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
Several studies have shown that peroxynitrite (ONOO-), formed upon the reaction of •NO and O2-, is increased in many cardiovascular diseases and is detrimental to myocardial function. Proteins associated with Ca2+ homeostasis regulation in the heart may be involved in these effects. Thus, the aim of this study was to elucidate the mechanisms associated with ONOO--induced effects. We evaluated [Ca2+]i regulation, sarco/endoplasmic reticulum Ca2+- binding proteins, and phosphorylation levels of the ryanodine receptor in isolated rat myocytes. Electrical field-induced intracellular Ca2+ transients and contractions were recorded simultaneously. Myocytes superfused with 3-morpholinosydnonimine N-ethylcarbamide (SIN-1), an ONOO- donor, decreased the amplitude of Ca2+ transients and contraction in a dose-response (1-200 μM) manner. Similarly, SIN-1 increased half-time decay in a concentration-dependent manner. Co-infusion of the ONOO- donor with FeTMPyP (1 μM), an ONOO- decomposition catalyst, inhibited the effects induced by ONOO-. Impaired sarcoplasmic reticulum Ca2+ uptake caused by ONOO- (SIN-1 200 μM) was confirmed by a reduction of caffeine-evoked Ca2+ release along with prolongation of the half-time decay. Surprisingly, ONOO- induced a spontaneous Ca2+ transient that started at the beginning of the relaxation phase and was inhibited by tetracaine. Also, reduced phosphorylation at the ryanodine receptor 2 (RyR2)-Ser-2814 site was observed. In conclusion, deficient sarco/endoplasmic reticulum Ca2+-ATPase-mediated Ca2+ uptake concomitant with augmented Ca2+ release by RyR2 in myocytes may be associated with modification of myocyte Ca2+ handling by ONOO-. Thus, development of cardiac failure in diabetes, nephropathy, or hypertension may be related with elevated ONOO- in cardiac tissue.
- MeSH
- endoplazmatické retikulum účinky léků metabolismus MeSH
- fosforylace účinky léků MeSH
- intracelulární prostor metabolismus MeSH
- kardiomyocyty účinky léků metabolismus MeSH
- kofein farmakologie MeSH
- kontrakce myokardu účinky léků MeSH
- kyselina peroxydusitá metabolismus MeSH
- membránové transportní proteiny metabolismus MeSH
- molsidomin analogy a deriváty farmakologie MeSH
- potkani Wistar MeSH
- tetrakain farmakologie MeSH
- vápník metabolismus MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Chronic anthracycline (ANT) cardiotoxicity is a serious complication of cancer chemotherapy. Molsidomine, a NO-releasing drug, has been found cardioprotective in different models of I/R injury and recently in acute high-dose ANT cardiotoxicity. Hence, we examined whether its cardioprotective effects are translatable to chronic ANT cardiotoxicity settings without induction of nitrosative stress and interference with antiproliferative action of ANTs. The effects of molsidomine (0.025 and 0.5mg/kg, i.v.) were studied on the well-established model of chronic ANT cardiotoxicity in rabbits (daunorubicin/DAU/3mg/kg/week for 10 weeks). Molsidomine was unable to significantly attenuate mortality, development of heart failure and morphological damage induced by DAU. Molsidomine did not alter DAU-induced myocardial lipoperoxidation, MnSOD down-regulation, up-regulation of HO-1, IL-6, and molecular markers of cardiac remodeling. Although molsidomine increased 3-nitrotyrosine in the myocardium, this event had no impact on cardiotoxicity development. Using H9c2 myoblasts and isolated cardiomyocytes, it was found that SIN-1 (an active metabolite of molsidomine) induces significant protection against ANT toxicity, but only at high concentrations. In leukemic HL-60 cells, SIN-1 initially augmented ANT cytotoxicity (in low and clinically achievable concentrations), but it protected these cells against ANT in the high concentrations. UHPLC-MS/MS investigation demonstrated that the loss of ANT cytotoxicity after co-incubation of the cells in vitro with high concentrations of SIN-1 is caused by unexpected chemical depletion of DAU molecule. The present study demonstrates that cardioprotective effects of molsidomine are not translatable to clinically relevant chronic form of ANT cardiotoxicity. The augmentation of antineoplastic effects of ANT in low (nM) concentrations may deserve further study.
- MeSH
- antibiotika antitumorózní toxicita MeSH
- antracykliny toxicita MeSH
- chronická nemoc MeSH
- daunomycin toxicita MeSH
- donory oxidu dusnatého farmakologie MeSH
- doxorubicin toxicita MeSH
- kardiotonika farmakologie MeSH
- kardiotoxicita MeSH
- králíci MeSH
- molsidomin farmakologie MeSH
- nádorové buněčné linie MeSH
- nemoci srdce chemicky indukované prevence a kontrola MeSH
- oxidační stres účinky léků MeSH
- peroxidace lipidů účinky léků MeSH
- proliferace buněk účinky léků MeSH
- reaktivní formy kyslíku metabolismus MeSH
- remodelace komor účinky léků MeSH
- srdeční selhání prevence a kontrola MeSH
- zvířata MeSH
- Check Tag
- králíci MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Jumonji (JMJ, Jarid2), a prototypical member of the jumonji domain-containing protein family, plays a major role in embryonic cardiac development, but its role in the developed heart is unclear. Cardiomyocytes from neonatal mouse heart were treated in culture with NO donor SIN-1, 500 microM, for 2, 4, and 20 h. SIN-1 treatment was associated with a significant and 6.9 +/- 2.5 fold increase in jmj gene expression over all time points. The expression of jmj increased markedly and significantly 4.2 +/- 1.1 fold, 16.6 +/- 4.1 fold, and 2.7 +/- 0.3 fold, respectively, at time points 2 h, 4 h, and 20 h after treatment. The ability of the increase in gene expression to translate into an increase in cellular protein expression was ascertained by Western blotting, which showed an increase in the JMJ protein in whole-cell lysates. Because of the relationship of JMJ to Rb and ANP in the heart, gene expression of these proteins was also examined. SIN-1 produced a small but significant increase in Rb2, but not Rb1 or Rb-binding proteins 4, 6, or 7. In contrast, SIN-1 produced a marked and significant reduction in natriuretic peptide precursor type B but not type C to 0.24 +/- 0.09 fold of the control. These data suggest that JMJ may be a critical, previously unrecognized factor that mediates some of the cellular effects of NO, that NO may be able to increase JMJ in diseases associated with reduced JMJ expression.
- MeSH
- donory oxidu dusnatého farmakologie MeSH
- kardiomyocyty metabolismus účinky léků MeSH
- kultivované buňky MeSH
- molsidomin analogy a deriváty farmakologie MeSH
- myši MeSH
- natriuretický peptid typu B genetika metabolismus MeSH
- oxid dusnatý metabolismus MeSH
- protein p130 podobný retinoblastomu genetika MeSH
- proteiny nervové tkáně genetika metabolismus MeSH
- regulace genové exprese MeSH
- sekvenční analýza hybridizací s uspořádaným souborem oligonukleotidů MeSH
- srdce MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
Nitráty jsou nejdéle a velmi často používané léky v terapii anginy pectoris. Indikací je především symptomatická léčba myokardiální ischémie. V intravenózní aplikaci mohou být použity v terapii akcelerované hypertenze a srdečního selhávání. Při chronické perorální medikaci je problémem vznik tolerance. Nejsou ale důkazy o tom, že by terapie nitráty snižovala riziko vzniku koronárních příhod a prodlužovala život (studie GISSI-3, ISIS-4).
Nitrates are the longest and very frequently used drugs in the therapy of angina pectoris. Their indication is first of all symptomatic treatment of myocardial ischemia. As an intravenous application they may be used in the therapy of accelerated hypertension and heart failure. The occurrence of tolerance is the problem of their chronic oral application. But there is no evidence that the nitrate therapy decreases the risk of occurrence of coronary events and prolongs life (studies GISSI-3, ISIS-4).
- Klíčová slova
- Cialis, Molsihexal, Monosan, IsoMack, Nitropohl, Nitromint,
- MeSH
- angina pectoris farmakoterapie MeSH
- blokátory kalciových kanálů farmakokinetika MeSH
- inhibitory fosfodiesteras aplikace a dávkování MeSH
- isosorbiddinitrát analogy a deriváty aplikace a dávkování farmakologie MeSH
- lidé MeSH
- molsidomin aplikace a dávkování farmakologie MeSH
- nitroglycerin aplikace a dávkování farmakokinetika farmakologie MeSH
- srdeční selhání farmakoterapie MeSH
- Check Tag
- lidé MeSH
- MeSH
- arterie patologie účinky léků MeSH
- finanční podpora výzkumu jako téma MeSH
- hypertenze diagnóza chemicky indukované MeSH
- krevní tlak MeSH
- molsidomin farmakologie MeSH
- NG-nitroargininmethylester farmakologie MeSH
- oxid dusnatý nedostatek MeSH
- pentaerythritoltetranitrát farmakologie MeSH
- potkani inbrední SHR MeSH
- potkani Wistar MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- srovnávací studie MeSH
- MeSH
- angina pectoris diagnóza farmakoterapie patofyziologie MeSH
- beta blokátory farmakologie terapeutické užití MeSH
- blokátory kalciových kanálů farmakologie terapeutické užití MeSH
- dusičnany aplikace a dávkování farmakologie terapeutické užití MeSH
- koronární nemoc farmakoterapie terapie MeSH
- lidé MeSH
- molsidomin farmakologie terapeutické užití MeSH
- rizikové faktory MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
- MeSH
- arteria iliaca fyziologie patofyziologie MeSH
- hypertenze patofyziologie MeSH
- krysa rodu rattus MeSH
- molsidomin aplikace a dávkování farmakologie MeSH
- pentaerythritoltetranitrát aplikace a dávkování farmakologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- Publikační typ
- kongresy MeSH
- MeSH
- diagnostické techniky a postupy metody přístrojové vybavení MeSH
- dospělí MeSH
- dusičnany farmakologie metabolismus MeSH
- koronární nemoc farmakoterapie MeSH
- lidé středního věku MeSH
- lidé MeSH
- molsidomin farmakologie metabolismus MeSH
- oxid dusnatý analýza biosyntéza MeSH
- senioři MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- senioři MeSH
- Publikační typ
- srovnávací studie MeSH
