Purinergic modulation of norepinephrine release and uptake in rat brain cortex: contribution of glial cells

2013 ◽  
Vol 110 (11) ◽  
pp. 2580-2591 ◽  
Author(s):  
Diana Pinho ◽  
Clara Quintas ◽  
Filipa Sardo ◽  
Teresa Magalhães Cardoso ◽  
Glória Queiroz
Keyword(s):  
Receptor Antagonist ◽  
Brain Cortex ◽  
Purinergic Signaling ◽  
Inhibitory Effect ◽  
Receptor Subtypes ◽  
Nucleoside Transporter ◽  
Norepinephrine Release ◽  
Noradrenergic Transmission ◽  
Norepinephrine Uptake ◽  
Rat Cortical Slices

The pathogenesis of psychiatric and neurodegenerative diseases is often associated with a deregulation of noradrenergic transmission. Considering the potential involvement of purinergic signaling in the modulation of noradrenergic transmission in the brain cortex, this study aimed to identify the P2Y receptor subtypes involved in the modulation of neuronal release and neuronal/glial uptake of norepinephrine. Electrical stimulation (100 pulses at 5 Hz) of rat cortical slices induced norepinephrine release that was inhibited by ATP and ADP (0.01–1 mM), adenosine 5′- O-(2-thiodiphosphate) (ADPβS, 0.03–0.3 mM), and UDP (0.1–1 mM). The effect of ADPβS was mediated by P2Y1receptors and possibly by A1/P2Y1heterodimers since it was attenuated by the A1receptor antagonist DPCPX and by the P2Y1receptor antagonist MRS 2500 but was resistant to the effect of adenosine deaminase (ADA). UDP inhibited norepinephrine release through activation of P2Y6receptors, an effect that was abolished by the P2Y6receptor antagonist MRS 2578 and by DPCPX, indicating that it depends on the formation and/or release of adenosine and activation of A1receptors. Supporting this hypothesis, the inhibitory effect of UDP was also prevented by inhibition of ectonucleotidases, by ADA and was attenuated by the inhibitor of nucleoside transporter 6-[(4-nitrobenzyl)thio]-9-β-d-ribofuranosylpurine (NBTI). Additionally, the inhibitory effect of UDP was attenuated when norepinephrine uptake 1 or 2 was inhibited. In astroglial cultures, ADPβS and UDP increased norepinephrine uptake mainly by activation of P2Y1and P2Y6receptors, respectively. The results indicate that neuronal and glial P2Y1and P2Y6receptors may represent new targets of intervention to regulate noradrenergic transmission in CNS diseases.

Stimulation of neurons in rat ARC inhibits gastric acid secretion via hypothalamic CRF1/2- and NPY-Y1 receptors

2003 ◽  
Vol 285 (6) ◽  
pp. G1075-G1083 ◽  
Author(s):  
Johannes J. Tebbe ◽  
Silke Mronga ◽  
Martin K.-H. Schäfer ◽  
Jens Rüter ◽  
Peter Kobelt ◽  
...  
Keyword(s):  
Acid Secretion ◽  
Receptor Antagonist ◽  
Gastric Acid Secretion ◽  
Gastric Acid ◽  
Excitatory Amino Acid ◽  
Inhibitory Effect ◽  
Receptor Subtypes ◽  
Npy Receptor ◽  
Y1 Receptors ◽  
Open Question

Neuropeptide Y (NPY) neuronal projections from the arcuate nucleus (ARC) have been proposed to target corticotropin-releasing factor (CRF)-positive neurons in the paraventricular nucleus (PVN) as part of the ARC-PVN axis. The existence of a positive feedback loop involving CRF receptors in the PVN has been suggested. Exogenous NPY and CRF in the PVN have been shown to inhibit gastric acid secretion. Recently, we have demonstrated that activation of ARC neurons inhibits gastric acid secretion via vagal pathways. To what extent NPY- and CRF-mediated mechanisms in the PVN contribute to the CNS modulation of gastric acid secretion is still an open question. In the present study, we performed consecutive bilateral microinjections of antagonists to NPY receptor subtypes Y1 and Y2 and to CRF1/2 receptors in the PVN and of the excitatory amino acid kainate in the ARC to assess the role of NPY- and CRF-mediated mechanisms in the kainate-induced effects on gastric acid secretion. Gastric acid secretion was measured at the basal condition and during pentagastrin (16 μg/kg body wt) stimulation. Microinjection of vehicle in the PVN and kainate in the ARC decreased gastric acid secretion. Microinjection of the specific NPY-Y1 receptor antagonist BIBP-3226 (200 pmol) and the nonspecific CRF1/2 antagonist astressin (30 pmol) in the PVN abolished the inhibitory effect of neuronal activation in the ARC by kainate on gastric acid secretion. The CRF antagonist astressin was more effective. Pretreatment with the NPY-Y2 receptor antagonist BIIE-0246 (120 pmol) in the PVN had no significant effect. Our results indicate that activation of neurons in the ARC inhibits gastric acid secretion via CRF1/2 and NPY-Y1 receptor-mediated pathways in the PVN.

Central CRF inhibits gastric emptying of a nutrient solid meal in rats: the role of CRF2receptors

1998 ◽  
Vol 274 (5) ◽  
pp. G965-G970 ◽  
Author(s):  
V. Martinez ◽  
E. Barquist ◽  
J. Rivier ◽  
Y. Taché
Keyword(s):  
Gastric Emptying ◽  
Receptor Antagonist ◽  
Rank Order ◽  
Inhibitory Effect ◽  
Receptor Subtype ◽  
Receptor Subtypes ◽  
Dependent Manner ◽  
Solid Meal ◽  
Purina Chow

Corticotropin-releasing factor (CRF)-related peptides exhibit different affinity for the receptor subtypes 1 and 2 cloned in the rat brain. We investigated, in conscious rats, the effects of intracisternal (IC) injection of CRF (rat/human) on the 5-h rate of gastric emptying of a solid nutrient meal (Purina chow and water ad libitum for 3 h) and the CRF receptor subtype involved. CRF, urotensin I (suckerfish), and sauvagine (frog) injected IC inhibited gastric emptying in a dose-dependent manner, with ED50 values of 0.31, 0.13, and 0.08 μg/rat, respectively. Rat CRF-(6—33) (0.1–10 μg ic) had no effect. The nonselective CRF1and CRF2 receptor antagonist, astressin, injected IC completely blocked the inhibitory effect of IC CRF, urotensin I, and sauvagine with antagonist-to-agonist ratios of 3:1, 10:1, and 16:1, respectively. The CRF1-selective receptor antagonist NBI-27914 injected IC at a ratio of 170:1 had no effect. These data show that central CRF and CRF-related peptides are potent inhibitors of gastric emptying of a solid meal with a rank order of potency characteristic of the CRF2receptor subtype affinity (sauvagine > urotensin I > CRF). In addition, the reversal by astressin but not by the CRF1-selective receptor antagonist further supports the view that the CRF2 receptor subtype is primarily involved in central CRF-induced delayed gastric emptying.

Phospholipase C from Clostridium Perfringens Induces Human Platelet Aggregation in Plasma

1988 ◽  
Vol 59 (02) ◽  
pp. 236-239 ◽  
Author(s):  
Giovanna Barzaghi ◽  
Chiara Cerletti ◽  
Giovanni de Gaetano
Keyword(s):  
Platelet Aggregation ◽  
Receptor Antagonist ◽  
Phospholipase C ◽  
Clostridium Perfringens ◽  
Human Platelet ◽  
Ex Vivo ◽  
Platelet Rich Plasma ◽  
Platelet Activating Factor ◽  
Inhibitory Effect ◽  
Thromboxane Receptor Antagonist

SummaryWe studied the aggregating effect of different concentrations of phospholipase C (PLC) (extracted from Clostridium perfringens) on human platelet-rich plasma (PRP). PRP was preincubated with PLC for 3 min at 37° C and the platelet aggregation was followed for 10 min. The threshold aggregating concentration (TAG) of PLC was 3-4 U/ml.We also studied the potentiation of PLC with other stimuli on platelet aggregation. Potentiating stimuli, such as arachidonic acid (AA), ADP. Platelet Activating Factor (PAF) and U-46619 (a stable analogue of cyclic endoperoxides) were all used at subthreshold concentrations. We also studied the possible inhibitory effect of aspirin, apyrase, TMQ, a prostaglandin endoper- oxide/thromboxane receptor antagonist and BN-52021, a PAF receptor antagonist. Only aspirin and apyrase were able to reduce aggregation induced by PLC alone and PLC + AA and PLC + ADP respectively. TMQ and BN-52021 were inactive. In ex vivo experiments oral aspirin (500 mg) partially inhibited platelet aggregation induced by PLC alone, PLC + AA and PLC + ADP 2 and 24 h after administration. Aspirin 20 mg for 7 days also reduced aggregation induced by PLC + AA.

scholarly journals Melatonin MT1 and MT2 Receptors Exhibit Distinct Effects in the Modulation of Body Temperature across the Light/Dark Cycle

2019 ◽  
Vol 20 (10) ◽  
pp. 2452 ◽  
Author(s):  
Martha López-Canul ◽  
Seung Hyun Min ◽  
Luca Posa ◽  
Danilo De Gregorio ◽  
Annalida Bedini ◽  
...  
Keyword(s):  
Body Temperature ◽  
Receptor Antagonist ◽  
Partial Agonist ◽  
Receptor Subtypes ◽  
Dark Phase ◽  
Light Phase ◽  
Dark Cycle ◽  
Simultaneous Activation ◽  
Type 3 ◽  
G Protein Coupled

Melatonin (MLT) is a neurohormone that regulates many physiological functions including sleep, pain, thermoregulation, and circadian rhythms. MLT acts mainly through two G-protein-coupled receptors named MT1 and MT2, but also through an MLT type-3 receptor (MT3). However, the role of MLT receptor subtypes in thermoregulation is still unknown. We have thus investigated the effects of selective and non-selective MLT receptor agonists/antagonists on body temperature (Tb) in rats across the 12/12-h light–dark cycle. Rectal temperature was measured every 15 min from 4:00 a.m. to 9:30 a.m. and from 4:00 p.m. to 9:30 p.m., following subcutaneous injection of each compound at either 5:00 a.m. or 5:00 p.m. MLT (40 mg/kg) had no effect when injected at 5 a.m., whereas it decreased Tb during the light phase only when injected at 5:00 p.m. This effect was blocked by the selective MT2 receptor antagonist 4P-PDOT and the non-selective MT1/MT2 receptor antagonist, luzindole, but not by the α1/MT3 receptors antagonist prazosin. However, unlike MLT, neither the selective MT1 receptor partial agonist UCM871 (14 mg/kg) nor the selective MT2 partial agonist UCM924 (40 mg/kg) altered Tb during the light phase. In contrast, UCM871 injected at 5:00 p.m. increased Tb at the beginning of the dark phase, whereas UCM924 injected at 5:00 a.m. decreased Tb at the end of the dark phase. These effects were blocked by luzindole and 4P-PDOT, respectively. The MT3 receptor agonist GR135531 (10 mg/kg) did not affect Tb. These data suggest that the simultaneous activation of both MT1 and MT2 receptors is necessary to regulate Tb during the light phase, whereas in a complex but yet unknown manner, they regulate Tb differently during the dark phase. Overall, MT1 and MT2 receptors display complementary but also distinct roles in modulating circadian fluctuations of Tb.

scholarly journals Role of beta-adrenergic receptor subtypes in pig uterus contractility with inflammation

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Barbara Jana ◽  
Jarosław Całka
Keyword(s):  
Adrenergic Receptors ◽  
Adrenergic Receptor ◽  
Domestic Animals ◽  
Inhibitory Effect ◽  
Receptor Subtypes ◽  
Beta Adrenergic Receptor ◽  
Pharmacological Modulation ◽  
Uterine Inflammation ◽  
Myometrial Contractility

AbstractUterine inflammation is a very common and serious condition in domestic animals. To development and progression of this pathology often lead disturbances in myometrial contractility. Participation of β1-, β2- and β3-adrenergic receptors (ARs) in noradrenaline (NA)-influenced contractility of the pig inflamed uterus was studied. The gilts of SAL- and E.coli-treated groups were administered saline or E.coli suspension into the uterine horns, respectively. Laparotomy was only done in the CON group. Compared to the period before NA administration, this neurotransmitter reduced the tension, amplitude and frequency in uterine strips of the CON and SAL groups. In the E.coli group, NA decreased the amplitude and frequency, and these parameters were lower than in other groups. In the CON, SAL and E.coli groups, β1- and β3-ARs antagonists in more cases did not significantly change and partly eliminated NA inhibitory effect on amplitude and frequency, as compared to NA action alone. In turn, β2-ARs antagonist completely abolished NA relaxatory effect on these parameters in three groups. Summarizing, NA decreases the contractile amplitude and frequency of pig inflamed uterus via all β-ARs subtypes, however, β2-ARs have the greatest importance. Given this, pharmacological modulation of particular β-ARs subtypes can be used to increase inflamed uterus contractility.

Subcellular Localization and Complements of GABAA and GABAC Receptors on Bullfrog Retinal Bipolar Cells

2000 ◽  
Vol 84 (2) ◽  
pp. 666-676 ◽  
Author(s):  
Jiu-Lin Du ◽  
Xiong-Li Yang
Keyword(s):  
Subcellular Localization ◽  
Receptor Antagonist ◽  
Gaba Receptor ◽  
Drug Application ◽  
Bipolar Cells ◽  
Visual Signals ◽  
Receptor Subtypes ◽  
Inner Retina ◽  
Axon Terminals ◽  
Retinal Bipolar Cells

γ-Aminobutyric acid (GABA) receptors on retinal bipolar cells (BCs) are highly relevant to spatial and temporal integration of visual signals in the outer and inner retina. In the present work, subcellular localization and complements of GABAA and GABACreceptors on BCs were investigated by whole cell recordings and local drug application via multi-barreled puff pipettes in the bullfrog retinal slice preparation. Four types of the BCs (types 1–4) were identified morphologically by injection of Lucifer yellow. According to the ramification levels of the axon terminals and the responses of these cells to glutamate (or kainate) applied at their dendrites, types 1 and 2 of BCs were supposed to be off type, whereas types 3 and 4 of BCs might be on type. Bicuculline (BIC), a GABAA receptor antagonist, and imidazole-4-acetic acid (I4AA), a GABAC receptor antagonist, were used to distinguish GABA receptor-mediated responses. In all BCs tested, not only the axon terminals but also the dendrites showed high GABA sensitivity mediated by both GABAA and GABACreceptors. Subcellular localization and complements of GABAA and GABAC receptors at the dendrites and axon terminals were highly related to the dichotomy of offand on BCs. In the case of off BCs, GABAA receptors were rather evenly distributed at the dendrites and axon terminals, but GABAC receptors were predominantly expressed at the axon terminals. Moreover, the relative contribution of GABAC receptors to the axon terminals was prevalent over that of GABAA receptors, while the situation was reversed at the dendrites. In the case of on BCs, GABAA and GABAC receptors both preferred to be expressed at the axon terminals; relative contributions of these two GABA receptor subtypes to both the sites were comparable, while GABAC receptors were much less expressed than GABAA receptors. GABAA, but not GABAC receptors, were expressed clusteringly at axons of a population of BCs. In a minority of BCs, I4AA suppressed the GABAC responses at the dendrites, but not at the axon terminal, implying that the GABAC receptors at these two sites may be heterogeneous. Taken together, these results suggest that GABAA and GABAC receptors may play different roles in the outer and inner retina and the differential complements of the two receptors on off and on BCs may be closely related to physiological functions of these cells.

Cerebrovascular characterization of clazosentan, the first nonpeptide endothelin receptor antagonist clinically effective for the treatment of cerebral vasospasm. Part I: Inhibitory effect on endothelinA receptor—mediated contraction

2005 ◽  
Vol 102 (6) ◽  
pp. 1101-1107 ◽  
Author(s):  
Hartmut Vatter ◽  
Michael Zimmermann ◽  
Veronika Tesanovic ◽  
Andreas Raabe ◽  
Lothar Schilling ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Cerebral Vasospasm ◽  
Isometric Force ◽  
Inhibitory Effect ◽  
Affinity Constant ◽  
Dependent Manner ◽  
Content Type ◽  
The Right ◽  
Fine Print

Object. The central role of endothelin (ET)—1 in the development of cerebral vasospasm after subarachnoid hemorrhage is indicated by the successful treatment of this vasospasm in several animal models by using selective ETA receptor antagonists. Clazosentan is a selective ETA receptor antagonist that provides for the first time clinical proof that ET-1 is involved in the pathogenesis of cerebral vasospasm. The aim of the present investigation was, therefore, to define the pharmacological properties of clazosentan that affect ETA receptor—mediated contraction in the cerebrovasculature. Methods. Isometric force measurements were performed in rat basilar artery (BA) ring segments with (E+) and without (E−) endothelial function. Concentration effect curves (CECs) were constructed by cumulative application of ET-1 or big ET-1 in the absence or presence of clazosentan (10−9, 10−8, and 10−7 M). The inhibitory potency of clazosentan was determined by the value of the affinity constant (pA2). The CECs for contraction induced by ET-1 and big ET-1 were shifted to the right in the presence of clazosentan in a parallel dose-dependent manner, which indicates competitive antagonism. The pA2 values for ET-1 were 7.8 (E+) and 8.6 (E−) and the corresponding values for big ET-1 were 8.6 (E+) and 8.3 (E−). Conclusions. The present data characterize clazosentan as a potent competitive antagonist of ETA receptor—mediated constriction of the cerebrovasculature by ET-1 and its precursor big ET-1. These functional data may also be used to define an in vitro profile of an ET receptor antagonist with a high probability of clinical efficacy.

Spinal Endogenous Acetylcholine Contributes to the Analgesic Effect of Systemic Morphine in Rats

2001 ◽  
Vol 95 (2) ◽  
pp. 525-530 ◽  
Author(s):  
Shao-Rui Chen ◽  
Hui-Lin Pan
Keyword(s):  
Spinal Cord ◽  
Receptor Antagonist ◽  
Analgesic Effect ◽  
Antinociceptive Effect ◽  
Intrathecal Injection ◽  
Radiant Heat ◽  
Cholinergic Receptor ◽  
Inhibitory Effect ◽  
Withdrawal Latency ◽  
Aziridinium Ion

Background Systemic morphine is known to cause increased release of acetyicholine in the spinal cord. Intrathecal injection of the cholinergic receptor agonists or acetyicholinesterase inhibitors produces antinociception in both animals and humans. In the present study, we explored the functional importance of spinal endogenous acetylcholine in the analgesic action produced by intravenous morphine. Methods Rats were implanted with intravenous and intrathecal catheters. The antinociceptive effect of morphine was determined by the paw-withdrawal latency in response to a radiant heat stimulus after intrathecal treatment with atropine (a muscarinic receptor antagonist), mecamylamine (a nicotinic receptor antagonist), or cholinergic neurotoxins (ethylcholine mustard aziridinium ion [AF64A] and hemicholinium-3). Results Intravenous injection of 2.5 mg/kg morphine increased significantly the paw-withdrawal latency. Intrathecal pretreatment with 30 microg atropine (n = 7) or 50 microg mecamylamine (n = 6) both attenuated significantly the antinociceptive effect of morphine. The inhibitory effect of atropine on the effect of morphine was greater than that of mecamylanilne. Furthermore, the antinociceptive effect of morphine was significantly reduced in rats pretreated with intrathecal AF64A (n = 7) or hemicholinium-3 (n = 6) to inhibit the high-affinity choline transporter and acetylcholine synthesis. We found that intrathecal AF64A reduced significantly the [3H]hemicholinium-3 binding sites but did not affect its affinity in the dorsal spinal cord. Conclusions The data in the current study indicate that spinal endogenous acetylcholine plays an important role in mediating the analgesic effect of systemic morphine through both muscarinic and nicotinic receptors.

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