340,675 research outputs found

    Human interleukin-1 receptor antagonist is expressed in liver

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    AbstractUsing PCR and Northern blot analysis, an IL-1 receptor antagonist specific transcript was amplified from HepG2- and liver mRNA, cDNA clones coding for IL-1 receptor antagonist were isolated from a liver cDNA library and sequence comparison revealed complete identity with the secreted, monocytic form of IL-1 receptor antagonist

    Comparison of antimüllerian hormone levels and antral follicle count as predictor of ovarian response to controlled ovarian stimulation in good-prognosis patients at individual fertility clinics in two multicenter trials

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    Objective To compare antimüllerian hormone (AMH) and antral follicle count (AFC) as predictors of ovarian response to controlled ovarian stimulation at individual fertility clinics. Design Retrospective analysis of individual study center data in two multicenter trials. Centers that provided >10 patients were included in the analysis. Setting A total of 19 (n = 519 patients) and 18 study centers (n = 686 patients) participating in a long GnRH agonist trial (MERIT) and a GnRH antagonist trial (MEGASET), respectively. Patient(s) Infertile women of good prognosis. Intervention(s) Long GnRH agonist or GnRH antagonist cycles. Main Outcome Measure(s) Correlation between AMH and AFC, and oocyte yield by each study center for each trial. Results(s) Antimüllerian hormone was more strongly correlated with oocyte yield than AFC: r = 0.56 vs. r = 0.28 in the GnRH agonist cohort, and r = 0.55 vs. r = 0.33 in the GnRH antagonist cohort. The correlation was numerically higher for AMH than for AFC at a significantly higher proportion of study centers: 17 (89%) and 15 (83%) centers in the long GnRH agonist and GnRH antagonist trial, respectively. Assessment of the relative capacity of AMH and AFC for predicting oocyte yield demonstrated that AMH dominated the model: AMH, R2 = 0.29 and 0.23; AFC: R2 = 0.07 and 0.07; AMH + AFC: R2 = 0.30 and 0.23 for long GnRH agonist and GnRH antagonist trials, respectively. Conclusions(s) Antimüllerian hormone was a stronger predictor of ovarian response to gonadotropin therapy than AFC at the study center level in both randomized trials utilizing GnRH agonist and GnRH antagonist protocols. Antral follicle count provided no added predictive value beyond AMH.</p

    Effects of a Secretin Receptor Antagonist on Cerebellar Learning

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    Eyeblink conditioning (EBC) is an important procedure used to understand the neuronal plasticity that occurs with learning and memory. Delay EBC requires a brainstem-cerebellar circuit while the role of the cerebellum in trace EBC is not as well understood because it requires a more complex neural circuitry involving regions of the medial prefrontal cortex and hippocampus. Secretin is a neuropeptide that is found in high concentrations within the cerebellum. Previous work has shown that blocking secretin’s effects in the cerebellum with intra-cerebellar infusion of relatively large volume of a secretin receptor antagonist impairs delay EBC (Fuchs et al. 2014). Here we study the effect that intra-cerebellar infusion of 0.5 μL secretin receptor antagonist (5-27 secretin) or vehicle prior to training sessions 1 and 2 has on delay and trace EBC in rats. A 600-ms tone CS was used for the delay EBC paradigm and a 300-ms tone CS followed by a 300-ms trace interval was used for the trace EBC paradigm. For delay EBC, the delay vehicle and antagonist groups displayed similar acquisition of conditioned responses (CRs). There was a trend for the trace antagonist group to underperform compared to the trace vehicle group though not quite at a significant level. One explanation for why the results for the delay EBC do not support previous work is that slow learning occurred in the delay vehicle group that may have prevented the effects of secretin receptor antagonist from reaching significance. The trend for the trace antagonist group to display decreased acquisition of CRs suggests that the cerebellum does play an important role in trace EBC. However, in order to better understand the neural circuitry involved in trace EBC, future work should analyze the role that cerebellar secretin itself has on trace EBC

    Interaction of GABA and Excitatory Amino Acids in the Basolateral Amygdala: Role in Cardiovascular Regulation

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    Activation of the amygdala in rats produces cardiovascular changes that include increases in heart rate and arterial pressure as well as behavioral changes characteristic of emotional arousal. The objective of the present study was to examine the interaction of GABA and excitatory amino acid (EAA) receptors in the basolateral amygdala (BLA) in regulating cardiovascular function. Microinjection of the GABAA receptor antagonist bicuculline methiodide (BMI) or the E A A receptor agonists NMDA or AMPA into the same region of the BLA of conscious rats produced dose-related increases in heart rate and arterial pressure. Injection of the nonselective EAA receptor antagonist kynurenic acid into the BLA prevented or reversed the cardiovascular changes caused by local injection of BMI or the noncompetitive GABA antagonist picrotoxin. Conversely, local pretreatment with the glutamate reuptake inhibitorl-trans-pyrrolidine-2,4-dicarboxylic acid enhanced the effects of intra-amygdalar injection of BMI. The cardiovascular effects of BMI were also attenuated by injection of either the NMDA antagonist 3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP) or the AMPA receptor antagonist 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide (NBQX). When these two EAA receptor antagonists were combined, their ability to suppress BMI-induced tachycardic and pressor responses was additive. These findings indicate that the cardiovascular effects caused by blockade of GABAergic inhibition in the BLA of the rat are dependent on activation of local NMDA and AMPA receptors

    Interaction of hypothalamic GABA\u3csub\u3eA\u3c/sub\u3e and excitatory amino acid receptors controlling heart rate in rats

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    We have previously shown that microinjection of drugs that impair gamma-aminobutyric acid (GABA)-mediated synaptic inhibition into the dorsomedial hypothalamus (DMH) of rats generates cardiovascular and behavioral changes that mimic the response to stress. The purpose of this study was to examine the role of excitatory amino acid (EAA) receptors in the DMH in generating the cardiovascular changes caused by withdrawal of local GABAergic inhibition in urethan-anesthetized rats. Local treatment of the DMH with the nonselective EAA antagonist kynurenic acid blocked or reversed the increases in heart rate and blood pressure caused by microinjection of the GABAA antagonists bicuculline methiodide (BMI) or picrotoxin into the same region. Conversely, similar injection of xanthurenic acid, a structural analogue of kynurenic acid without significant effects on EAA receptors, did not significantly alter the cardiovascular changes produced by either GABAA antagonist. The tachycardic effects of BMI were also attenuated by injection of either the N-methyl-D-aspartate (NMDA) receptor antagonist 2-amino-5-phosphonopentanoic acid or the non-NMDA EAA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione. When the two EAA receptor antagonists were combined, their effects to suppress the BMI-induced tachycardia were additive. These findings suggest that the cardiovascular effects caused by blockade of GABAergic inhibition in the DMH of the rat are dependent on activation of local NMDA and non-NMDA EAA receptors

    Kinin-B1 receptors in ischaemia-induced pancreatitis: Functional importance and cellular localisation

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    In this study we compare the role of kininB1 and B2 receptors during ischaemia/reperfusion of rat pancreas. Our investigations were prompted by the observation that infusion of a kininB2 receptor antagonist produced significant improvement in acute experimental pancreatitis. In an acute model with two hours of ischaemia/two hours of reperfusion, application of the kininB1 receptor antagonist (CP-0298) alone, or in combination with kininB2 receptor antagonist (CP-0597), significantly reduced the number of adherent leukocytes in postcapillary venules. In a chronic model with five days of reperfusion, the continuous application of kininB1 receptor antagonist or a combination of kininB1 and B2 receptor antagonists markedly reduced the survival rate. In kininreceptor binding studies kininB1 receptor showed a 22-fold increase in expression during the time of ischaemia/ reperfusion. Carboxypeptidase M activity was upregulated 10-fold following two hours of ischaemia and two hours of reperfusion, provided the appropriate specific ligand, desArg10-kallidin and/or desArg9-bradykinin, was used. The occurrence of kininB1 receptor binding sites on acinar cell membranes was demonstrated by microautoradiography. With a specific antibody, the localisation of kininB1 receptor protein was confirmed at the same sites. In conclusion, we have demonstrated the upregulation of the pancreatic acinar cell kininB1 receptors during ischaemia/reperfusion. The novel functional finding was that antagonism of the kininB1 receptors decreased the survival rate in an experimental model of pancreatitis

    Non-equivalence of key positively charged residues of the free fatty acid 2 receptor in the recognition and function of agonist versus antagonist ligands

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    Short chain fatty acids (SCFAs) are produced in the gut by bacterial fermentation of poorly digested carbohydrates. A key mediator of their actions is the G protein-coupled Free Fatty Acid 2 (FFA2) receptor and this has been suggested as a therapeutic target for the treatment of both metabolic and inflammatory diseases. However, a lack of understanding of the molecular determinants dictating how ligands bind to this receptor has hindered development. We have developed a novel radiolabelled FFA2 antagonist in order to probe ligand binding to FFA2 and in combination with mutagenesis and molecular modelling studies define how agonist and antagonist ligands interact with the receptor. Although both agonist and antagonist ligands contain negatively charged carboxylates that interact with two key positively charged arginine residues in transmembrane domains V and VII of FFA2, there are clear differences in how these interactions occur. Specifically, while agonists require interaction with both arginine residues to bind the receptor, antagonists require an interaction with only one of the two. Moreover, different chemical series of antagonist interact preferentially with different arginine residues. A homology model capable of rationalizing these observations was developed and provides a tool that will be invaluable for identifying improved FFA2 agonists and antagonists to further define function and therapeutic opportunities of this receptor

    Anti-nausea effects and pharmacokinetics of ondansetron, maropitant and metoclopramide in a low-dose cisplatin model of nausea and vomiting in the dog: a blinded crossover study

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    Nausea is a subjective sensation which is difficult to measure in non-verbal species. The aims of this study were to determine the efficacy of three classes of antiemetic drugs in a novel low dose cisplatin model of nausea and vomiting and measure change in potential nausea biomarkers arginine vasopressin (AVP) and cortisol. A four period cross-over blinded study was conducted in eight healthy beagle dogs of both genders. Dogs were administered 18 mg/m2 cisplatin intravenously, followed 45 min later by a 15 min infusion of either placebo (saline) or antiemetic treatment with ondansetron (0.5 mg/kg; 5-HT3 antagonist), maropitant (1 mg/kg; NK1 antagonist) or metoclopramide (0.5 mg/kg; D2 antagonist). The number of vomits and nausea associated behaviours, scored on a visual analogue scale, were recorded every 15 min for 8 h following cisplatin administration. Plasma samples were collected to measure AVP, cortisol and antiemetic drug concentrations

    Effect of an antiandrogenic H<inf>2</inf> receptor antagonist on hepatic regeneration in rats

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    Because biochemical 'feminization' of the liver in males is observed with hepatic regeneration and because the hepatic regenerative response in females is greater than that in males, the posibility that antiandrogens might potentiate liver regeneration was investigated. Before 70% hepatectomy, adult male Wistar rats were treated with cimetidine, and antiandrogenic H2 antagonist, at doses up to 10 times greater than those used clinically. Control animals received either the saline vehicle or ranitidine, an H2 antagonist without antiandrogenic properties. Treatment with cimetidine reduced the hepatic cytosolic androgen receptor content compared with ranitidine treatment. Hepatectomy caused a further reduction in androgen receptor activity in all groups. Hepatic cytosolic estrogen receptor activity was comparable in all groups throughout the study. Moreover, the rate of liver growth and the levels of ornithine decarboxylase and thymidine kinase activity induced as part of the regenerative response were similar in all groups. Thus, cimetidine, despite its ability to bind to androgen receptors, and ranitidine, an H2 receptor antagonist without antiandrogen action, do not modulate the hepatic regenerative response to a 70% partial hepatectomy
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