VASOPRESSIN/physiology Dotaz Zobrazit nápovědu
Amino acid sequence of oxytocin, identified already in 1906 as the uterotonic component of neurohypophyseal extracts, was established in 1953 by Vincent du Vigneaud in New York and Hans Tuppy in Vienna. Its structure was verified by the total synthesis one year after in the du Vigneaud laboratory. In the following years, simplified synthetic strategies elaborated in a number of laboratories worldwide enabled structural modifications of individual sites in the peptide chain, aiming at a detailed elucidation of their influence upon pharmacologic features of oxytocin. Frequently, these peptide analogues opened the way to new, clinically useful drugs. The research on vasopressin, the other main peptide hormone of posterior pituitary, underwent a similar development. Among the first who elaborated a more flexible alternative to du Vigneaud protocol was the peptide group at the Institute of Organic Chemistry and Biochemistry, Czechoslovak Academy of Sciences (ÚOCHB) in Prague, chaired by Josef Rudinger. Its research activities were broadly supported – sometimes even enabled – by František Šorm, director of the Institute. This opened a way to an easier synthesis of oxytocin analogues. Design strategy in Prague was focused on oxytocin analogues with an enhanced metabolic stability (prolongation of half-life in vivo), and on analogues acting as inhibitors to its uterotonic/galactobolic response. In the former case, design strategy has originated from studies of enzymatic stability of oxytocin, accomplished in the biochemical laboratories at the ÚOCHB, or reported in earlier communications. Doseresponse and time-response behaviour of analogues in which potential sites of enzymatic attacks were replaced by resistant sequences, and modified peptides investigated in a number of in situ and/or ex vivo pharmacological experiments. Of particular interest were analogues in which one or both sulphur atoms in the –S-S– bridge were replaced by the methylene group (–CH2–), the so-called carba-analogues. Individual analogues of this series possessed, in various degrees, biological activities of oxytocin but not a prolongation of their responses in pharmacological models or in their physiological clearance. Thus, the carba analogues document, firstly, that the integrity of the disulfide bridge in not a necessary condition of oxytocin (or vasopressin) activity, and secondly, that the –S-S– bridge is not the rate determining site of neurohypophyseal hormone inactivation in vivo. In an attempt to prolong the action of oxytocin, its N-a-group was acylated by an additional amino acid or a short peptide, in expectation that such analogues would act as prohormones: splitting of additional substituent by tissue aminopeptidases would in vivo produce “free” oxytocin (therapeutically, the analogues would act as oxytocin depots). A number of in vivo experiments verified this “hormonogen” model and brought forth some clinically interesting substances; some of them are in use until now. In the latter case, the search for structural modifications potentially leading to antagonism indeed brought some new antagonists but, in particular, contributed to the notion of continuous change from “full” agonism via partial agonism to antagonism, according to the tissue conditions. Such a change could have been achieved for uterotonic response of several analogues by changing calcium and magnesium concentrations in the tissue medium. Ideas originated by Rudinger’s group brought about several clinically useful peptides like Carbetocin, Atosiban, Glypressin, Terlipressin. Very successful was the Prague vasopressin analogue dDAVP (Desmopressin) licensed to the Swedish pharmaceutical company Ferring Läkemedel AB. Josef Rudinger left Czechoslovakia in 1968 and became a professor of molecular biology at the Swiss Federal Institute of Technology (ETH). He passed away, 51 years old, in 1975.
- MeSH
- biomedicínský výzkum * dějiny MeSH
- dějiny 20. století MeSH
- desmopresin dějiny MeSH
- lidé MeSH
- neurohypofyzární hormony dějiny MeSH
- oxytocin * dějiny MeSH
- vasopresiny dějiny MeSH
- Check Tag
- dějiny 20. století MeSH
- lidé MeSH
- Publikační typ
- biografie MeSH
- historické články MeSH
- Geografické názvy
- Česká republika MeSH
Amino acid sequence of oxytocin, identified already in 1906 as the uterotonic component of neurohypophyseal extracts, was established in 1953 by Vincent du Vigneaud in New York and Hans Tuppy in Vienna. Its structure was verified by the total synthesis one year after in the du Vigneaud laboratory. In the following years, simplified synthetic strategies elaborated in a number of laboratories worldwide enabled structural modifications of individual sites in the peptide chain, aiming at a detailed elucidation of their influence upon pharmacologic features of oxytocin. Frequently, these peptide analogues opened the way to new, clinically useful drugs. The research on vasopressin, the other main peptide hormone of posterior pituitary, underwent a similar development. Among the first who elaborated a more flexible alternative to du Vigneaud protocol was the peptide group at the Institute of Organic Chemistry and Biochemistry, Czechoslovak Academy of Sciences (ÚOCHB) in Prague, chaired by Josef Rudinger. Its research activities were broadly supported – sometimes even enabled – by František Šorm, director of the Institute. This opened a way to an easier synthesis of oxytocin analogues. Design strategy in Prague was focused on oxytocin analogues with an enhanced metabolic stability (prolongation of half-life in vivo), and on analogues acting as inhibitors to its uterotonic/galactobolic response. In the former case, design strategy has originated from studies of enzymatic stability of oxytocin, accomplished in the biochemical laboratories at the ÚOCHB, or reported in earlier communications. Dose-response and time-response behaviour of analogues in which potential sites of enzymatic attacks were replaced by resistant sequences, and modified peptides investigated in a number of in situ and/or ex vivo pharmacological experiments. Of particular interest were analogues in which one or both sulphur atoms in the –S-S– bridge were replaced by the methylene group (–CH2–), the so-called carba-analogues. Individual analogues of this series possessed, in various degrees, biological activities of oxytocin but not a prolongation of their responses in pharmacological models or in their physiological clearance. Thus, the carba analogues document, firstly, that the integrity of the disulfide bridge in not a necessary condition of oxytocin (or vasopressin) activity, and secondly, that the –S-S– bridge is not the rate determining site of neurohypophyseal hormone inactivation in vivo. In an attempt to prolong the action of oxytocin, its N-α-group was acylated by an additional amino acid or a short peptide, in expectation that such analogues would act as prohormones: splitting of additional substituent by tissue aminopeptidases would in vivo produce "free" oxytocin (therapeutically, the analogues would act as oxytocin depots). A number of in vivo experiments verified this "hormonogen" model and brought forth some clinically interesting substances; some of them are in use until now. In the latter case, the search for structural modifications potentially leading to antagonism indeed brought some new antagonists but, in particular, contributed to the notion of continuous change from "full" agonism via partial agonism to antagonism, according to the tissue conditions. Such a change could have been achieved for uterotonic response of several analogues by changing calcium and magnesium concentrations in the tissue medium. Ideas originated by Rudinger's group brought about several clinically useful peptides like Carbetocin, Atosiban, Glypressin, Terlipressin. Very successful was the Prague vasopressin analogue dDAVP (Desmopressin) licensed to the Swedish pharmaceutical company Ferring Läkemedel AB. Josef Rudinger left Czechoslovakia in 1968 and became a professor of molecular biology at the Swiss Federal Institute of Technology (ETH). He passed away, 51 years old, in 1975.
Magnocellular neurons in the supraoptic nucleus (SON), which synthesize and release arginine vasopressin (AVP) and oxytocin (OT), express several subtypes of ATP-stimulated purinergic P2X receptors (P2XR) that modulate neuronal activity as well as neurotransmitter and hormone release. However, the physiological impact of this modulation is not well understood. Here, we tested a hypothesis that P2XRs play a role in the sustained release of hormones from SON neurons stimulated through fasting/refeeding. We studied the effect of 2 h of refeeding after 48 h of fasting on P2XR and P2YR mRNA expression and ATP-induced presynaptic and postsynaptic responses in the SON of 30-day-old rats. Quantitative real-time PCR revealed that the expression of P2X2R and AVP mRNA was upregulated, whereas P2X4R, P2X7R, P2Y2R, and OT mRNA levels were not significantly changed and P2Y1R mRNA expression was decreased. Whole-cell patch clamp recordings performed on isolated rat brain slices showed that the amplitude of the ATP-stimulated somatic current and the ATP-induced increases in the frequency of spontaneous GABAergic inhibitory postsynaptic currents were significantly higher in SON neurons from fasted/refed rats than in SON neurons from normally fed rats. No evidence was found for changes in the presynaptic effect of ATP in SON neurons not expressing somatic P2XRs. These results suggest that the increased activity of SON neurons synthesizing AVP is associated with enhanced expression of P2X2Rs on neuronal cell bodies and their GABAergic presynaptic nerve terminals.
- Publikační typ
- časopisecké články MeSH
The neurohormones arginine-vasopressin (AVP) and oxytocin (OT) synthesised in supraoptic and paraventricular nuclei of neurohypophysis regulate lactation, systemic water homeostasis and nociception. Using transgenic rats expressing AVP and OT tagged with fluorescent proteins we demonstrate that both neurohormones are expressed in sensory neurones both in vitro, in primary cultures, and in situ, in the intact ganglia; this expression was further confirmed with immunocytochemistry. Both neurohormones were expressed in nociceptive neurones immunopositive to transient receptor potential vannilloid 1 (TRPV1) channel antibodies. The AVP and OT-expressing DRG neurones responded to AVP, OT, 50 mM K+ and capsaicin with [Ca2+]i transients; responses to AVP and OT were specifically blocked by the antagonists of V1 AVP and OT receptors. Probing the extracellular incubation saline with ELISA revealed AVP and OT secretion from isolated DRGs; this secretion was inhibited by tetanus toxin (TeNT) indicating the role for vesicular release. Expression of OT, but not AVP in DRG neurones significantly increased during lactation. Together, the results indicate novel physiological roles (possibly related to nociception and mood regulation) of AVP and OT in the sensory neurones.
- MeSH
- dehydratace metabolismus MeSH
- exocytóza * MeSH
- fluorescence MeSH
- laktace * MeSH
- nervové receptory metabolismus MeSH
- nocicepce MeSH
- oxytocin metabolismus MeSH
- potkani transgenní MeSH
- receptory oxytocinu metabolismus MeSH
- receptory vasopresinů metabolismus MeSH
- spinální ganglia metabolismus MeSH
- vasopresiny metabolismus MeSH
- zadní lalok hypofýzy metabolismus MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- MeSH
- analýza moči metody MeSH
- desmopresin aplikace a dávkování terapeutické užití MeSH
- diagnostické techniky a postupy MeSH
- dítě MeSH
- klinické alarmy MeSH
- lidé MeSH
- management nemoci MeSH
- močení MeSH
- noční enuréza * diagnóza terapie MeSH
- pití MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- Publikační typ
- směrnice pro lékařskou praxi MeSH
- MeSH
- analýza moči metody MeSH
- desmopresin aplikace a dávkování terapeutické užití MeSH
- diagnostické techniky a postupy MeSH
- dítě MeSH
- klinické alarmy MeSH
- lidé MeSH
- management nemoci MeSH
- močení MeSH
- noční enuréza * diagnóza terapie MeSH
- pití MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- Publikační typ
- přehledy MeSH
Characterisation of G protein-coupled receptors (GPCR) relies on the availability of a toolbox of ligands that selectively modulate different functional states of the receptors. To uncover such molecules, we explored a unique strategy for ligand discovery that takes advantage of the evolutionary conservation of the 600-million-year-old oxytocin/vasopressin signalling system. We isolated the insect oxytocin/vasopressin orthologue inotocin from the black garden ant (Lasius niger), identified and cloned its cognate receptor and determined its pharmacological properties on the insect and human oxytocin/vasopressin receptors. Subsequently, we identified a functional dichotomy: inotocin activated the insect inotocin and the human vasopressin V1b receptors, but inhibited the human V1aR. Replacement of Arg8 of inotocin by D-Arg8 led to a potent, stable and competitive V1aR-antagonist ([D-Arg8]-inotocin) with a 3,000-fold binding selectivity for the human V1aR over the other three subtypes, OTR, V1bR and V2R. The Arg8/D-Arg8 ligand-pair was further investigated to gain novel insights into the oxytocin/vasopressin peptide-receptor interaction, which led to the identification of key residues of the receptors that are important for ligand functionality and selectivity. These observations could play an important role for development of oxytocin/vasopressin receptor modulators that would enable clear distinction of the physiological and pathological responses of the individual receptor subtypes.
- MeSH
- antagonisté antidiuretického hormonu izolace a purifikace metabolismus MeSH
- Formicidae MeSH
- lidé MeSH
- mutační analýza DNA MeSH
- neuropeptidy genetika izolace a purifikace metabolismus MeSH
- receptory vasopresinů agonisté MeSH
- rekombinantní proteiny genetika izolace a purifikace metabolismus MeSH
- substituce aminokyselin MeSH
- vazba proteinů MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The magnocellular vasopressin (AVP) and oxytocin (OT) neurones exhibit specific electrophysiological behaviour, synthesise AVP and OT peptides and secrete them into the neurohypophysial system in response to various physiological stimulations. The activity of these neurones is regulated by the very same peptides released either somato-dendritically or when applied to supraoptic nucleus (SON) preparations in vitro. The AVP and OT, secreted somato-dendritically (i.e. in the SON proper) act through specific autoreceptors, induce distinct Ca(2+) signals and regulate cellular events. Here, we demonstrate that about 70% of freshly isolated individual SON neurones from the adult non-transgenic or transgenic rats bearing AVP (AVP-eGFP) or OT (OT-mRFP1) markers, produce distinct spontaneous [Ca(2+)]i oscillations. In the neurones identified (through specific fluorescence), about 80% of AVP neurones and about 60% of OT neurones exhibited these oscillations. Exposure to AVP triggered [Ca(2+)]i oscillations in silent AVP neurones, or modified the oscillatory pattern in spontaneously active cells. Hyper- and hypo-osmotic stimuli (325 or 275 mOsmol/l) respectively intensified or inhibited spontaneous [Ca(2+)]i dynamics. In rats dehydrated for 3 or 5days almost 90% of neurones displayed spontaneous [Ca(2+)]i oscillations. More than 80% of OT-mRFP1 neurones from 3 to 6-day-lactating rats were oscillatory vs. about 44% (OT-mRFP1 neurones) in virgins. Together, these results unveil for the first time that both AVP and OT neurones maintain, via Ca(2+) signals, their remarkable intrinsic in vivo physiological properties in an isolated condition.
- MeSH
- dehydratace MeSH
- neurony metabolismus MeSH
- nucleus supraopticus metabolismus MeSH
- osmolární koncentrace MeSH
- oxytocin metabolismus MeSH
- potkani Wistar MeSH
- vápník metabolismus MeSH
- vápníková signalizace * MeSH
- vasopresiny metabolismus MeSH
- zelené fluorescenční proteiny metabolismus MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Polycystická choroba ledvin autosomálně dominantního typu je nejčastější dědičné onemocnění ledvin. Pacienti jsou často dispenzarizováni již od dětského věku, kdy je důležitá především striktní kontrola krevního tlaku s pravidelným 24hodinovým monitoringem. Část pacientů je léčena inhibitory angiotenzin-konvertujícího enzymu již od dětského věku. Nyní jsou pacientům doporučována symptomatická opatření – dostatečný příjem tekutiny, omezení nápojů s kofeinem a theinem, omezení příjmu soli a zdravý životní styl. Nejdůležitější již pro mladé pacienty s polycystickou chorobou ledvin autosomálně dominantního typu s normální renální funkcí je přísná kontrola krevního tlaku (podle poslední studie hodnoty do 110/75 mmHg). Z klinických studií jsou nadějné tolvaptan (blokátor vazopresinových V2-receptorů) a deriváty somatostatinu. U dětských pacientů vyšla pozitivně i studie s pravastatinem. Imunosupresiva sirolimus a everolimus vykazovaly u pacientů s polycystickou chorobou ledvin autosomálně dominantního typu řadu nežádoucích účinků bez jasného pozitivního působení.
Polycystic kidney disease of autosomal dominant type is the most common hereditary kidney disease. Patients are often monitored from childhood, because it is necessary to strictly control their blood pressure, with 24 hour monitoring. Some of the patients are treated with inhibitors of angiotensin-converting enzymes from childhood already. Nowadays, patients are primarily recommended to follow symptomatic measures – sufficient hydration, reduced intake of beverages containing caffeine or thein, reduced salt intake and a generally healthy lifestyle. The most important thing for young patients with autosomal dominant polycystic kidney disease with normal renal function is strict blood pressure control (according to latest studies, it should be below 110/75 mmHg). From clinical studies, tolvapatan (vasopressin V2-receptor blocker) and somatostatin derivatives are showing promise. In child patients, a study with pravastatin showed positive results as well. The immunosuppressives sirolimus and everolismus had many adverse effects and no clear positive influence in patients with autosomal dominant polycystic kidney disease.
- Klíčová slova
- studie ALADIN,
- MeSH
- antagonisté antidiuretického hormonu * aplikace a dávkování ekonomika farmakologie škodlivé účinky terapeutické užití MeSH
- beta blokátory terapeutické užití MeSH
- blokátory kalciových kanálů aplikace a dávkování farmakologie škodlivé účinky terapeutické užití MeSH
- blokátory receptorů AT1 pro angiotensin II aplikace a dávkování farmakologie terapeutické užití MeSH
- dieta s nízkým obsahem soli MeSH
- dítě MeSH
- diuretika terapeutické užití MeSH
- dvojitá slepá metoda MeSH
- everolimus MeSH
- hodnocení léčiv MeSH
- hypertenze * diagnóza etiologie farmakoterapie prevence a kontrola MeSH
- hypertrofie levé komory srdeční farmakoterapie MeSH
- imidazolinové receptory agonisté terapeutické užití MeSH
- inhibitory ACE aplikace a dávkování farmakologie terapeutické užití MeSH
- klinické zkoušky jako téma MeSH
- kombinovaná farmakoterapie MeSH
- laboratorní zvířata MeSH
- lidé MeSH
- lisinopril aplikace a dávkování farmakologie terapeutické užití MeSH
- magnetická rezonanční tomografie využití MeSH
- měření krevního tlaku * normy využití MeSH
- metformin MeSH
- monitorování fyziologických funkcí MeSH
- monitorování léčiv MeSH
- myši MeSH
- nízkoproteinová dieta MeSH
- oktreotid MeSH
- pití MeSH
- pohybová aktivita MeSH
- polycystická choroba ledvin * diagnóza etiologie farmakoterapie genetika patofyziologie prevence a kontrola MeSH
- polycystické ledviny autozomálně dominantní diagnóza etiologie farmakoterapie prevence a kontrola MeSH
- pravastatin aplikace a dávkování farmakologie terapeutické užití MeSH
- preklinické hodnocení léčiv MeSH
- prospektivní studie MeSH
- proteinurie chemicky indukované prevence a kontrola MeSH
- randomizované kontrolované studie jako téma MeSH
- sirolimus aplikace a dávkování farmakologie škodlivé účinky terapeutické užití MeSH
- somatostatin * analogy a deriváty aplikace a dávkování farmakologie terapeutické užití MeSH
- statiny MeSH
- tolvaptan MeSH
- vyšetření funkce ledvin MeSH
- výsledek terapie MeSH
- životní styl MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- myši MeSH