The placenta represents a non-neuronal organ capable of transporting and metabolizing monoamines. Since these bioactive molecules participate in numerous processes essential for placental and fetal physiology, any imbalance in their levels during pregnancy may affect brain development, projecting a higher risk of behavioral disorders in childhood or adulthood. Notably, the monoamine system in the placenta is a target of various psychoactive drugs and can be disrupted in several pregnancy pathologies. As research in pregnant women poses significant ethical restrictions, animal models are widely employed to study monoamine homeostasis as a mechanism involved in fetal programming. However, detailed knowledge of monoamine transport in the rat placenta is still lacking. Moreover, relatability to the human placental monoamine system is not examined. The present study provides insights into the transplacental monoamine dynamics between maternal and fetal circulation. We show that norepinephrine maternal-to-fetal transport is <4% due to high metabolism within the trophoblast. In contrast, dopamine maternal-to-fetal transport exceeds 25%, likely through passive transport across the membrane. In addition, we show high clearance of norepinephrine and dopamine from the fetal circulation mediated by the organic cation transporter 3 (OCT3). Altogether, we present transcriptional and functional evidence that the in situ rat placenta perfusion represents a suitable model for (patho)physiological investigation of dopamine and norepinephrine homeostasis in the fetoplacental unit. With the rapid advancements in drug discovery and environmental toxicity, the use of rat placenta as a preclinical model could facilitate screening of possible xenobiotic effects on monoamine homeostasis in the placenta.

• MeSH
• biologický transport MeSH
• dopamin * metabolismus   farmakologie   MeSH
• krysa rodu rattus MeSH
• maternofetální výměna látek MeSH
• noradrenalin metabolismus   MeSH
• placenta * metabolismus   MeSH
• těhotenství MeSH
• trofoblasty metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Labile redox-active iron ions have been implicated in various neurodegenerative disorders, including the Parkinson's disease (PD). Iron chelation has been successfully used in clinical practice to manage iron overload in diseases such as thalassemia major; however, the use of conventional iron chelators in pathological states without systemic iron overload remains at the preclinical investigative level and is complicated by the risk of adverse outcomes due to systemic iron depletion. In this study, we examined three clinically-used chelators, namely, desferrioxamine, deferiprone and deferasirox and compared them with experimental agent salicylaldehyde isonicotinoyl hydrazone (SIH) and its boronate-masked prochelator BSIH for protection of differentiated PC12 cells against the toxicity of catecholamines 6-hydroxydopamine and dopamine and their oxidation products. All the assayed chelating agents were able to significantly reduce the catecholamine toxicity in a dose-dependent manner. Whereas hydrophilic chelator desferrioxamine exerted protection only at high and clinically unachievable concentrations, deferiprone and deferasirox significantly reduced the catecholamine neurotoxicity at concentrations that are within their plasma levels following standard dosage. SIH was the most effective iron chelator to protect the cells with the lowest own toxicity of all the assayed conventional chelators. This favorable feature was even more pronounced in prochelator BSIH that does not chelate iron unless its protective group is cleaved in disease-specific oxidative stress conditions. Hence, this study demonstrated that while iron chelation may have general neuroprotective potential against catecholamine auto-oxidation and toxicity, SIH and BSIH represent promising lead molecules and warrant further studies in more complex animal models.

• MeSH
• buňky PC12 MeSH
• chelátory železa * farmakologie   MeSH
• deferasirox farmakologie   MeSH
• deferipron farmakologie   MeSH
• deferoxamin farmakologie   MeSH
• dopamin farmakologie   MeSH
• katecholaminy farmakologie   MeSH
• krysa rodu rattus MeSH
• oxidační stres MeSH
• oxidopamin farmakologie   MeSH
• přetížení železem * MeSH
• železo farmakologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

• Klíčová slova
• inotropní látky, senzitizéry vápníku,
• MeSH
• adrenalin agonisté   aplikace a dávkování   škodlivé účinky   MeSH
• digoxin farmakologie   škodlivé účinky   MeSH
• dobutamin aplikace a dávkování   farmakologie   škodlivé účinky   MeSH
• dopamin aplikace a dávkování   farmakologie   MeSH
• inhibitory fosfodiesterasy 3 aplikace a dávkování   klasifikace   škodlivé účinky   terapeutické užití   MeSH
• isoprenalin aplikace a dávkování   farmakologie   škodlivé účinky   MeSH
• kardiovaskulární látky farmakologie   klasifikace   škodlivé účinky   MeSH
• kardiovaskulární nemoci * farmakoterapie   MeSH
• kontrakce myokardu účinky léků   MeSH
• léková kontraindikace MeSH
• lékové interakce MeSH
• lidé MeSH
• nežádoucí účinky léčiv MeSH
• směrnice pro lékařskou praxi jako téma MeSH
• srdeční glykosidy farmakologie   krev   MeSH
• sympatomimetika * aplikace a dávkování   farmakologie   klasifikace   škodlivé účinky   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

Léčba akutního srdečního selhání je náročná a hospitalizační mortalita zůstává vysoká – až 10 %. Základem jsou stále diuretika, především kličková, a léčba komplikací, jako jsou infekce, léčba diabetes mellitus a další. Další medikaci můžeme obecně rozdělit na vazodilatační léky a pozitivně inotropní léky. Vazodilatační léky jsou vhodné především u nemocných s TKs > 100 mm Hg, lépe více než 115 mm Hg, a používají se nitráty a nitroprusid sodný. Nesiritid neprokázal snížení mortality a ve výzkumu je ularitid a serelaxin. Z pozitivně inotropních léků se užívá dopamin, dobutamin a inhibitory fosfodiesterázy 5, ani jedna léková skupina ale nemá průkaz na snížení mortality ve velké klinické mortalitní studii. Slibný se jeví omecantiv mecarbil, ale první mortalitní studie ATOMIC taktéž neprokázala snížení mortality. Levosimendan je zástupce kalciových senzitizerů, se kterým bylo provedeno několik velkých klinických studií s neutrálním či mírně pozitivním výsledkem. Objevují se i první informace o možnosti opakovaného podání levosimendanu. Součástí léčby je samozřejmě i analgosedace, antiagregační a antikoagulační léčba, kyslík a nefarmakologické postupy.

Treatment of acute heart failure remains complicated and in-hospital mortality remains high at 10%. Diuretics are still the drug of first choice, mainly loop diuretics. It is important to treat complications like infections, diabetes mellitus, etc. Other treatments can be divided into vasodilators and positive inotropic drugs. Vasodilators are especially suitable for patients with BPs > 100 mmHg or even >115 mmHg, and the drugs of choice include nitrates and nitroprusside. Nesiritide has not shown a decrease in mortality, while ularitide and serelaxin are being tested. Dopamine, dobutamine and phosphodiesterase 5 inhibitors are representatives of positive inotropic drugs, but none of them has clear mortality data. Promising data were shown with omecamtiv mecarbil, but the first mortality trial, ATOMIC, showed neutral results. Levosimendan is the only calcium sensitizer with a large clinical program and with neutral and slightly positive results. Repetitive use of levosimendan is also recommended. Antiaggregation, anticoagulation, analgesics and sedatives are also part of acute heart failure treatment, as well as oxygen and non-pharmacological methods.

• MeSH
• adrenalin farmakologie   MeSH
• agonisté beta-1-adrenergních receptorů farmakologie   MeSH
• antiarytmika farmakologie   MeSH
• diuretika farmakologie   MeSH
• dopamin farmakologie   MeSH
• inhibitory fosfodiesterasy 3 farmakologie   MeSH
• kardiotonika farmakologie   MeSH
• klinické zkoušky jako téma MeSH
• lidé MeSH
• natriuretické peptidy farmakologie   MeSH
• noradrenalin farmakologie   MeSH
• směrnice pro lékařskou praxi jako téma MeSH
• srdeční selhání * diagnóza   mortalita   terapie   MeSH
• vazodilatancia farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH
• přehledy MeSH

RATIONALE AND OBJECTIVES: Ghrelin, an orexigenic (appetite stimulating) peptide activates binding sites in the ventral tegmental area (a structure linked with the neural reward system) allowing it to participate in reward-seeking behavior. An increasing number of studies over the past few years have demonstrated ghrelin's role in alcohol, cocaine, and nicotine abuse. However, the role of ghrelin, in opioid effects, has rarely been examined. The aim of the present study was to ascertain whether a ghrelin antagonist (JMV2959) was able to inhibit markers of morphine-induced activation of the neural reward system, namely morphine-induced increase of dopamine in the nucleus accumbens and behavioral changes in rats. METHODS: We used in vivo microdialysis to determine changes of dopamine and its metabolites in the nucleus accumbens shell in rats following morphine (MO, 5, 10 mg/kg s.c.) administration with and without ghrelin antagonist pretreatment (JMV2959, 3, 6 mg/kg i.p., 20 min before MO). Induced behavioral changes were simultaneously monitored. RESULTS: JMV2959 significantly and dose dependently reduced MO-induced dopamine release in the nucleus accumbens shell and affected concentration of by-products associated with dopamine metabolism: 3-methoxytyramine (3-MT), 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA). JMV2959 pretreatment also significantly reduced MO-induced behavioral stimulation, especially stereotyped behavior. CONCLUSIONS: Ghrelin secretagogue receptors (GHS-R1A) appear to be involved in the opioid-induced changes in the mesolimbic dopaminergic system associated with the reward processing.

• MeSH
• chování zvířat účinky léků   MeSH
• dopamin analogy a deriváty   metabolismus   farmakologie   MeSH
• ghrelin metabolismus   MeSH
• glycin aplikace a dávkování   analogy a deriváty   farmakologie   MeSH
• krysa rodu rattus MeSH
• kyselina 3,4-dihydroxyfenyloctová metabolismus   MeSH
• kyselina homovanilová farmakologie   MeSH
• mikrodialýza MeSH
• morfin aplikace a dávkování   farmakologie   MeSH
• nucleus accumbens účinky léků   metabolismus   MeSH
• odměna MeSH
• opioidní analgetika aplikace a dávkování   farmakologie   MeSH
• potkani Wistar MeSH
• receptory ghrelinu antagonisté a inhibitory   metabolismus   MeSH
• stereotypní chování účinky léků   MeSH
• triazoly aplikace a dávkování   farmakologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

BACKGROUND/AIMS: Central dopaminergic activity is probably linked to regulation of glucose and lipid metabolism and weight maintenance. The aim of our study was to evaluate the relationship between central dopaminergic activity measured using the apomorphine challenge test and metabolic parameters in healthy men. METHODS: Forty-two healthy men (average age 43.5 ± 7.4 years, body mass index, BMI, 27.4 ± 5.7) were examined anthropometrically and biochemically (glycemia, lipids, glycated hemoglobin). Central dopaminergic activity was assessed as the area under the curve (AUC) of prolactin (PRL) and growth hormone (GH) responses to the apomorphine challenge test after sublingual administration of apomorphine in a dose of 0.033 mg/kg. Insulin resistance was quantified by calculation of glucose disposal and metabolic clearance rate during a euglycemic hyperinsulinemic clamp on two insulin levels (1 and 10 mIU/kg/min). Linear regression was used for statistical analysis. RESULTS: Hormonal responses correlated negatively with age (for AUC/GH r = -0.33; p = 0.031) and BMI (AUC/GH r = -0.41; p = 0.007). After adjustment for age and BMI, a statistically significant negative correlations between AUC/PRL and total cholesterol (r = -0.41; p = 0.007), AUC/GH and HbA1c (r = -0.37; p = 0.016) and AUC/GH and HOMA (homeostasis model assessment; r = -0.345; p = 0.025) were observed. CONCLUSION: Central dopaminergic activity declines with age and BMI. Higher total cholesterol, glycated hemoglobin and insulin resistance parameters are connected with lower central dopamine tone.

• MeSH
• agonisté dopaminu farmakologie   MeSH
• apomorfin farmakologie   MeSH
• centrální nervový systém účinky léků   metabolismus   fyziologie   MeSH
• dopamin metabolismus   farmakologie   MeSH
• dopaminergní neurony účinky léků   metabolismus   fyziologie   MeSH
• dospělí MeSH
• energetický metabolismus * účinky léků   MeSH
• index tělesné hmotnosti MeSH
• inzulin krev   metabolismus   MeSH
• inzulinová rezistence fyziologie   MeSH
• krevní glukóza metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• zdraví MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky MeSH
• práce podpořená grantem MeSH

Noradrenalin je silně vazokonstrikčně působící katecholamin, který jen nevýznamně ovlivňuje velikost srdečního výdeje a tepovou frekvenci. Proto by jeho užití mohlo příznivě ovlivnit přežívání pacientů v kardiogenním šoku. Autoři porovnávají účinky noradrenalinu s ostatními vazopresory a v tomto kontextu hodnotí jeho indikační výhody a omezení.

Norepinephrine is powerful vasoconstrictor with only minimal impact on cardiac output and heart rate. Hence use of norepinephrine may favourably influence outcome in cardiogenic shock patiens. Authors compare effects of norepinephrine with other vasopressors and in this context evaluate its indication benefits and limitations.

• MeSH
• adrenalin škodlivé účinky   terapeutické užití   MeSH
• akutní nemoc MeSH
• dopamin aplikace a dávkování   farmakologie   terapeutické užití   MeSH
• farmakoterapie metody   trendy   MeSH
• hemodynamika účinky léků   MeSH
• infarkt myokardu komplikace   MeSH
• kardiogenní šok farmakoterapie   komplikace   MeSH
• kardiotonika terapeutické užití   MeSH
• katecholaminy MeSH
• lidé MeSH
• lypresin analogy a deriváty   terapeutické užití   MeSH
• noradrenalin farmakologie   terapeutické užití   MeSH
• srdeční frekvence účinky léků   MeSH
• vasopresiny farmakologie   terapeutické užití   MeSH
• vazokonstriktory terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

Modulation of synaptic transmission in the spinal cord dorsal horn is thought to be involved in the development and maintenance of different pathological pain states. The proinflamatory cytokine, tumor necrosis factor alpha (TNFalpha), is an established pain modulator in both the peripheral and the central nervous system. Up-regulation of TNFalpha and its receptors (TNFR) in dorsal root ganglion (DRG) cells and in the spinal cord has been shown to play an important role in neuropathic and inflammatory pain conditions. Transient receptor potential vanilloid 1 (TRPV1) receptors are known as molecular integrators of nociceptive stimuli in the periphery, but their role on the spinal endings of nociceptive DRG neurons is unclear. The endogenous TRPV1 receptor agonist N-oleoyldopamine (OLDA) was shown previously to activate spinal TRPV1 receptors. In our experiments the possible influence of TNFalpha on presynaptic spinal cord TRPV1 receptor function was investigated. Using the patch-clamp technique, miniature excitatory postsynaptic currents (mEPSCs) were recorded in superficial dorsal horn neurons in acute slices after incubation with 60 nM TNFalpha. A population of dorsal horn neurons with capsaicin sensitive primary afferent input recorded after the TNFalpha pretreatment had a basal mEPSC frequency of 1.35 +/- 0.20 Hz (n = 13), which was significantly higher when compared to a similar population of neurons in control slices (0.76 +/- 0.08 Hz; n = 53; P < 0.01). In control slices application of a low concentration of OLDA (0.2 uM) did not evoke any change in mEPSC frequency. After incubation with TNFalpha, OLDA (0.2 uM) application to slices induced a significant increase in mEPSC frequency (155.5 +/- 17.5%; P < 0.001; n = 10). Our results indicate that TNFalpha may have a significant impact on nociceptive signaling at the spinal cord level that could be mediated by increased responsiveness of presynaptic TRPV1 receptors to endogenous agonists. This could be of major importance, especially during pathological conditions, when increased levels of TNFalpha and TNFR are present in the spinal cord.

• MeSH
• analýza rozptylu MeSH
• buňky zadních rohů míšních účinky léků   metabolismus   MeSH
• dopamin analogy a deriváty   farmakologie   MeSH
• excitační postsynaptické potenciály účinky léků   fyziologie   MeSH
• kationtové kanály TRPV metabolismus   MeSH
• krysa rodu rattus MeSH
• metoda terčíkového zámku MeSH
• mícha účinky léků   metabolismus   MeSH
• miniaturní postsynaptické potenciály účinky léků   fyziologie   MeSH
• nervový přenos účinky léků   fyziologie   MeSH
• potkani Wistar MeSH
• TNF-alfa farmakologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

For over 30 years empirical studies have repeatedly demonstrated that the biosynthesis of morphine by diverse animal and human tissues occurs. Recently, the blue mussel's neural tissues and human white blood cells were used to demonstrate the de novo biosynthesis of morphine for small precursor molecules derived from the aromatic amino acid L-tyrosine. Because catecholamine precursors, i.e., L-3,4-dihydroxyphenylalanine (L-DOPA), were also found to be utilized as morphine precursors, a novel reciprocally interactive mechanism is apparent that links catecholamine and opioid pathways in the activation and inhibition of diverse tissue responses. Additionally, these observations provide new insights into morphinergic signalling that transcend analgesia and addiction. We have also linked the biological effects of nitric oxide into a common effect in endogenous morphine signalling. Given the singular importance of dopamine and morphine's interaction in the CNS, the presence and association of this signalling with nitric oxide all promises to provide novel answers for mental health phenomena, which have been lacking because of the inability in accepting the empirical endogenous morphine studies.

• MeSH
• dopamin farmakologie   MeSH
• katecholaminy metabolismus   MeSH
• leukocyty metabolismus   MeSH
• levodopa metabolismus   MeSH
• lidé MeSH
• morfin biosyntéza   farmakologie   MeSH
• Mytilus edulis metabolismus   MeSH
• opioidní peptidy metabolismus   MeSH
• oxid dusnatý farmakologie   MeSH
• signální transdukce MeSH
• tyrosin metabolismus   MeSH
• závislost na morfiu psychologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• přehledy MeSH

Transient receptor potential vanilloid (TRPV1) receptors are abundant in a subpopulation of primary sensory neurons that convey nociceptive information from the periphery to the spinal cord dorsal horn. The TRPV1 receptors are expressed on both the peripheral and central branches of these dorsal root ganglion (DRG) neurons and can be activated by capsaicin, heat, low pH, and also by recently described endogenous lipids. Using patch-clamp recordings from superficial dorsal horn (DH) neurons in acute spinal cord slices, the effect of application of the endogenous TRPV1 agonist N-oleoyldopamine (OLDA) on the frequency of miniature excitatory postsynaptic currents (mEPSCs) was evaluated. A high concentration OLDA (10 microM) solution was needed to increase the mEPSC frequency, whereas low concentration OLDA (0.2 microM) did not evoke any change under control conditions. The increase was blocked by the TRPV1 antagonists SB366791 or BCTC. Application of a low concentration of OLDA evoked an increase in mEPSC frequency after activation of protein kinase C by phorbol ester (PMA) and bradykinin or in slices from animals with peripheral inflammation. Increasing the bath temperature from 24 to 34 degrees C enhanced the basal mEPSC frequency, but the magnitude of changes in the mEPSC frequency induced by OLDA administration was similar at both temperatures. Our results suggest that presumed endogenous agonists of TRPV1 receptors, like OLDA, could have a considerable impact on synaptic transmission in the spinal cord, especially when TRPV1 receptors are sensitized. Spinal TRPV1 receptors could play a pivotal role in modulation of nociceptive signaling in inflammatory pain.

• MeSH
• analýza rozptylu MeSH
• anilidy farmakologie   MeSH
• bradykinin farmakologie   MeSH
• cinnamáty farmakologie   MeSH
• dopamin analogy a deriváty   farmakologie   MeSH
• excitační postsynaptické potenciály MeSH
• forbolové estery farmakologie   MeSH
• kationtové kanály TRPV agonisté   antagonisté a inhibitory   MeSH
• krysa rodu rattus MeSH
• měření bolesti metody   MeSH
• metoda terčíkového zámku metody   MeSH
• mícha cytologie   MeSH
• modely nemocí na zvířatech MeSH
• nervové receptory účinky léků   MeSH
• neurogenní zánět chemicky indukované   patofyziologie   MeSH
• novorozená zvířata MeSH
• potkani Wistar MeSH
• signální transdukce fyziologie   účinky léků   MeSH
• spinální ganglia cytologie   MeSH
• techniky in vitro MeSH
• teplota MeSH
• vazodilatancia farmakologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• práce podpořená grantem MeSH