednotka alfa genetika   metabolismus   MeSH
• funkce levé komory srdeční účinky léků   MeSH
• infarkt myokardu enzymologie   patologie   patofyziologie   prevence a kontrola   MeSH
• kyselina 8,11,14-eikosatrienová analogy a deriváty   farmakologie   MeSH
• modely nemocí na zvířatech MeSH
• myokard enzymologie   patologie   MeSH
• potkani Sprague-Dawley MeSH
• prolyl-4-hydroxylasy HIF genetika   metabolismus   MeSH
• proteolýza MeSH
• remodelace komor účinky léků   MeSH
• reperfuzní poškození myokardu enzymologie   patologie   patofyziologie   prevence a kontrola   MeSH
• signální transdukce účinky léků   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

Currently, there are no satisfactory interventions to protect the heart against the detrimental effects of ischemia-reperfusion injury. Although ischemic preconditioning (PC) is the most powerful form of intrinsic cardioprotection, its application in humans is limited to planned interventions, due to its short duration and technical requirements. However, many organs/tissues are capable of producing "remote" PC (RPC) when subjected to brief bouts of ischemia-reperfusion. RPC was first described in the heart where brief ischemia in one territory led to protection in other area. Later on, RPC started to be used in patients with acute myocardial infarction, albeit with ambiguous results. It is hypothesized that the connection between the signal triggered in remote organ and protection induced in the heart can be mediated by humoral and neural pathways, as well as via systemic response to short sublethal ischemia. However, although RPC has a potentially important clinical role, our understanding of the mechanistic pathways linking the local stimulus to the remote organ remains incomplete. Nevertheless, RPC appears as a cost-effective and easily performed intervention. Elucidation of protective mechanisms activated in the remote organ may have therapeutic and diagnostic implications in the management of myocardial ischemia and lead to development of pharmacological RPC mimetics.

• MeSH
• časové faktory MeSH
• infarkt myokardu metabolismus   patologie   patofyziologie   prevence a kontrola   MeSH
• ischemické přivykání metody   MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• myokard metabolismus   patologie   MeSH
• regionální krevní průtok MeSH
• reperfuzní poškození myokardu metabolismus   patologie   patofyziologie   prevence a kontrola   MeSH
• signální transdukce MeSH
• výsledek terapie MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH