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10 záznamů v Medvik Filtry

Článek

Photopic light-mediated down-regulation of local α1A-adrenergic signaling protects blood-retina barrier in experimental autoimmune uveoretinitis

Stofkova, Andrea
Autor Stofkova, Andrea Division of Molecular Psychoimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, 060-0815, Japan. andrea.stofkova@lf3.cuni.cz. Department of Physiology, Third Faculty of Medicine, Charles University, Prague, Czech Republic. andrea.stofkova@lf3.cuni.cz
Kamimura, Daisuke
Autor Kamimura, Daisuke Division of Molecular Psychoimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, 060-0815, Japan
Ohki, Takuto
Autor Ohki, Takuto Division of Molecular Psychoimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, 060-0815, Japan
Ota, Mitsutoshi
Autor Ota, Mitsutoshi Division of Molecular Psychoimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, 060-0815, Japan
Arima, Yasunobu
Autor Arima, Yasunobu Division of Molecular Psychoimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, 060-0815, Japan
Murakami, Masaaki
Autor Murakami, Masaaki Division of Molecular Psychoimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, 060-0815, Japan. murakami@igm.hokudai.ac.jp

Scientific reports. 2019 ; 9 (1) : 2353. [pub] 20190220

Sci Rep
ISSN 2045-2322
Medvik
Zdroj

We have reported the gateway reflex, which describes specific neural activations that regulate immune cell gateways at specific blood vessels in the central nervous system (CNS). Four types of gateway reflexes exist, all of which induce alterations in endothelial cells at specific vessels of the blood-brain barrier followed by inflammation in the CNS in the presence of CNS-autoreactive T cells. Here we report a new gateway reflex that suppresses the development of retinal inflammation by using an autoreactive T cell-mediated ocular inflammation model. Exposure to photopic light down-regulated the adrenoceptor pathway to attenuate ocular inflammation by suppressing breaching of the blood-retina barrier. Mechanistic analysis showed that exposure to photopic light down-regulates the expression of α1A-adrenoceptor (α1AAR) due to high levels of norepinephrine and epinephrine, subsequently suppressing inflammation. Surgical ablation of the superior cervical ganglion (SCG) did not negate the protective effect of photopic light, suggesting the involvement of retinal noradrenergic neurons rather than sympathetic neurons from the SCG. Blockade of α1AAR signaling under mesopic light recapitulated the protective effect of photopic light. Thus, targeting regional adrenoceptor signaling might represent a novel therapeutic strategy for autoimmune diseases including those that affect organs separated by barriers such as the CNS and eyes.

Článek

Ca2+ sensitization and Ca2+ entry in the control of blood pressure and adrenergic vasoconstriction in conscious Wistar-Kyoto and spontaneously hypertensive rats

Journal of hypertension. 2013 ; 31 (10) : 2025-35.

J Hypertens
ISSN 1473-5598
Medvik
Zdroj

BACKGROUND: Calcium entry through nifedipine-sensitive L-type voltage-dependent calcium channels (L-VDCC) is augmented in spontaneously hypertensive rats (SHR) characterized by enhanced sympathetic vasoconstriction. However, the changes of calcium sensitization mediated by RhoA/Rho kinase pathway are less understood. METHODS AND RESULTS: The participation of calcium entry and calcium sensitization in the control of blood pressure (BP) and vascular contraction was studied in SHR and normotensive Wistar-Kyoto (WKY) rats. The acute administration of fasudil (Rho kinase inhibitor) caused BP decrease which lasted longer in SHR. Fasudil also attenuated adrenergic contraction in femoral or mesenteric arteries of WKY and SHR. BP reduction elicited by fasudil in WKY was more pronounced than that induced by L-VDCC blocker nifedipine (-33±2 vs. -15±3% of baseline BP, P<0.001), whereas both inhibitors were similarly effective in SHR (-36±4 vs. -41±2%). Fasudil pretreatment also attenuated BP elevation elicited by L-VDCC agonist BAY K8644 more in WKY than in SHR (-63±4 vs. -42±5%, P<0.001), indicating reduced calcium sensitization in SHR. Moreover, fasudil pretreatment shifted norepinephrine dose-response curves to the right more in WKY than in SHR. The additional nifedipine pretreatment shifted these curves further to the right but this shift was more pronounced in SHR than in WKY. Thus adrenergic vasoconstriction is more dependent on L-VDCC in SHR and on RhoA/Rho kinase pathway in WKY rats. CONCLUSION: Ca sensitization mediated by RhoA/Rho kinase pathway is attenuated in SHR compared with normotensive WKY rats. This might be a part of the compensation for enhanced Ca entry through L-VDCC in genetic hypertension.

Článek

Coupled nitric oxide and autonomic receptor functional responses in the normal and inflamed urinary bladder of the rat

Physiological research. 2012 ; 61 (4) : 371-380.

Physiol. Res. (Print)
ISSN 1802-9973
Medvik
Zdroj

Both divisions of the autonomic nervous system are involved in regulation of urinary bladder function. Several substances, other than noradrenaline and acetylcholine, seem to play important roles in physiology and pathophysiology of lower urinary tract. In the current study, we aimed to examine if there exist interplays between nitric oxide (NO) and autonomic transmitters and if such interactions vary in different parts of the urinary bladder in healthy and cyclophosphamide (CYP)-induced cystitic rats; when administered to the animals (100 mg/kg; i.p.), the cytotoxic CYP metabolite acrolein induces bladder inflammation. In the current study a series of in vitro functional studies were performed on detrusor muscle strip preparations. Stimulation with electrical field stimulation (EFS), methacholine, adenosine 5´-triphosphate (ATP), and adrenaline evoked contractile responses in isolated bladder preparations that were significantly reduced in cyclophosphamide (CYP)-treated rats. While the nitric oxide synthase inhibitor N(omega)-nitro-L-arginine (L-NNA; 10(-4) M) did not affect contractile responses in normal, healthy strip preparations, it significantly increased the contractile responses to EFS, methacholine and adrenaline, but not to ATP, in the bladders from the CYP-treated rats. In the CYP-treated rats, the ATP-evoked relaxatory part of its dual response (an initial contraction followed by a relaxation) was 6-fold increased in comparison with that of normal preparations, whereas the isoprenaline relaxation was halved in the CYP-treated. While L-NNA (10(-4) M) had no effect on the isoprenaline-evoked relaxations, it reduced the ATP-evoked relaxations in strip preparations from the bladder body of CYP-treated rats. Stimulation of beta(2)- and beta(3)-adrenoceptors evoked relaxations and both responses were reduced in cystitis, the latter to a larger extent. In the trigone, the reduced ATP-evoked contractile response in the inflamed strips was increased by L-NNA, while L-NNA had no effect on the ATP-evoked relaxations, neither on the relaxations in healthy nor on the larger relaxations in the inflamed trigone. The study shows that both contractile and relaxatory functions are altered in the state of inflammation. The parasympathetic nerve-mediated contractions of the body of the bladder, evoked by the release of ATP and acetylcholine, were substantially reduced in cystitis. The relaxations to beta-adrenoceptor and purinoceptor stimulation were also reduced but only the ATP-evoked relaxation involved NO.

MeSH
adenosintrifosfát metabolismus MeSH
adrenergní receptory metabolismus MeSH
cyklofosfamid farmakologie MeSH
cystitida metabolismus patofyziologie MeSH
hladké svalstvo účinky léků metabolismus patofyziologie MeSH
krysa rodu rattus MeSH
močový měchýř metabolismus patofyziologie MeSH
oxid dusnatý metabolismus farmakologie MeSH
potkani Sprague-Dawley MeSH
purinergní receptory metabolismus MeSH
svalová kontrakce účinky léků MeSH
zvířata MeSH
Check Tag
krysa rodu rattus MeSH
mužské pohlaví MeSH
zvířata MeSH
Publikační typ
časopisecké články MeSH
práce podpořená grantem MeSH

Článek

Nevýznamnější lékové interakce antipsychotik v průběhu věku
[Most significant drug interactions of antipsychotics in relation to age]

Přikryl, Radovan, 1974-2015
Autor Autorita CEITEC – MU (Středoevropský technologický institut) Psychiatrická klinika LF MU a FN, Brno

Postgraduální medicína. 2012 ; 14 (1) : 77-82.

Postgraduální med.
ISSN 1212-4184
Medvik
Zdroj

Lékovou interakci můžeme charakterizovat jako jev, kdy se plazmatická koncentrace, a tím i účinky původního léku změní, protože k léku přidáme lék jiný nebo dojde ke kombinaci s určitými druhy potravin. Význam lékových interakcí vzrůstá s polypragmazií. Interakce antipsychotik vznikají na úrovni farmakodynamické a farmakokinetické. Farmakokinetika studuje absorpci, distribuci, metabolismus a exkreci farmaka či jeho metabolitů v lidském těle. Farmakodynamika sleduje profil a intenzitu farmakologického působení daného léku. Z pohledu farmakodynamiky antipsychotika ovlivňují zejména dopaminové, serotoninové, adrenergní, muskarinové a histaminové receptory. Mezi farmakodynamické interakce rovněž patří epileptogenní působení antipsychotik, riziko prodloužení QTc intervalu, hematotoxicita či útlum centrální nervové soustavy. Farmakokinetické interakce antipsychotik spočívají v ovlivnění jejich absorpce, distribuce, metabolismu a exkrece. Nejdůležitější je fáze metabolizace zahrnující oxidaci, redukci a hydrolýzu antipsychotik. Nejvýznamnější je oxidace antipsychotik cytochromem P 450, pro interakce antipsychotik mají potom největší význam tři jeho izoenzymy 2D6, 1A2 a 3A4). Mezi základní znalosti psychiatrů by mělo patřit povědomí o receptorovém profilu a hlavní cesty metabolismu daného psychofarmaka.

Drug interaction can be defined as occurring when the concentration of one drug in the blood plasma (and therefore its effects) are modified either when another drug is added, or in combination with certain foodstuffs or other substances. The significance of drug interaction increases with polypharmacy. Antipsychotics can have interactions on pharmacokinetic level and on pharmacodynamic level. Pharmacokinetics studies absorption, distribution, metabolism and excretion of the drug or its metabolites in the human body. Pharmacodynamics studies the profile and intensity of the pharmacological effects of the given drug. From the point of view of pharmacodynamics, antipsychotics affect mainly the dopamine, serotonin, adrenergic, muscarine and histamine receptors. Other pharmacodynamical interactions include epileptogenic effects of antipsychotics, the risk of prolonging the QTc interval, hematotoxicity and inhibition of central nervous system. Pharmacokinetic interactions of antipsychotics consist in influences to their absorption, metabolism and excretion. The crucial phase is their metabolisation, including oxidation, reduction and hydrolysis of antipsychotics. Oxidation of antipsychotics by cytochrome P 450 is the most significant process there, and the isoenzymes 2D6, 1A2 and 3A4 have the most importance in regards to interaction of antipsychotics. For psychiatrists, awareness of the receptor profile and main metabolic pathways of the psychoactive drugs prescribed should be considered as one of the basic pieces of knowledge.

Článek

Carvedilol and adrenergic agonists suppress the lipopolysaccharide-induced NO production in RAW 264.7 macrophages via the adrenergic receptors

Journal of physiology and pharmacology. 2009 ; 60 (1) : 143-150.

J Physiol Pharmacol
Medvik
Zdroj

The interaction of adrenergic agonists and/or antagonists with the adrenergic receptors expressed on immunologically active cells including macrophages plays an important role in regulation of inflammatory responses. Our study investigated the effects of carvedilol, a unique vasodilating beta-adrenergic antagonist, and endogenous adrenergic agonists (adrenalin, noradrenalin, and dopamine) and/or antagonists (prazosin, atenolol) on lipopolysaccharide-stimulated nitric oxide (NO) production from murine macrophage cell line RAW 264.7. The production of NO was determined as the concentration of nitrites in cell supernatants (Griess reaction) and inducible nitric oxide synthase (iNOS) protein expression (Western blot analysis). Scavenging properties against NO were measured electrochemically. Carvedilol in a concentration range of 1, 5, 10 and 25 microM inhibited iNOS protein expression and decreased the nitrite concentration in cell supernatants. Adrenalin, noradrenalin or dopamine also inhibited the iNOS protein expression and the nitrite accumulation. Prazosine and atenolol prevented the effect of both carvedilol and adrenergic agonists on nitrite accumulation and iNOS expression in lipopolysaccharide-stimulated cells. These results, together with the absence of scavenging properties of carvedilol against NO, imply that both carvedilol and adrenergic agonists suppress the lipopolysaccharide-evoked NO production by macrophages through the activation and modulation of signaling pathways connected with adrenergic receptors.

Článek

Distribution of mRNA and binding sites of adrenoceptors and muscarinic receptors in the rat heart

Life sciences. 2006 ; 79 (2) : 112-120.

ISSN 0024-3205
Medvik
Zdroj

Since there exist some obscurities in the expression of mRNAs and their receptors in the heart, we have investigated the gene expression (mRNA levels) of adrenoceptors (alpha1A-, alpha1B-, beta1-, beta2-, beta3-) and muscarinic receptors (M2) and the density of receptor binding sites (alpha1A-, alpha1B-, beta1-, beta2-adrenoceptors, muscarinic receptors). Moreover, the heart regions consist of tissue rich in ganglion cells (that are of importance in heart neural circuits) and those virtually free of them (myocytes). Therefore, we have examined the differences in the distribution of mRNAs/receptor binding sites in the atrial samples of the heart rich in ganglion cells vs. those are virtually free of them. Binding sites and mRNAs of muscarinic receptors and alpha1B-adrenoceptors differ in their distribution in different heart regions. The mRNAs for beta1- and beta2-adrenoceptors were almost equally distributed herein, while the amount of beta-adrenoceptors significantly differs in the heart regions. The alpha1A- and beta3-adrenoceptors mRNAs were also found in all investigated heart regions, but at significantly lower level and have not shown region differences. This is a new finding, especially to beta3-adrenoceptors, as they were not regularly found in each heart regions. alpha1B-adrenoceptors have similar distribution of their mRNAs and binding sites in some heart parts. Thus, we can conclude that there are noticeable differences in the presence of receptors in heart regions that contain ganglion cells in comparison to those are virtually free of them.