BACKGROUND: The brain stem contains important nuclei that control cardiovascular function via the sympathetic nervous system (SNS), which is strongly influenced by nitric oxide. Its biological activity is also largely determined by oxygen free radicals. Despite many experimental studies, the role of AT1R-NAD(P)H oxidase-superoxide pathway in NO-deficiency is not yet sufficiently clarified. We determined changes in free radical signaling and antioxidant and detoxification response in the brain stem of young and adult Wistar rats during chronic administration of exogenous NO inhibitors. METHODS: Young (4 weeks) and adult (10 weeks) Wistar rats were treated with 7-nitroindazole (7-NI group, 10 mg/kg/day), a specific nNOS inhibitor, with NG-nitro-L-arginine-methyl ester (L-NAME group, 50 mg/kg/day), a nonspecific NOS inhibitor, and with drinking water (Control group) during 6 weeks. Systolic blood pressure was measured by non-invasive plethysmography. Expression of genes (AT1R, AT2R, p22phox, SOD and NOS isoforms, HO-1, MDR1a, housekeeper GAPDH) was identified by real-time PCR. NOS activity was detected by conversion of [3H]-L-arginine to [3H]-L-citrulline and SOD activity was measured using UV VIS spectroscopy. RESULTS: We observed a blood pressure elevation and decrease in NOS activity only after L-NAME application in both age groups. Gene expression of nNOS (youngs) and eNOS (adults) in the brain stem decreased after both inhibitors. The radical signaling pathway triggered by AT1R and p22phox was elevated in L-NAME adults, but not in young rats. Moreover, L-NAME-induced NOS inhibition increased antioxidant response, as indicated by the observed elevation of mRNA SOD3, HO-1, AT2R and MDR1a in adult rats. 7-NI did not have a significant effect on AT1R-NADPH oxidase-superoxide pathway, yet it affected antioxidant response of mRNA expression of SOD1 and stimulated total activity of SOD in young rats and mRNA expression of AT2R in adult rats. CONCLUSION: Our results show that chronic NOS inhibition by two different NOS inhibitors has age-dependent effect on radical signaling and antioxidant/detoxificant response in Wistar rats. While 7-NI had neuroprotective effect in the brain stem of young Wistar rats, L-NAME- induced NOS inhibition evoked activation of AT1R-NAD(P)H oxidase pathway in adult Wistar rats. Triggering of the radical pathway was followed by activation of protective compensation mechanism at the gene expression level.

• Klíčová slova
• Antioxidant response, Brain stem, NOS inhibition, Radical signaling,
• MeSH
• antioxidancia metabolismus   MeSH
• indazoly farmakologie   MeSH
• inhibitory enzymů farmakologie   MeSH
• krysa rodu Rattus MeSH
• metabolická inaktivace * MeSH
• mozkový kmen účinky léků   metabolismus   MeSH
• NG-nitroargininmethylester farmakologie   MeSH
• oxid dusnatý nedostatek   MeSH
• potkani Wistar MeSH
• synthasa oxidu dusnatého antagonisté a inhibitory   MeSH
• věkové faktory MeSH
• volné radikály metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• 7-nitroindazole MeSH Prohlížeč
• antioxidancia MeSH
• indazoly MeSH
• inhibitory enzymů MeSH
• NG-nitroargininmethylester MeSH
• oxid dusnatý MeSH
• synthasa oxidu dusnatého MeSH
• volné radikály MeSH

Lactacystin is a proteasome inhibitor that interferes with several factors involved in heart remodelling. The aim of this study was to investigate whether the chronic administration of lactacystin induces hypertension and heart remodelling and whether these changes can be modified by captopril or melatonin. In addition, the lactacystin-model was compared with NG-nitro-l-arginine-methyl ester (L-NAME)- and continuous light-induced hypertension. Six groups of three-month-old male Wistar rats (11 per group) were treated for six weeks as follows: control (vehicle), L-NAME (40 mg/kg/day), continuous light (24 h/day), lactacystin (5 mg/kg/day) alone, and lactacystin with captopril (100 mg/kg/day), or melatonin (10 mg/kg/day). Lactacystin treatment increased systolic blood pressure (SBP) and induced fibrosis of the left ventricle (LV), as observed in L-NAME-hypertension and continuous light-hypertension. LV weight and the cross-sectional area of the aorta were increased only in L-NAME-induced hypertension. The level of oxidative load was preserved or reduced in all three models of hypertension. Nitric oxide synthase (NOS) activity in the LV and kidney was unchanged in the lactacystin group. Nuclear factor-kappa B (NF-κB) protein expression in the LV was increased in all treated groups in the cytoplasm, however, in neither group in the nucleus. Although melatonin had no effect on SBP, only this indolamine (but not captopril) reduced the concentration of insoluble and total collagen in the LV and stimulated the NO-pathway in the lactacystin group. We conclude that chronic administration of lactacystin represents a novel model of hypertension with collagenous rebuilding of the LV, convenient for testing antihypertensive drugs or agents exerting a cardiovascular benefit beyond blood pressure reduction.

• Klíčová slova
• captopril, fibrosis, hypertension, lactacystin, melatonin, remodelling,
• MeSH
• acetylcystein škodlivé účinky   analogy a deriváty   MeSH
• antihypertenziva aplikace a dávkování   farmakologie   MeSH
• fibróza MeSH
• hypertenze chemicky indukované   farmakoterapie   etiologie   MeSH
• kaptopril aplikace a dávkování   farmakologie   MeSH
• krysa rodu Rattus MeSH
• melatonin aplikace a dávkování   farmakologie   MeSH
• modely nemocí na zvířatech MeSH
• NG-nitroargininmethylester škodlivé účinky   MeSH
• potkani Wistar MeSH
• remodelace komor účinky léků   MeSH
• srdeční komory účinky léků   patologie   MeSH
• světlo škodlivé účinky   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH
• Názvy látek
• acetylcystein MeSH
• antihypertenziva MeSH
• kaptopril MeSH
• lactacystin MeSH Prohlížeč
• melatonin MeSH
• NG-nitroargininmethylester MeSH

Activation of nuclear factor-κB (NF-κB) by increased production of reactive oxygen species (ROS) might induce transcription and expression of different antioxidant enzymes and also of nitric oxide synthase (NOS) isoforms. Thus, we aimed at studying the effect of NF-κB inhibition, caused by JSH-23 (4-methyl-N (1)-(3-phenyl-propyl)-benzene-1,2-diamine) injection, on ROS and NO generation in hereditary hypertriglyceridemic (HTG) rats. 12-week-old, male Wistar and HTG rats were treated with JSH-23 (bolus, 10 μmol, i.v.). After one week, blood pressure (BP), superoxide dismutase (SOD) activity, SOD1, endothelial NOS (eNOS), and NF-κB (p65) protein expressions were higher in the heart of HTG rats compared to control rats. On the other hand, NOS activity was decreased. In HTG rats, JSH-23 treatment increased BP and heart conjugated dienes (CD) concentration (measured as the marker of tissue oxidative damage). Concomitantly, SOD activity together with SOD1 expression was decreased, while NOS activity and eNOS protein expression were increased significantly. In conclusion, NF-κB inhibition in HTG rats led to decreased ROS degradation by SOD followed by increased oxidative damage in the heart and BP elevation. In these conditions, increased NO generation may represent rather a counterregulatory mechanism activated by ROS. Nevertheless, this mechanism was not sufficient enough to compensate BP increase in HTG rats.

• MeSH
• exprese genu účinky léků   MeSH
• fenylendiaminy farmakologie   MeSH
• glutathion analýza   MeSH
• hyperlipoproteinemie typ IV patologie   veterinární   MeSH
• krevní tlak účinky léků   MeSH
• krysa rodu Rattus MeSH
• myokard metabolismus   MeSH
• oxid dusnatý metabolismus   MeSH
• oxidační stres účinky léků   MeSH
• potkani Wistar MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• srdeční komory metabolismus   MeSH
• superoxiddismutasa genetika   metabolismus   MeSH
• synthasa oxidu dusnatého, typ III genetika   metabolismus   MeSH
• synthasa oxidu dusnatého genetika   metabolismus   MeSH
• tělesná hmotnost účinky léků   MeSH
• transkripční faktor RelA genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• 4-methyl-N1-(3-phenylpropyl)benzene-1,2-diamine MeSH Prohlížeč
• fenylendiaminy MeSH
• glutathion MeSH
• oxid dusnatý MeSH
• reaktivní formy kyslíku MeSH
• superoxiddismutasa MeSH
• synthasa oxidu dusnatého, typ III MeSH
• synthasa oxidu dusnatého MeSH
• transkripční faktor RelA MeSH

We aimed to perform a chemical analysis of both Alibernet red wine and an alcohol-free Alibernet red wine extract (AWE) and to investigate the effects of AWE on nitric oxide and reactive oxygen species production as well as blood pressure development in normotensive Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHRs). Total antioxidant capacity together with total phenolic and selected mineral content was measured in wine and AWE. Young 6-week-old male WKY and SHR were treated with AWE (24,2 mg/kg/day) for 3 weeks. Total NOS and SOD activities, eNOS and SOD1 protein expressions, and superoxide production were determined in the tissues. Both antioxidant capacity and phenolic content were significantly higher in AWE compared to wine. The AWE increased NOS activity in the left ventricle, aorta, and kidney of SHR, while it did not change NOS activity in WKY rats. Similarly, increased SOD activity in the plasma and left ventricle was observed in SHR only. There were no changes in eNOS and SOD1 expressions. In conclusion, phenolics and minerals included in AWE may contribute directly to increased NOS and SOD activities of SHR. Nevertheless, 3 weeks of AWE treatment failed to affect blood pressure of SHR.

• MeSH
• antioxidancia chemie   farmakologie   MeSH
• aorta účinky léků   enzymologie   MeSH
• hypertenze metabolismus   patologie   MeSH
• krysa rodu Rattus MeSH
• ledviny účinky léků   enzymologie   MeSH
• minerály analýza   farmakologie   MeSH
• oxid dusnatý metabolismus   MeSH
• polyfenoly analýza   farmakologie   MeSH
• potkani inbrední SHR MeSH
• potkani inbrední WKY MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• rostlinné extrakty chemie   farmakologie   MeSH
• srdeční komory účinky léků   enzymologie   MeSH
• superoxiddismutasa 1 MeSH
• superoxiddismutasa metabolismus   MeSH
• synthasa oxidu dusnatého, typ III metabolismus   MeSH
• víno analýza   MeSH
• Vitis chemie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antioxidancia MeSH
• minerály MeSH
• oxid dusnatý MeSH
• polyfenoly MeSH
• reaktivní formy kyslíku MeSH
• rostlinné extrakty MeSH
• Sod1 protein, rat MeSH Prohlížeč
• superoxiddismutasa 1 MeSH
• superoxiddismutasa MeSH
• synthasa oxidu dusnatého, typ III MeSH

Increased blood pressure (BP) in genetic hypertension is usually caused by high activity of sympathetic nervous system (SNS) which is enhanced by central angiotensin II but lowered by central nitric oxide (NO). We have therefore evaluated NO synthase (NOS) activity as well as neuronal NOS (nNOS), inducible NOS (iNOS) and endothelial NOS (eNOS) protein expression in brainstem and midbrain of adult spontaneously hypertensive rats (SHR) characterized by enhanced sympathetic vasoconstriction. We also studied possible participation of brain NO in antihypertensive effects of chronic captopril treatment of adult SHR. NOS activity was increased in midbrain of SHR compared to Wistar-Kyoto (WKY) rats. This could be ascribed to enhanced iNOS expression, whereas nNOS expression was unchanged and eNOS expression was reduced in this brain region. In contrast, no significant changes of NOS activity were found in brainstem of SHR in which nNOS and iNOS expression was unchanged, but eNOS expression was increased. Chronic captopril administration lowered BP of adult SHR mainly by attenuation of sympathetic tone, whereas the reduction of angiotensin II-dependent vasoconstriction and the decrease of residual BP (amelioration of structural remodeling of resistance vessels) were less important. This treatment did not affect significantly either NOS activity or expression of any NOS isoform in the two brain regions. Our data do not support the hypothesis that altered brain NO formation contributes to sympathetic hyperactivity and high BP of adult SHR with established hypertension.

• MeSH
• kaptopril farmakologie   MeSH
• krevní tlak účinky léků   fyziologie   MeSH
• krysa rodu Rattus MeSH
• mozek účinky léků   enzymologie   MeSH
• NG-nitroargininmethylester farmakologie   MeSH
• pentoliniumtartrát farmakologie   MeSH
• potkani inbrední SHR MeSH
• potkani inbrední WKY MeSH
• renin-angiotensin systém účinky léků   MeSH
• sympatický nervový systém účinky léků   MeSH
• synthasa oxidu dusnatého, typ I metabolismus   MeSH
• synthasa oxidu dusnatého, typ II metabolismus   MeSH
• synthasa oxidu dusnatého, typ III metabolismus   MeSH
• synthasa oxidu dusnatého antagonisté a inhibitory   metabolismus   MeSH
• tělesná hmotnost účinky léků   MeSH
• velikost orgánu účinky léků   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• kaptopril MeSH
• NG-nitroargininmethylester MeSH
• pentoliniumtartrát MeSH
• synthasa oxidu dusnatého, typ I MeSH
• synthasa oxidu dusnatého, typ II MeSH
• synthasa oxidu dusnatého, typ III MeSH
• synthasa oxidu dusnatého MeSH