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Sample records for 5-ht2a receptor blocker

  1. INSIGHTS INTO THE REGULATION OF 5-HT2A RECEPTORS BY SCAFFOLDING PROTEINS AND KINASES

    PubMed Central

    Allen, John A.; Yadav, Prem N.

    2008-01-01

    SUMMARY 5-HT2A serotonin receptors are essential molecular targets for the actions of LSD-like hallucinogens and atypical antipsychotic drugs. 5-HT2A serotonin receptors also mediate a variety of physiological processes in peripheral and central nervous systems including platelet aggregation, smooth muscle contraction, and the modulation of mood and perception. Scaffolding proteins have emerged as important regulators of 5-HT2A receptors and our recent studies suggest multiple scaffolds exist for 5-HT2A receptors including PSD95, arrestin, and caveolin. In addition, a novel interaction has emerged between p90 ribosomal S6 kinase and 5-HT2A receptors which attenuates receptor signaling. This article reviews our recent studies and emphasizes the role of scaffolding proteins and kinases in the regulation of 5-HT2A trafficking, targeting and signaling. PMID:18640136

  2. Evaluation of structural effects on 5-HT2A receptor antagonism by aporphines: identification of a new aporphine with 5-HT2A antagonist activity

    PubMed Central

    Ponnala, Shashikanth; Gonzales, Junior; Kapadia, Nirav; Navarro, Hernan A.; Harding, Wayne W.

    2014-01-01

    A set of aporphine analogs related to nantenine was evaluated for antagonist activity at 5-HT2A and α1A adrenergic receptors. With regards to 5-HT2A receptor antagonism, a C2 allyl group is detrimental to activity. The chiral center of nantenine is not important for 5-HT2A antagonist activity, however the N6 nitrogen atom is a critical feature for 5-HT2A antagonism. Compound 12b was the most potent 5-HT2A aporphine antagonist identified in this study and has similar potency to previously identified aporphine antagonists 2 and 3. The ring A and N6 modifications examined were detrimental to α1A antagonism. A slight eutomeric preference for the R enantiomer of nantenine was observed in relation to α1A antagonism. PMID:24630561

  3. Increased hypothalamic 5-HT2A receptor gene expression and effects of pharmacologic 5-HT2A receptor inactivation in obese A{sup y} mice

    SciTech Connect

    Nonogaki, Katsunori . E-mail: knonogaki-tky@umin.ac.jp; Nozue, Kana; Oka, Yoshitomo

    2006-12-29

    Serotonin (5-hydroxytryptamine; 5-HT) 2A receptors contribute to the effects of 5-HT on platelet aggregation and vascular smooth muscle cell proliferation, and are reportedly involved in decreases in plasma levels of adiponectin, an adipokine, in diabetic subjects. Here, we report that systemic administration of sarpogrelate, a 5-HT2A receptor antagonist, suppressed appetite and increased hypothalamic pro-opiomelanocortin and cocaine- and amphetamine-regulated transcript, corticotropin releasing hormone, 5-HT2C, and 5-HT1B receptor gene expression. A{sup y} mice, which have ectopic expression of the agouti protein, significantly increased hypothalamic 5-HT2A receptor gene expression in association with obesity compared with wild-type mice matched for age. Systemic administration of sarpogrelate suppressed overfeeding, body weight gain, and hyperglycemia in obese A{sup y} mice, whereas it did not increase plasma adiponectin levels. These results suggest that obesity increases hypothalamic 5-HT2A receptor gene expression, and pharmacologic inactivation of 5-HT2A receptors inhibits overfeeding and obesity in A{sup y} mice, but did not increase plasma adiponectin levels.

  4. Activated astrocytes display increased 5-HT2a receptor expression in pathological states.

    PubMed

    Wu, C; Singh, S K; Dias, P; Kumar, S; Mann, D M

    1999-08-01

    In human brain tissues from patients dying with cerebral infarction, hypertensive encephalopathy, Alzheimer's disease, Huntington's disease, frontotemporal dementia, and Creutzfeldt-Jakob disease there is an activation of astrocytes. Such activated astrocytes display GFAP and strong 5-HT(2A), but not 5-HT(2B) or 5-HT(2C), receptor immunoreactivity; this 5-HT(2A) reaction has not been observed in normal, nonactivated astrocytes. It is suggested that an up-regulation of 5-HT(2A) receptors may be part of an early response reaction in astrocytes, possibly designed to maintain homeostasis or to induce secondary message pathways involving trophic factors or glycogenolysis. PMID:10415157

  5. Expression of serotonin 5-HT(2A) receptors in the human cerebellum and alterations in schizophrenia.

    PubMed

    Eastwood, S L; Burnet, P W; Gittins, R; Baker, K; Harrison, P J

    2001-11-01

    The occurrence of human cerebellar serotonin 5-HT(2A) receptors (5-HT(2A)R) is equivocal and their status in schizophrenia unknown. Using a range of techniques, we investigated cerebellar 5-HT(2A)R expression in 16 healthy subjects and 16 subjects with schizophrenia. Immunocytochemistry with a monoclonal antibody showed labelling of Purkinje cell bodies and dendrites, as well as putative astrocytes. Western blots showed a major band at approximately 45 kDa. Receptor autoradiography and homogenate binding with [(3)H]ketanserin revealed cerebellar 5-HT(2A)R binding sites present at levels approximately a third of that in prefrontal cortex. 5-HT(2A)R mRNA was detected by reverse transcriptase-polymerase chain reaction, with higher relative levels in men than women. Several aspects of 5-HT(2A)R expression were altered in schizophrenia. 5-HT(2A)R immunoreactivity in Purkinje cells was partially redistributed from soma to dendrites and was increased in white matter. 5-HT(2A)R mRNA was decreased in the male patients. 5-HT(2A)R measured by dot blots and [(3)H]ketanserin binding (B(max) and K(d)) were not significantly altered in schizophrenia. These data show that 5-HT(2A)R gene products (mRNA, protein, binding sites) are expressed in the human cerebellum at nonnegligible levels; this bears upon 5-HT(2A)R imaging studies which use the cerebellum as a reference region. 5-HT(2A)R expression is altered in schizophrenia; the shift of 5-HT(2A)R from soma to dendrites is noteworthy since atypical antipsychotics have the opposite effect. Finally, the results emphasise that expression of a receptor gene is a mutifaceted process. Measurement of multiple parameters is necessary to give a clear picture of the normal situation and to show the profile of alterations in a disease. PMID:11574947

  6. Reduced 5-HT2A receptor signaling following selective bilateral amygdala damage

    PubMed Central

    Schlaepfer, Thomas E.; Matusch, Andreas; Reich, Harald; Shah, Nadim J.; Zilles, Karl; Maier, Wolfgang; Bauer, Andreas

    2009-01-01

    Neurobiological evidence implicates the amygdala as well as serotonergic (serotonin, 5-HT) signaling via postsynaptic 5-HT2A receptors as essential substrates of anxiety behaviors. Assuming a functional interdependence of these substrates, we hypothesized that a low-fear behavioral phenotype due to bilateral lesion of the amygdala would be associated with significant 5-HT2A receptor changes. Thus, we used [18F]altanserin positron emission tomography (PET) referenced to radioligand plasma levels and corrected for partial volume effects to quantify the spatial distribution of 5-HT2A receptor binding potential (BPP) in a rare patient with Urbach–Wiethe disease and selective bilateral amygdala calcification damage relative to 10 healthy control subjects. Consistent with our a priori hypothesis, we observed a 70% global decrease in 5-HT2A receptor BPP in the Urbach–Wiethe patient relative to controls. Thus, brain abnormalities in this patient are not restricted to the amygdala, but extend to overall 5-HT neurotransmission via 5-HT2A receptors. Our findings provide important insights into the molecular architecture of human anxiety behaviors and suggest the 5-HT2A receptor as a promising pharmacological target to control pathological anxiety. PMID:19015089

  7. Activation of 5-HT2A/2C receptors reduces the excitability of cultured cortical neurons.

    PubMed

    Hu, Lingli; Liu, Chunhua; Dang, Minyan; Luo, Bin; Guo, Yiping; Wang, Haitao

    2016-10-01

    The abundant forebrain serotonergic projections are believed to modulate the activities of cortical neurons. 5-HT2 receptor among multiple subtypes of serotonin receptors contributes to the modulation of excitability, synaptic transmissions and plasticity. In the present study, whole-cell patch-clamp recording was adopted to examine whether activation of 5-HT2A/2C receptors would have any impact on the excitability of cultured cortical neurons. We found that 2,5-Dimethoxy-4-iodoamphetamine (DOI), a selective 5-HT2A/2C receptor agonist, rapidly and reversibly depressed spontaneous action potentials mimicking the effect of serotonin. The decreased excitability was also observed for current-evoked firing. Additionally DOI increased neuronal input resistance. Hyperpolarization-activated cyclic nucleotide-gated cationic channels (HCN) did not account for the inhibition of spontaneous firing. The synaptic contribution was ruled out in that DOI augmented excitation and attenuated inhibition to actually favor an increase in the excitability. Our findings revealed that activation of 5-HT2A/2C receptors reduces neuronal excitability, which would deepen our understanding of serotonergic modulation of cortical activities. PMID:27585751

  8. 5-HT2A receptor activation is necessary for CO2-induced arousal

    PubMed Central

    Smith, Haleigh R.; MacAskill, Amanda; Richerson, George B.

    2015-01-01

    Hypercapnia-induced arousal from sleep is an important protective mechanism pertinent to a number of diseases. Most notably among these are the sudden infant death syndrome, obstructive sleep apnea and sudden unexpected death in epilepsy. Serotonin (5-HT) plays a significant role in hypercapnia-induced arousal. The mechanism of 5-HT's role in this protective response is unknown. Here we sought to identify the specific 5-HT receptor subtype(s) involved in this response. Wild-type mice were pretreated with antagonists against 5-HT receptor subtypes, as well as antagonists against adrenergic, cholinergic, histaminergic, dopaminergic, and orexinergic receptors before challenge with inspired CO2 or hypoxia. Antagonists of 5-HT2A receptors dose-dependently blocked CO2-induced arousal. The 5-HT2C receptor antagonist, RS-102221, and the 5-HT1A receptor agonist, 8-OH-DPAT, attenuated but did not completely block CO2-induced arousal. Blockade of non-5-HT receptors did not affect CO2-induced arousal. None of these drugs had any effect on hypoxia-induced arousal. 5-HT2 receptor agonists were given to mice in which 5-HT neurons had been genetically eliminated during embryonic life (Lmx1bf/f/p) and which are known to lack CO2-induced arousal. Application of agonists to 5-HT2A, but not 5-HT2C, receptors, dose-dependently restored CO2-induced arousal in these mice. These data identify the 5-HT2A receptor as an important mediator of CO2-induced arousal and suggest that, while 5-HT neurons can be independently activated to drive CO2-induced arousal, in the absence of 5-HT neurons and endogenous 5-HT, 5-HT receptor activation can act in a permissive fashion to facilitate CO2-induced arousal via another as yet unidentified chemosensor system. PMID:25925320

  9. Serotonin 5-HT(2A) receptor activation induces 2-arachidonoylglycerol release through a phospholipase c-dependent mechanism.

    PubMed

    Parrish, Jason C; Nichols, David E

    2006-11-01

    To date, several studies have demonstrated that phospholipase C-coupled receptors stimulate the production of endocannabinoids, particularly 2-arachidonoylglycerol. There is now evidence that endocannabinoids are involved in phospholipase C-coupled serotonin 5-HT(2A) receptor-mediated behavioral effects in both rats and mice. The main objective of this study was to determine whether activation of the 5-HT(2A) receptor leads to the production and release of the endocannabinoid 2-arachidonoylglycerol. NIH3T3 cells stably expressing the rat 5-HT(2A) receptor were first incubated with [(3)H]-arachidonic acid for 24 h. Following stimulation with 10 mum serotonin, lipids were extracted from the assay medium, separated by thin layer chromatography, and analyzed by liquid scintillation counting. Our results indicate that 5-HT(2A) receptor activation stimulates the formation and release of 2-arachidonoylglycerol. The 5-HT(2A) receptor-dependent release of 2-arachidonoylglycerol was partially dependent on phosphatidylinositol-specific phospholipase C activation. Diacylglycerol produced downstream of 5-HT(2A) receptor-mediated phospholipase D or phosphatidylcholine-specific phospholipase C activation did not appear to contribute to 2-arachidonoylglycerol formation in NIH3T3-5HT(2A) cells. In conclusion, our results support a functional model where neuromodulatory neurotransmitters such as serotonin may act as regulators of endocannabinoid tone at excitatory synapses through the activation of phospholipase C-coupled G-protein coupled receptors. PMID:17010161

  10. The serotonin 5-HT2A and 5-HT2C receptors interact with specific sets of PDZ proteins.

    PubMed

    Bécamel, Carine; Gavarini, Sophie; Chanrion, Benjamin; Alonso, Gérard; Galéotti, Nathalie; Dumuis, Aline; Bockaert, Joël; Marin, Philippe

    2004-05-01

    The 5-hydroxytryptamine type 2A (5-HT(2A)) receptor and the 5-HT(2C) receptor are closely related members of the G-protein-coupled receptors activated by serotonin that share very similar pharmacological profiles and cellular signaling pathways. These receptors express a canonical class I PDZ ligand (SXV) at their C-terminal extremity. Here, we have identified proteins that interact with the PDZ ligand of the 5-HT(2A) and 5-HT(2C) receptors by a proteomic approach associating affinity chromatography using immobilized synthetic peptides encompassing the PDZ ligand and mass spectrometry. We report that both receptor C termini interact with specific sets of PDZ proteins in vitro. The 5-HT(2C) receptor but not the 5-HT(2A) receptor binds to the Veli-3.CASK.Mint1 ternary complex and to SAP102. In addition, the 5-HT(2C) receptor binds more strongly to PSD-95 and MPP-3 than the 5-HT(2A) receptor. In contrast, a robust interaction between the 5-HT(2A) receptor and the channel-interacting PDZ protein CIPP was found, whereas CIPP did not significantly associate with the 5-HT(2C) receptor. We also show that residues located at the -1 position and upstream the PDZ ligand in the C terminus of the 5-HT(2A) and 5-HT(2C) receptors are major determinants in their interaction with specific PDZ proteins. Immunofluorescence and electron microscopy studies strongly suggested that these specific interactions also take place in living cells and that the 5-HT(2) receptor-PDZ protein complexes occur in intracellular compartments. The interaction of the 5-HT(2A) and the 5-HT(2C) receptor with specific sets of PDZ proteins may contribute to their different signal transduction properties.

  11. The role of serotonin 5-HT2A receptors in memory and cognition

    PubMed Central

    Zhang, Gongliang; Stackman, Robert W.

    2015-01-01

    Serotonin 5-HT2A receptors (5-HT2ARs) are widely distributed in the central nervous system, especially in brain region essential for learning and cognition. In addition to endogenous 5-HT, several hallucinogens, antipsychotics, and antidepressants function by targeting 5-HT2ARs. Preclinical studies show that 5-HT2AR antagonists have antipsychotic and antidepressant properties, whereas agonist ligands possess cognition-enhancing and hallucinogenic properties. Abnormal 5-HT2AR activity is associated with a number of psychiatric disorders and conditions, including depression, schizophrenia, and drug addiction. In addition to its traditional activity as a G protein-coupled receptor (GPCR), recent studies have defined novel operations of 5-HT2ARs. Here we review progress in the (1) receptor anatomy and biology: distribution, signaling, polymerization and allosteric modulation; and (2) receptor functions: learning and memory, hallucination and spatial cognition, and mental disorders. Based on the recent progress in basic research on the 5-HT2AR, it appears that post-training 5-HT2AR activation enhances non-spatial memory consolidation, while pre-training 5-HT2AR activation facilitates fear extinction. Further, the potential influence that 5-HT2AR-elicited visual hallucinations may have on visual cue (i.e., landmark) guided spatial cognition is discussed. We conclude that the development of selective 5-HT2AR modulators to target distinct signaling pathways and neural circuits represents a new possibility for treating emotional, neuropsychiatric, and neurodegenerative disorders. PMID:26500553

  12. Expression of α(1)-adrenergic receptors in rat prefrontal cortex: cellular co-localization with 5-HT(2A) receptors.

    PubMed

    Santana, Noemí; Mengod, Guadalupe; Artigas, Francesc

    2013-06-01

    The prefrontal cortex (PFC) is involved in behavioural control and cognitive processes that are altered in schizophrenia. The brainstem monoaminergic systems control PFC function, yet the cells/networks involved are not fully known. Serotonin (5-HT) and norepinephrine (NE) increase PFC neuronal activity through the activation of α(1)-adrenergic receptors (α(1)ARs) and 5-HT(2A) receptors (5-HT(2A)Rs), respectively. Neurochemical and behavioural interactions between these receptors have been reported. Further, classical and atypical antipsychotic drugs share nm in vitro affinity for α(1)ARs while having preferential affinity for D(2) and 5-HT(2A)Rs, respectively. Using double in situ hybridization we examined the cellular expression of α(1)ARs in pyramidal (vGluT1-positive) and GABAergic (GAD(65/67)-positive) neurons in rat PFC and their co-localization with 5-HT(2A)Rs. α(1)ARs are expressed by a high proportion of pyramidal (59-85%) and GABAergic (52-79%) neurons. The expression in pyramidal neurons exhibited a dorsoventral gradient, with a lower percentage of α(1)AR-positive neurons in infralimbic cortex compared to anterior cingulate and prelimbic cortex. The expression of α(1A), α(1B) and α(1D) adrenergic receptors was segregated in different layers and subdivisions. In all them there is a high co-expression with 5-HT(2A)Rs (∼80%). These observations indicate that NE controls the activity of most PFC pyramidal neurons via α(1)ARs, either directly or indirectly, via GABAergic interneurons. Antipsychotic drugs can thus modulate the activity of PFC via α(1)AR blockade. The high co-expression with 5-HT(2A)Rs indicates a convergence of excitatory serotonergic and noradrenergic inputs onto the same neuronal populations. Moreover, atypical antipsychotics may exert a more powerful control of PFC function through the simultaneous blockade of α(1)ARs and 5-HT(2A)Rs.

  13. 5-HT2A receptors control body temperature in mice during LPS-induced inflammation via regulation of NO production.

    PubMed

    Voronova, Irina P; Khramova, Galina M; Kulikova, Elizabeth A; Petrovskii, Dmitrii V; Bazovkina, Daria V; Kulikov, Alexander V

    2016-01-01

    G protein-coupled 5-HT2A receptors are involved in the regulation of numerous normal and pathological physiological functions. At the same time, its involvement in the regulation of body temperature (Tb) in normal conditions is obscure. Here we study the effect of the 5-HT2A receptor activation or blockade on Tb in sick animals. The experiments were carried out on adult C57BL/6 mouse males. Systemic inflammation and sickness were produced by lipopolysaccharide (LPS, 0.1mg/kg, ip), while the 5-HT2A receptor was stimulated or blocked through the administration of the receptor agonist DOI or antagonist ketanserin (1mg/kg), respectively. LPS, DOI or ketanserin alone produced no effect on Tb. However, administration of LPS together with a peripheral or central ketanserin injection reduced Tb (32.2°C). Ketanserin reversed the LPS-induced expression of inducible NO synthase in the brain. Consequently, an involvement of NO in the mechanism of the hypothermic effect of ketanserin in sick mice was hypothesized. Administration of LPS together with NO synthase inhibitor, l-nitro-arginine methyl ester (60mg/kg, ip) resulted in deep (28.5°C) and prolonged (8h) hypothermia, while administration of l-nitro-arginine methyl ester alone produced no effect on Tb. Thus, 5-HT2A receptors play a key role in Tb control in sick mice. Blockade of this GPCR produces hypothermia in mice with systemic inflammation via attenuation of LPS-induced NO production. These results indicate an unexpected role of 5-HT2A receptors in inflammation and NO production and have a considerable biological impact on understanding the mechanism of animal adaptation to pathogens and parasites. Moreover, adverse side effects of 5-HT2A receptor antagonists in patients with inflammation may be expected. PMID:26621247

  14. 5-HT2A receptors control body temperature in mice during LPS-induced inflammation via regulation of NO production.

    PubMed

    Voronova, Irina P; Khramova, Galina M; Kulikova, Elizabeth A; Petrovskii, Dmitrii V; Bazovkina, Daria V; Kulikov, Alexander V

    2016-01-01

    G protein-coupled 5-HT2A receptors are involved in the regulation of numerous normal and pathological physiological functions. At the same time, its involvement in the regulation of body temperature (Tb) in normal conditions is obscure. Here we study the effect of the 5-HT2A receptor activation or blockade on Tb in sick animals. The experiments were carried out on adult C57BL/6 mouse males. Systemic inflammation and sickness were produced by lipopolysaccharide (LPS, 0.1mg/kg, ip), while the 5-HT2A receptor was stimulated or blocked through the administration of the receptor agonist DOI or antagonist ketanserin (1mg/kg), respectively. LPS, DOI or ketanserin alone produced no effect on Tb. However, administration of LPS together with a peripheral or central ketanserin injection reduced Tb (32.2°C). Ketanserin reversed the LPS-induced expression of inducible NO synthase in the brain. Consequently, an involvement of NO in the mechanism of the hypothermic effect of ketanserin in sick mice was hypothesized. Administration of LPS together with NO synthase inhibitor, l-nitro-arginine methyl ester (60mg/kg, ip) resulted in deep (28.5°C) and prolonged (8h) hypothermia, while administration of l-nitro-arginine methyl ester alone produced no effect on Tb. Thus, 5-HT2A receptors play a key role in Tb control in sick mice. Blockade of this GPCR produces hypothermia in mice with systemic inflammation via attenuation of LPS-induced NO production. These results indicate an unexpected role of 5-HT2A receptors in inflammation and NO production and have a considerable biological impact on understanding the mechanism of animal adaptation to pathogens and parasites. Moreover, adverse side effects of 5-HT2A receptor antagonists in patients with inflammation may be expected.

  15. 5-HT2A Serotonin Receptor Density in Adult Male Rats’ Hippocampus after Morphine-based Conditioned Place Preference

    PubMed Central

    Mohammadi, Rabie; Jahanshahi, Mehrdad; Jameie, Seyed Behnamedin

    2016-01-01

    Introduction: A close interaction exists between the brain opioid and serotonin (5-HT) neurotransmitter systems. Brain neurotransmitter 5-HT plays an important role in the regulation of reward-related processing. However, a few studies have investigated the potential role of 5-HT2A receptors in this behavior. Therefore, the aim of the present study was to assess the influence of morphine and Conditioned Place Preference (CPP) on the density of 5-HT2A receptor in neurons of rat hippocampal formation. Methods: Morphine (10 mg/kg, IP) was injected in male Wistar rats for 7 consecutive days (intervention group), but control rats received just normal saline (1 mL/kg, IP). We used a hotplate test of analgesia to assess induction of tolerance to analgesic effects of morphine on days 1 and 8 of injections. Later, two groups of rats were sacrificed one day after 7 days of injections, their whole brains removed, and the striatum and PFC immediately dissected. Then, the NR1 gene expression was examined with a semi-quantitative RT-PCR method. Results: Our data showed that the maximum response was obtained with 2.5 mg/kg of morphine. The density of 5-HT2A receptor in different areas of the hippocampus increased significantly at sham-morphine and CPP groups (P<0.05). On the other hand, the CPP groups had more 5-HT2A receptors than sham-morphine groups and also the sham-morphine groups had more 5-HT2A receptors than the control groups. Conclusion: We concluded that the phenomenon of conditioned place preference induced by morphine can cause a significant increase in the number of serotonin 5-HT2A receptors in neurons of all areas of hippocampus. PMID:27563418

  16. Reelin influences the expression and function of dopamine D2 and serotonin 5-HT2A receptors: a comparative study.

    PubMed

    Varela, M J; Lage, S; Caruncho, H J; Cadavid, M I; Loza, M I; Brea, J

    2015-04-01

    Reelin is an extracellular matrix protein that plays a critical role in neuronal guidance during brain neurodevelopment and in synaptic plasticity in adults and has been associated with schizophrenia. Reelin mRNA and protein levels are reduced in various structures of post-mortem schizophrenic brains, in a similar way to those found in heterozygous reeler mice (HRM). Reelin is involved in protein expression in dendritic spines that are the major location where synaptic connections are established. Thus, we hypothesized that a genetic deficit in reelin would affect the expression and function of dopamine D2 and serotonin 5-HT2A receptors that are associated with the action of current antipsychotic drugs. In this study, D2 and 5-HT2A receptor expression and function were quantitated by using radioligand binding studies in the frontal cortex and striatum of HRM and wild-type mice (WTM). We observed increased expression (p<0.05) in striatum membranes and decreased expression (p<0.05) in frontal cortex membranes for both dopamine D2 and serotonin 5-HT2A receptors from HRM compared to WTM. Our results show parallel alterations of D2 and 5-HT2A receptors that are compatible with a possible hetero-oligomeric nature of these receptors. These changes are similar to changes described in schizophrenic patients and provide further support for the suitability of using HRM as a model for studying this disease and the effects of antipsychotic drugs. PMID:25637489

  17. Serotonin 5-HT2A receptor gene variants influence antidepressant response to repeated total sleep deprivation in bipolar depression.

    PubMed

    Benedetti, Francesco; Barbini, Barbara; Bernasconi, Alessandro; Fulgosi, Mara Cigala; Colombo, Cristina; Dallaspezia, Sara; Gavinelli, Chiara; Marino, Elena; Pirovano, Adele; Radaelli, Daniele; Smeraldi, Enrico

    2008-12-12

    5-HT2A receptor density in prefrontal cortex was associated with depression and suicide. 5-HT2A receptor gene polymorphism rs6313 was associated with 5-HT2A receptor binding potential, with the ability of individuals to use environmental support in order to prevent depression, and with sleep improvement after antidepressant treatment with mirtazapine. Studies on response to antidepressant drugs gave inconsistent results. Here we studied the effect of rs6313 on response to repeated total sleep deprivation (TSD) in 80 bipolar depressed inpatients treated with three consecutive TSD cycles (each one made of 36 h awake followed by a night of undisturbed sleep). All genotype groups showed comparable acute effects of the first TSD, but patients homozygotes for the T variant had better perceived and observed benefits from treatment than carriers of the C allele. These effects became significant after the first recovery night and during the following days, leading to a 36% higher final response rate (Hamilton depression rating<8). The higher density of postsynaptic excitatory 5-HT2A receptors in T/T homozygotes could have led to higher behavioural effects of increased 5-HT neurotransmission due to repeated TSD. Other possible mechanisms involve allostatic/homeostatic adaptation to sleep loss, and a different effect of the allele variants on epigenetic influences. Results confirm the interest for individual gene variants of the serotonin pathway in shaping clinical characteristics of depression and antidepressant response.

  18. The antidepressant 5-HT2A receptor antagonists pizotifen and cyproheptadine inhibit serotonin-enhanced platelet function.

    PubMed

    Lin, Olivia A; Karim, Zubair A; Vemana, Hari Priya; Espinosa, Enma V P; Khasawneh, Fadi T

    2014-01-01

    There is considerable interest in defining new agents or targets for antithrombotic purposes. The 5-HT2A receptor is a G-protein coupled receptor (GPCR) expressed on many cell types, and a known therapeutic target for many disease states. This serotonin receptor is also known to regulate platelet function. Thus, in our FDA-approved drug repurposing efforts, we investigated the antiplatelet activity of cyproheptadine and pizotifen, two antidepressant 5-HT2A Receptor antagonists. Our results revealed that cyproheptadine and pizotifen reversed serotonin-enhanced ADP-induced platelet aggregation in vitro and ex vivo. And the inhibitory effects of these two agents were found to be similar to that of EMD 281014, a 5-HT2A Receptor antagonist under development. In separate experiments, our studies revealed that these 5-HT2A receptor antagonists have the capacity to reduce serotonin-enhanced ADP-induced elevation in intracellular calcium levels and tyrosine phosphorylation. Using flow cytometry, we also observed that cyproheptadine, pizotifen, and EMD 281014 inhibited serotonin-enhanced ADP-induced phosphatidylserine (PS) exposure, P-selectin expression, and glycoprotein IIb-IIIa activation. Furthermore, using a carotid artery thrombosis model, these agents prolonged the time for thrombotic occlusion in mice in vivo. Finally, the tail-bleeding time was investigated to assess the effect of cyproheptadine and pizotifen on hemostasis. Our findings indicated prolonged bleeding time in both cyproheptadine- and pizotifen-treated mice. Notably, the increases in occlusion and bleeding times associated with these two agents were comparable to that of EMD 281014, and to clopidogrel, a commonly used antiplatelet drug, again, in a fashion comparable to clopidogrel and EMD 281014. Collectively, our data indicate that the antidepressant 5-HT2A antagonists, cyproheptadine and pizotifen do exert antiplatelet and thromboprotective effects, but similar to clopidogrel and EMD 281014, their

  19. Anti-thrombotic and vascular effects of AR246686, a novel 5-HT2A receptor antagonist.

    PubMed

    Adams, John W; Ramirez, Juan; Ortuno, Danny; Shi, Yunqing; Thomsen, William; Richman, Jeremy G; Morgan, Michael; Dosa, Peter; Teegarden, Bradley R; Al-Shamma, Hussien; Behan, Dominic P; Connolly, Daniel T

    2008-05-31

    We have evaluated the anti-platelet and vascular pharmacology of AR246686, a novel 5-hydroxytryptamine2A (5-HT2A) receptor antagonist. AR246686 displayed high affinity binding to membranes of HEK cells stably expressing recombinant human and rat 5-HT2A receptors (Ki=0.2 nM and 0.4 nM, respectively). Functional antagonism (IC50=1.9 nM) with AR246686 was determined by inhibition of ligand-independent inositol phosphate accumulation in the 5-HT2A stable cell line. We observed 8.7-fold and 1360-fold higher affinity of AR246686 for the 5-HT2A receptor vs. 5-HT2C and 5-HT2B receptors, respectively. AR246686 inhibited 5-HT-induced amplification of ADP-stimulated human platelet aggregation (IC50=21 nM). Similar potency was observed for inhibition of 5-HT stimulated DNA synthesis in rat aortic smooth muscle cells (IC(50)=10 nM) and 5-HT-mediated contraction in rat aortic rings. Effects of AR246686 on arterial thrombosis and bleeding time were studied in a rat model of femoral artery occlusion. Oral dosing of AR246686 to rats resulted in prolongation of time to occlusion at 1 mg/kg, whereas increased bleeding time was observed at a dose of 20 mg/kg. In contrast, both bleeding time and time to occlusion were increased at the same dose (10 mg/kg) of clopidogrel. These results demonstrate that AR246686 is a high affinity 5-HT2A receptor antagonist with potent activity on platelets and vascular smooth muscle. Further, oral administration results in anti-thrombotic effects at doses that are free of significant effects on traumatic bleeding time.

  20. APORPHINOID ANTAGONISTS OF 5-HT2A RECEPTORS: FURTHER EVALUATION OF RING A SUBSTITUENTS AND THE SIZE OF RING C

    PubMed Central

    Ponnala, Shashikanth; Kapadia, Nirav; Navarro, Hernán A.; Harding, Wayne W.

    2014-01-01

    A series of ring A modified analogs of nantenine as well as structural variants in ring C were synthesized and evaluated for antagonist activity at 5-HT2A and α1A receptors. Halogenation improves 5-HT2A antagonist potency in molecules containing a C1 methoxyl/C2 methoxyl or C1 methoxyl/C2 hydroxyl moiety. Bromination or iodination (but not chlorination) with the latter moiety also significantly increased α1A antagonist potency. Homologation or contraction of ring C adversely affected antagonist activity at both receptors, implying that a six-membered ring C motif is beneficial for high antagonist potency at both receptors. Molecular docking studies suggest that the improved antagonist activity (by virtue of improved affinity) of C3 halogenated aporphines in this study, is attributable to favorable interactions with the C3 halogen and F339 and/or F340. PMID:24766771

  1. Chronic treatment with LY341495 decreases 5-HT(2A) receptor binding and hallucinogenic effects of LSD in mice.

    PubMed

    Moreno, José L; Holloway, Terrell; Rayannavar, Vinayak; Sealfon, Stuart C; González-Maeso, Javier

    2013-03-01

    Hallucinogenic drugs, such as lysergic acid diethylamide (LSD), mescaline and psilocybin, alter perception and cognitive processes. All hallucinogenic drugs have in common a high affinity for the serotonin 5-HT(2A) receptor. Metabotropic glutamate 2/3 (mGlu2/3) receptor ligands show efficacy in modulating the cellular and behavioral responses induced by hallucinogenic drugs. Here, we explored the effect of chronic treatment with the mGlu2/3 receptor antagonist 2S-2-amino-2-(1S,2S-2-carboxycyclopropan-1-yl)-3-(xanth-9-yl)-propionic acid (LY341495) on the hallucinogenic-like effects induced by LSD (0.24mg/kg). Mice were chronically (21 days) treated with LY341495 (1.5mg/kg), or vehicle, and experiments were carried out one day after the last injection. Chronic treatment with LY341495 down-regulated [(3)H]ketanserin binding in somatosensory cortex of wild-type, but not mGlu2 knockout (KO), mice. Head-twitch behavior, and expression of c-fos, egr-1 and egr-2, which are responses induced by hallucinogenic 5-HT(2A) agonists, were found to be significantly decreased by chronic treatment with LY341495. These findings suggest that repeated blockade of the mGlu2 receptor by LY341495 results in reduced 5-HT(2A) receptor-dependent hallucinogenic effects of LSD.

  2. N-acetylcysteine modulates hallucinogenic 5-HT(2A) receptor agonist-mediated responses: behavioral, molecular, and electrophysiological studies.

    PubMed

    Lee, Mei-Yi; Chiang, Chun-Cheng; Chiu, Hong-Yi; Chan, Ming-Huan; Chen, Hwei-Hsien

    2014-06-01

    N-acetylcysteine (NAC) has been reported to reverse the psychotomimetic effects in the rodent phencyclidine model of psychosis and shown beneficial effects in treating patients with schizophrenia. The effect of NAC has been associated with facilitating the activity of cystine-glutamate antiporters on glial cells concomitant with the release of non-vesicular glutamate, which mainly stimulates the presynaptic metabotropic glutamate receptor subtype 2 receptors (mGluR2). Recent evidence demonstrated that functional interactions between serotonin 5-HT2A receptor (5-HT(2A)R) and mGluR2 are responsible to unique cellular responses when targeted by hallucinogenic drugs. The present study determined the effects of NAC on hallucinogenic 5-HT(2A)R agonist (±)1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI)-elicited behavioral and molecular responses in mice and DOI-evoked field potentials in the mouse cortical slices. NAC significantly attenuated DOI-induced head twitch response and expression of c-Fos and Egr-2 in the infralimbic and motor cortex and suppressed the increase in the frequency of excitatory field potentials elicited by DOI in the medial prefrontal cortex. In addition, the cystine-glutamate antiporter inhibitor (S)-4-carboxyphenylglycine (CPG) and the mGluR2 antagonist LY341495 reversed the suppressing effects of NAC on DOI-induced head twitch and molecular responses and increased frequency of excitatory field potentials, supporting that NAC attenuates the 5-HT(2A)R-mediated hallucinogenic effects via increased activity of cystine-glutamate antiporter followed by activation of mGluR2 receptors. These findings implicate NAC as a potential therapeutic agent for hallucinations and psychosis associated with hallucinogen use and schizophrenia.

  3. Blockade of 5-HT2A receptors suppresses hyperthermic but not cardiovascular responses to psychosocial stress in rats.

    PubMed

    Beig, M I; Baumert, M; Walker, F R; Day, T A; Nalivaiko, E

    2009-03-31

    The aim of this study was to determine whether 5-HT2A receptors mediate cardiovascular and thermogenic responses to acute psychological stresses. For this purpose, adult male Wistar hooded rats instrumented for telemetric recordings of either electrocardiogram (ECG) (n=12) or arterial pressure (n=12) were subjected, on different days, to four 15-min episodes of social defeat. Prior to stress, animals received s.c. injection of the selective 5-HT2A receptor antagonist SR-46349B (trans-4-((3Z)3-[(2-dimethylaminoethyl)oxyimino]-3-(2-fluorophenyl)propen-1-yl)-phenol, hemifumarate) (at doses of 0.3, 1.0 and 3.0 mg/kg) or vehicle. The drug had no effect on basal heart rate or heart rate variability indexes, arterial pressure, and core body temperature. Social defeat elicited significant and substantial tachycardic (347+/-7 to 500+/-7 bpm), pressor (77+/-4 to 97+/-4 mm Hg) and hyperthermic (37.0+/-0.3 to 38.5+/-0.1 degrees C) responses. Blockade of 5-HT2A receptors, at all doses of the antagonist, completely prevented stress-induced hyperthermia. In contrast, stress-induced cardiovascular responses were not affected by the blockade (except small reduction of tachycardia by the highest dose of the drug). We conclude that in rats, 5-HT2A receptors mediate stress-induced hyperthermic responses, but are not involved in the genesis of stress-induced rises in heart rate or arterial pressure, and do not participate in cardiovascular control at rest. PMID:19356699

  4. Clozapine, but not olanzapine, disrupts conditioned avoidance response in rats by antagonizing 5-HT2A/2C receptors.

    PubMed

    Li, Ming; Sun, Tao; Mead, Alexa

    2012-04-01

    The present study was designed to assess the role of 5-HT(2A/2C) receptors in the acute and repeated effect of clozapine and olanzapine in a rat conditioned avoidance response model, a validated model of antipsychotic activity. Male Sprague-Dawley rats that were previously treated with either phencyclidine (0.5-2.0 mg/kg, sc), amphetamine (1.25-5.0 mg/kg, sc), or saline and tested in a prepulse inhibition of acoustic startle study were used. They were first trained to acquire avoidance response to a white noise (CS1) and a pure tone (CS2) that differed in their ability to predict the occurrence of footshock. Those who acquired avoidance response were administered with clozapine (10.0 mg/kg, sc) or olanzapine (1.0 mg/kg, sc) together with either saline or 1-2,5-dimethoxy-4-iodo-amphetamine (DOI, a selective 5-HT(2A/2C) agonist, 1.0 or 2.5 mg/kg, sc), and their conditioned avoidance responses were tested for four consecutive days. After two drug-free retraining days, the long-term repeated effect was assessed in a challenge test during which all rats were injected with a low dose of clozapine (5 mg/kg, sc) or olanzapine (0.5 mg/kg). Results show that pretreatment of DOI dose-dependently reversed the acute disruptive effect of clozapine on both CS1 and CS2 avoidance responses, whereas it had little effect in reversing the acute effect of olanzapine. On the challenge test, pretreatment of DOI did not alter the clozapine-induced tolerance or the olanzapine-induced sensitization effect. These results confirmed our previous findings and suggest that clozapine, but not olanzapine, acts on through 5-HT(2A/2C) receptors to achieve its acute avoidance disruptive effect and likely its therapeutic effects. The long-term clozapine tolerance and olanzapine sensitization effects appear to be mediated by non-5-HT(2A/2C) receptors.

  5. C-(4,5,6-trimethoxyindan-1-yl)methanamine: a mescaline analogue designed using a homology model of the 5-HT2A receptor.

    PubMed

    McLean, Thomas H; Chambers, James J; Parrish, Jason C; Braden, Michael R; Marona-Lewicka, Danuta; Kurrasch-Orbaugh, Deborah; Nichols, David E

    2006-07-13

    A conformationally restricted analogue of mescaline, C-(4,5,6-trimethoxyindan-1-yl)-methanamine, was designed using a 5-HT(2A) receptor homology model. The compound possessed 3-fold higher affinity and potency than and efficacy equal to that of mescaline at the 5-HT(2A) receptor. The new analogue substituted fully for LSD in drug discrimination studies and was 5-fold more potent than mescaline. Resolution of this analogue into its enantiomers corroborated the docking experiments, showing the R-(+) isomer to have higher affinity and potency and to have efficacy similar to that of mescaline at the 5-HT(2A) receptor.

  6. Latent inhibition is attenuated by noise and partially restored by a 5-HT2A receptor antagonist.

    PubMed

    McDonald, L M; Moran, P M; Vythelingum, G N; Joseph, M H; Stephenson, J D; Gray, J A

    2002-12-01

    Latent inhibition (LI) is a model of attention, which is a cognitive process that can be modulated by stressors such as chronic intermittent broadband noise, e.g. caused by building work, which is particularly stressful to rats. The aim of this study was to analyse the effect of chronic noise stress, caused by a building project, on LI, and its interaction with SR 46,349B, a 5-HT2A receptor antagonist. Control groups from LI experiments conducted during periods of chronic intermittent noise were compared with control groups from LI experiments conducted in normal quiet conditions. The interaction of SR 46,349B with the effects of chronic noise stress was then tested. Chronic intermittent noise attenuated LI, an effect which was partially reversed by SR 46,349B, 2.4 mg/kg i.p. Attenuation of LI by chronic intermittent noise and reversal of this effect by SR 46,349B support suggestions that stress can modulate attention and that 5-HT2A receptors are involved in mediating the effects of chronic stress.

  7. 5-HT2A Receptor Binding in the Frontal Cortex of Parkinson's Disease Patients and Alpha-Synuclein Overexpressing Mice: A Postmortem Study.

    PubMed

    Rasmussen, Nadja Bredo; Olesen, Mikkel Vestergaard; Brudek, Tomasz; Plenge, Per; Klein, Anders Bue; Westin, Jenny E; Fog, Karina; Wörtwein, Gitta; Aznar, Susana

    2016-01-01

    The 5-HT2A receptor is highly involved in aspects of cognition and executive function and seen to be affected in neurodegenerative diseases like Alzheimer's disease and related to the disease pathology. Even though Parkinson's disease (PD) is primarily a motor disorder, reports of impaired executive function are also steadily being associated with this disease. Not much is known about the pathophysiology behind this. The aim of this study was thereby twofold: (1) to investigate 5-HT2A receptor binding levels in Parkinson's brains and (2) to investigate whether PD associated pathology, alpha-synuclein (AS) overexpression, could be associated with 5-HT2A alterations. Binding density for the 5-HT2A-specific radioligand [(3)H]-MDL 100.907 was measured in membrane suspensions of frontal cortex tissue from PD patients. Protein levels of AS were further measured using western blotting. Results showed higher AS levels accompanied by increased 5-HT2A receptor binding in PD brains. In a separate study, we looked for changes in 5-HT2A receptors in the prefrontal cortex in 52-week-old transgenic mice overexpressing human AS. We performed region-specific 5-HT2A receptor binding measurements followed by gene expression analysis. The transgenic mice showed lower 5-HT2A binding in the frontal association cortex that was not accompanied by changes in gene expression levels. This study is one of the first to look at differences in serotonin receptor levels in PD and in relation to AS overexpression. PMID:27579212

  8. 5-HT2A Receptor Binding in the Frontal Cortex of Parkinson's Disease Patients and Alpha-Synuclein Overexpressing Mice: A Postmortem Study.

    PubMed

    Rasmussen, Nadja Bredo; Olesen, Mikkel Vestergaard; Brudek, Tomasz; Plenge, Per; Klein, Anders Bue; Westin, Jenny E; Fog, Karina; Wörtwein, Gitta; Aznar, Susana

    2016-01-01

    The 5-HT2A receptor is highly involved in aspects of cognition and executive function and seen to be affected in neurodegenerative diseases like Alzheimer's disease and related to the disease pathology. Even though Parkinson's disease (PD) is primarily a motor disorder, reports of impaired executive function are also steadily being associated with this disease. Not much is known about the pathophysiology behind this. The aim of this study was thereby twofold: (1) to investigate 5-HT2A receptor binding levels in Parkinson's brains and (2) to investigate whether PD associated pathology, alpha-synuclein (AS) overexpression, could be associated with 5-HT2A alterations. Binding density for the 5-HT2A-specific radioligand [(3)H]-MDL 100.907 was measured in membrane suspensions of frontal cortex tissue from PD patients. Protein levels of AS were further measured using western blotting. Results showed higher AS levels accompanied by increased 5-HT2A receptor binding in PD brains. In a separate study, we looked for changes in 5-HT2A receptors in the prefrontal cortex in 52-week-old transgenic mice overexpressing human AS. We performed region-specific 5-HT2A receptor binding measurements followed by gene expression analysis. The transgenic mice showed lower 5-HT2A binding in the frontal association cortex that was not accompanied by changes in gene expression levels. This study is one of the first to look at differences in serotonin receptor levels in PD and in relation to AS overexpression.

  9. 5-HT2A Receptor Binding in the Frontal Cortex of Parkinson's Disease Patients and Alpha-Synuclein Overexpressing Mice: A Postmortem Study

    PubMed Central

    Rasmussen, Nadja Bredo; Olesen, Mikkel Vestergaard; Plenge, Per; Klein, Anders Bue; Westin, Jenny E.; Fog, Karina

    2016-01-01

    The 5-HT2A receptor is highly involved in aspects of cognition and executive function and seen to be affected in neurodegenerative diseases like Alzheimer's disease and related to the disease pathology. Even though Parkinson's disease (PD) is primarily a motor disorder, reports of impaired executive function are also steadily being associated with this disease. Not much is known about the pathophysiology behind this. The aim of this study was thereby twofold: (1) to investigate 5-HT2A receptor binding levels in Parkinson's brains and (2) to investigate whether PD associated pathology, alpha-synuclein (AS) overexpression, could be associated with 5-HT2A alterations. Binding density for the 5-HT2A-specific radioligand [3H]-MDL 100.907 was measured in membrane suspensions of frontal cortex tissue from PD patients. Protein levels of AS were further measured using western blotting. Results showed higher AS levels accompanied by increased 5-HT2A receptor binding in PD brains. In a separate study, we looked for changes in 5-HT2A receptors in the prefrontal cortex in 52-week-old transgenic mice overexpressing human AS. We performed region-specific 5-HT2A receptor binding measurements followed by gene expression analysis. The transgenic mice showed lower 5-HT2A binding in the frontal association cortex that was not accompanied by changes in gene expression levels. This study is one of the first to look at differences in serotonin receptor levels in PD and in relation to AS overexpression. PMID:27579212

  10. Effects of dominance status on conditioned defeat and expression of 5-HT1A and 5-HT2A receptors

    PubMed Central

    Morrison, Kathleen E.; Swallows, Cody L.; Cooper, Matthew A.

    2011-01-01

    Past experience can alter how individuals respond to stressful events. The brain serotonin system is a key factor modulating stress-related behavior and may contribute to individual variation in coping styles. In this study we investigated whether dominant and subordinate hamsters respond differently to social defeat and whether their behavioral responses are associated with changes in 5-HT1A and 5-HT2A receptor immunoreactivity in several limbic brain regions. We paired weight-matched hamsters in daily aggressive encounters for two weeks so that they formed a stable dominance relationship. We also included controls that were exposed to an empty cage each day for two weeks. Twenty-four hours after the final pairing or empty cage exposure, subjects were socially defeated in 3, 5-min encounters with a more aggressive hamster. Twenty-four hours after social defeat, animals were tested for conditioned defeat in a 5-min social interaction test with a non-aggressive intruder. We collected brains following conditioned defeat testing and performed immunohistochemistry for 5-HT1A and 5-HT2A receptors. We found that dominants showed less submissive and defensive behavior at conditioned defeat testing compared to both subordinates and controls. Additionally, both dominants and subordinates had an increased number of 5-HT1A immunopositive cells in the basolateral amygdala compared to controls. Subordinates also had more 5-HT1A immunopositive cells in the dorsal medial amygdala than did controls. Finally, dominants had fewer 5-HT1A immunopositive cells in the paraventricular nucleus of the hypothalamus compared to controls. Our results indicate that dominant social status results in a blunted conditioned defeat response and a distinct pattern of 5-HT1A receptor expression, which may contribute to resistance to conditioned defeat. PMID:21362435

  11. Effects of dominance status on conditioned defeat and expression of 5-HT1A and 5-HT2A receptors.

    PubMed

    Morrison, Kathleen E; Swallows, Cody L; Cooper, Matthew A

    2011-08-01

    Past experience can alter how individuals respond to stressful events. The brain serotonin system is a key factor modulating stress-related behavior and may contribute to individual variation in coping styles. In this study we investigated whether dominant and subordinate hamsters respond differently to social defeat and whether their behavioral responses are associated with changes in 5-HT1A and 5-HT2A receptor immunoreactivity in several limbic brain regions. We paired weight-matched hamsters in daily aggressive encounters for two weeks so that they formed a stable dominance relationship. We also included controls that were exposed to an empty cage each day for two weeks. Twenty-four hours after the final pairing or empty cage exposure, subjects were socially defeated in 3, 5-min encounters with a more aggressive hamster. Twenty-four hours after social defeat, animals were tested for conditioned defeat in a 5-min social interaction test with a non-aggressive intruder. We collected brains following conditioned defeat testing and performed immunohistochemistry for 5-HT1A and 5-HT2A receptors. We found that dominants showed less submissive and defensive behavior at conditioned defeat testing compared to both subordinates and controls. Additionally, both dominants and subordinates had an increased number of 5-HT1A immunopositive cells in the basolateral amygdala compared to controls. Subordinates also had more 5-HT1A immunopositive cells in the dorsal medial amygdala than did controls. Finally, dominants had fewer 5-HT1A immunopositive cells in the paraventricular nucleus of the hypothalamus compared to controls. Our results indicate that dominant social status results in a blunted conditioned defeat response and a distinct pattern of 5-HT1A receptor expression, which may contribute to resistance to conditioned defeat.

  12. The 5-HT2A serotonin receptor in executive function: Implications for neuropsychiatric and neurodegenerative diseases.

    PubMed

    Aznar, Susana; Hervig, Mona El-Sayed

    2016-05-01

    Executive function entails the interplay of a group of cognitive processes enabling the individual to anticipate consequences, attain self-control, and undertake appropriate goal-directed behaviour. Serotonin signalling at serotonin 2A receptors (5-HT2AR) has important effects on these behavioural and cognitive pathways, with the prefrontal cortex (PFC) as the central actor. Indeed, the 5-HT2ARs are highly expressed in PFC, where they modulate cortical activity and local network oscillations (brain waves). Numerous psychiatric and neurodegenerative diseases result in disrupted executive function. Animal and human studies have linked these disorders with alterations in the 5-HT2AR system, making this an important pharmacological target for the treatment of disorders with impaired cognitive function. This review aims to describe the current state of knowledge on the role of 5-HT2AR signalling in components of executive function, and how 5-HT2AR systems may relate to executive dysfunctions occurring in psychiatric and neurodegenerative diseases. We hope thereby to provide insight into how pharmacotherapy targeting the 5-HT2AR may ameliorate (or exacerbate) aspects of these disorders. PMID:26891819

  13. Discovering the mechanisms underlying serotonin (5-HT)2A and 5-HT2C receptor regulation following nicotine withdrawal in rats.

    PubMed

    Zaniewska, Magdalena; Alenina, Natalia; Wydra, Karolina; Fröhler, Sebastian; Kuśmider, Maciej; McCreary, Andrew C; Chen, Wei; Bader, Michael; Filip, Małgorzata

    2015-08-01

    We have previously demonstrated that nicotine withdrawal produces depression-like behavior and that serotonin (5-HT)2A/2C receptor ligands modulate that mood-like state. In the present study we aimed to identify the mechanisms (changes in radioligand binding, transcription or RNA-editing) related to such a behavioral outcome. Rats received vehicle or nicotine (0.4 mg/kg, s.c.) for 5 days in home cages. Brain 5-HT2A/2C receptors were analyzed on day 3 of nicotine withdrawal. Nicotine withdrawal increased [(3)H]ketanserin binding to 5-HT2A receptors in the ventral tegmental area and ventral dentate gyrus, yet decreased binding in the nucleus accumbens shell. Reduction in [(3)H]mesulergine binding to 5-HT2C receptors was seen in the ventral dentate gyrus. Profound decrease in the 5-HT2A receptor transcript level was noted in the hippocampus and ventral tegmental area. Out of five 5-HT2C receptor mRNA editing sites, deep sequencing data showed a reduction in editing at the E site and a trend toward reduction at the C site in the hippocampus. In the ventral tegmental area, a reduction for the frequency of CD 5-HT2C receptor transcript was seen. These results show that the reduction in the 5-HT2A receptor transcript level may be an auto-regulatory response to the increased receptor density in the hippocampus and ventral tegmental area during nicotine withdrawal, while decreased 5-HT2C receptor mRNA editing may explain the reduction in receptor labeling in the hippocampus. Serotonin (5-HT)2A/2C receptor ligands alleviate depression-like state in nicotine-withdrawn rats. Here, we show that the reduction in 5-HT2A receptor transcript level may be an auto-regulatory response to the increased receptor number in the hippocampus and ventral tegmental area during nicotine withdrawal, while attenuated 5-HT2C receptor mRNA editing in the hippocampus might explain reduced inverse agonist binding to 5-HT2C receptor and suggest a shift toward a population of more active receptors. 5

  14. 4-Bromo-2,5-dimethoxyphenethylamine (2C-B) and structurally related phenylethylamines are potent 5-HT2A receptor antagonists in Xenopus laevis oocytes

    PubMed Central

    Villalobos, Claudio A; Bull, Paulina; Sáez, Patricio; Cassels, Bruce K; Huidobro-Toro, J Pablo

    2004-01-01

    We recently described that several 2-(2,5-dimethoxy-4-substituted phenyl)ethylamines (PEAs), including 4-I=2C-I, 4-Br=2C-B, and 4-CH3=2C-D analogs, are partial agonists at 5-HT2C receptors, and show low or even negligible intrinsic efficacy at 5-HT2A receptors. These results raised the proposal that these drugs may act as 5-HT2 antagonists. To test this hypothesis, Xenopus laevis oocytes were microinjected with the rat clones for 5-HT2A or 5-HT2C receptors. The above-mentioned PEAs and its 4-H analog (2C-H) blocked the 5-HT-induced currents at 5-HT2A, but not at the 5-HT2C receptor, revealing 5-HT2 receptor subtype selectivity. The 5-HT2A receptor antagonism required a 2-min preincubation to attain maximum inhibition. All PEAs tested shifted the 5-HT concentration–response curves to the right and downward. Their potencies varied with the nature of the C(4) substituent; the relative rank order of their 5-HT2A receptor antagonist potency was 2C-I>2C-B>2C-D>2C-H. The present results demonstrate that in X. laevis oocytes, a series of 2,5-dimethoxy-4-substituted PEAs blocked the 5-HT2A but not the 5-HT2C receptor-mediated responses. As an alternative hypothesis, we suggest that the psychostimulant activity of the PEAs may not be exclusively associated with partial or full 5-HT2A receptor agonism. PMID:15006903

  15. Pyramidal Neurons in Rat Prefrontal Cortex Projecting to Ventral Tegmental Area and Dorsal Raphe Nucleus Express 5-HT2A Receptors

    PubMed Central

    Vázquez-Borsetti, Pablo; Cortés, Roser

    2009-01-01

    The prefrontal cortex (PFC) is involved in higher brain functions altered in schizophrenia. Classical antipsychotics modulate cortico-limbic circuits mainly through subcortical D2 receptor blockade, whereas second generation (atypical) antipsychotics preferentially target cortical 5-HT receptors. Anatomical and functional evidence supports a PFC-based control of the brainstem monoaminergic nuclei. Using a combination of retrograde tracing experiments and in situ hybridization we report that a substantial proportion of PFC pyramidal neurons projecting to the dorsal raphe (DR) and/or ventral tegmental area (VTA) express 5-HT2A receptors. Cholera-toxin B application into the DR and the VTA retrogradely labeled projection neurons in the medial PFC (mPFC) and in orbitofrontal cortex (OFC). In situ hybridization of 5-HT2A receptor mRNA in the same tissue sections labeled a large neuronal population in mPFC and OFC. The percentage of DR-projecting neurons expressing 5-HT2A receptor mRNA was ∼60% in mPFC and ∼75% in OFC (n = 3). Equivalent values for VTA-projecting neurons were ∼55% in both mPFC and ventral OFC. Thus, 5-HT2A receptor activation/blockade in PFC may have downstream effects on dopaminergic and serotonergic systems via direct descending pathways. Atypical antipsychotics may distally modulate monoaminergic cells through PFC 5-HT2A receptor blockade, presumably decreasing the activity of neurons receiving direct cortical inputs. PMID:19029064

  16. Small molecule drug screening in Drosophila identifies the 5HT2A receptor as a feeding modulation target

    PubMed Central

    Gasque, Gabriel; Conway, Stephen; Huang, Juan; Rao, Yi; Vosshall, Leslie B.

    2013-01-01

    Dysregulation of eating behavior can lead to obesity, which affects 10% of the adult population worldwide and accounts for nearly 3 million deaths every year. Despite this burden on society, we currently lack effective pharmacological treatment options to regulate appetite. We used Drosophila melanogaster larvae to develop a high-throughput whole organism screen for drugs that modulate food intake. In a screen of 3630 small molecules, we identified the serotonin (5-hydroxytryptamine or 5-HT) receptor antagonist metitepine as a potent anorectic drug. Using cell-based assays we show that metitepine is an antagonist of all five Drosophila 5-HT receptors. We screened fly mutants for each of these receptors and found that serotonin receptor 5-HT2A is the sole molecular target for feeding inhibition by metitepine. These results highlight the conservation of molecular mechanisms controlling appetite and provide a method for unbiased whole-organism drug screens to identify novel drugs and molecular pathways modulating food intake. PMID:23817146

  17. Potential role of cortical 5-HT(2A) receptors in the anxiolytic action of cyamemazine in benzodiazepine withdrawal.

    PubMed

    Benyamina, Amine; Naassila, Mickaël; Bourin, Michel

    2012-07-30

    The antipsychotic cyamemazine is a potent serotonin 5-HT(2A) receptor (5-HT(2AR)) antagonist. A positron emission tomography (PET) study in human patients showed that therapeutic doses of cyamemazine produced near saturation of 5-HT(2AR) occupancy in the frontal cortex, whereas dopamine D(2) occupancy remained below the level for motor side effects observed with typical antipsychotics. Recently, numerous studies have revealed the involvement of 5-HT(2AR) in the pathophysiology of anxiety and a double-blind, randomized clinical trial showed similar efficacy of cyamemazine and bromazepam in reducing the anxiety associated with benzodiazepine withdrawal. Therefore, we reviewed the above articles about 5-HT(2AR) and anxiety in order to understand better the anxiolytic mechanisms of cyamemazine in benzodiazepine withdrawal. The 5-HT(2AR) is the most abundant serotonin receptor subtype in the cortex. Non-pharmacological studies with antisense oligodeoxynucleotides and genetically modified mice clearly showed that cortical 5-HT(2AR) signaling positively modulates anxiety-like behavior. With a few exceptions, most other studies reviewed here further support this view. Therefore, the anxiolytic efficacy of cyamemazine in benzodiazepine withdrawal can be due to a 5-HT(2AR) antagonistic activity at the cortical level.

  18. Cartography of 5-HT1A and 5-HT2A Receptor Subtypes in Prefrontal Cortex and Its Projections.

    PubMed

    Mengod, Guadalupe; Palacios, José M; Cortés, Roser

    2015-07-15

    Since the development of chemical neuroanatomical tools in the 1960s, a tremendous wealth of information has been generated on the anatomical components of the serotonergic system, at the microscopic level in the brain including the prefrontal cortex (PFC). The PFC receives a widespread distribution of serotonin (5-hydroxytryptamine, 5-HT) terminals from the median and dorsal raphe nuclei. 5-HT receptors were first visualized using radioligand autoradiography in the late 1980s and early 1990s and showed, in contrast to 5-HT innervation, a differential distribution of binding sites associated with different 5-HT receptor subtypes. Due to the cloning of the different 5-HT receptor subtype genes in the late 1980s and early 1990s, it was possible, using in situ hybridization histochemistry, to localize cells expressing mRNA for these receptors. Double in situ hybridization histochemistry and immunohistochemistry allowed for the chemical characterization of the phenotype of cells expressing 5-HT receptors. Tract tracing technology allowed a detailed cartography of the neuronal connections of PFC and other brain areas. Based on these data, maps have been constructed that reflect our current understanding of the different circuits where 5-HT receptors can modulate the electrophysiological, pharmacological, and behavioral functions of the PFC. We will review current knowledge regarding the cellular localization of 5-HT1A and 5-HT2A receptors in mammalian PFC and their possible functions in the neuronal circuits of the PFC. We will discuss data generated in our laboratory as well as in others, focusing on localization in the pyramidal and GABAergic neuronal cell populations in different mammalian species using molecular neuroanatomy and on the connections with other brain regions. PMID:25739427

  19. Cartography of 5-HT1A and 5-HT2A Receptor Subtypes in Prefrontal Cortex and Its Projections.

    PubMed

    Mengod, Guadalupe; Palacios, José M; Cortés, Roser

    2015-07-15

    Since the development of chemical neuroanatomical tools in the 1960s, a tremendous wealth of information has been generated on the anatomical components of the serotonergic system, at the microscopic level in the brain including the prefrontal cortex (PFC). The PFC receives a widespread distribution of serotonin (5-hydroxytryptamine, 5-HT) terminals from the median and dorsal raphe nuclei. 5-HT receptors were first visualized using radioligand autoradiography in the late 1980s and early 1990s and showed, in contrast to 5-HT innervation, a differential distribution of binding sites associated with different 5-HT receptor subtypes. Due to the cloning of the different 5-HT receptor subtype genes in the late 1980s and early 1990s, it was possible, using in situ hybridization histochemistry, to localize cells expressing mRNA for these receptors. Double in situ hybridization histochemistry and immunohistochemistry allowed for the chemical characterization of the phenotype of cells expressing 5-HT receptors. Tract tracing technology allowed a detailed cartography of the neuronal connections of PFC and other brain areas. Based on these data, maps have been constructed that reflect our current understanding of the different circuits where 5-HT receptors can modulate the electrophysiological, pharmacological, and behavioral functions of the PFC. We will review current knowledge regarding the cellular localization of 5-HT1A and 5-HT2A receptors in mammalian PFC and their possible functions in the neuronal circuits of the PFC. We will discuss data generated in our laboratory as well as in others, focusing on localization in the pyramidal and GABAergic neuronal cell populations in different mammalian species using molecular neuroanatomy and on the connections with other brain regions.

  20. Maternal lipopolysaccharide treatment differentially affects 5-HT(2A) and mGlu2/3 receptor function in the adult male and female rat offspring.

    PubMed

    Wischhof, Lena; Irrsack, Ellen; Dietz, Frank; Koch, Michael

    2015-10-01

    Maternal infection during pregnancy increases the risk for the offspring to develop schizophrenia. However, it is still not fully understood which biochemical mechanisms are responsible for the emergence of neuropsychiatric symptoms following prenatal immune activation. The serotonin (5-hydroxytryptamine, 5-HT) and glutamate system have prominently been associated with the schizophrenia pathophysiology but also with the mechanism of antipsychotic drug actions. Here, we investigated the behavioral and cellular response to 5-HT2A and metabotropic glutamate (mGlu)2/3 receptor stimulation in male and female offspring born to lipopolysaccharide (LPS)-treated mothers. Additionally, we assessed protein expression levels of prefrontal 5-HT2A and mGlu2 receptors. Prenatally LPS-exposed male and female offspring showed locomotor hyperactivity and increased head-twitch behavior in response to the 5-HT2A receptor agonist DOI. In LPS-exposed male offspring, the mGlu2/3 receptor agonist LY379268 failed to reduce DOI-induced prepulse inhibition deficits. In LPS-males, the behavioral changes were further accompanied by enhanced DOI-induced c-Fos protein expression and an up-regulation of prefrontal 5-HT2A receptors. No changes in either 5-HT2A or mGlu2 receptor protein levels were found in female offspring. Our data support the hypothesis of an involvement of maternal infection during pregnancy contributing, at least partially, to the pathology of schizophrenia. Identifying biochemical alterations that parallel the behavioral deficits may help to improve therapeutic strategies in the treatment of this mental illness. Since most studies in rodents almost exclusively include male subjects, our data further contribute to elucidating possible gender differences in the effects of prenatal infection on 5-HT2A and mGlu2/3 receptor function. PMID:26051401

  1. THE SEROTONIN (5-HT) 5-HT2A RECEPTOR: ASSOCIATION WITH INHERENT AND COCAINE-EVOKED BEHAVIORAL DISINHIBITION IN RATS

    PubMed Central

    Anastasio, Noelle C.; Stoffel, Erin C.; Fox, Robert G.; Bubar, Marcy J.; Rice, Kenner C.; Moeller, F. Gerard; Cunningham, Kathryn A.

    2011-01-01

    Alterations in the balance of functional activity within the serotonin (5-HT) system are hypothesized to underlie impulse control. Cocaine-dependent subjects consistently demonstrate greater impulsivity relative to non-drug using control subjects. Preclinical studies suggest that the 5-HT2A receptor (5-HT2AR) contributes to the regulation of impulsive behavior and also mediates some of the behavioral effects of cocaine. We hypothesized that the selective 5-HT2AR antagonist M100907 would reduce inherent levels of impulsivity and attenuate impulsive responding induced by cocaine in two animal models of impulsivity, the differential reinforcement of low rate (DRL) task and the one-choice serial reaction time (1-CSRT) task. M100907 reduced rates of responding in the DRL task and premature responding in the 1-CSRT task. Conversely, cocaine disrupted rates of responding in the DRL task and increased premature responding in the 1-CSRT task. M100907 attenuated cocaine-induced increases in specific markers of behavioral disinhibition in the DRL and 1-CSRT tasks. These results suggest that the 5-HT2AR regulates inherent impulsivity, and that blockade of the 5-HT2AR alleviates specific aspects of elevated levels of impulsivity induced by cocaine exposure. These data point to the 5-HT2AR as an important regulatory substrate in impulse control. PMID:21499079

  2. Activation of 5-HT2a Receptors in the Basolateral Amygdala Promotes Defeat-Induced Anxiety and the Acquisition of Conditioned Defeat in Syrian Hamsters

    PubMed Central

    Clinard, Catherine T.; Bader, Lauren R.; Sullivan, Molly A.; Cooper, Matthew A.

    2014-01-01

    Conditioned defeat is a model in Syrian hamsters (Mesocricetus auratus) in which normal territorial aggression is replaced by increased submissive and defensive behavior following acute social defeat. The conditioned defeat response involves both a fear-related memory for a specific opponent as well as anxiety-like behavior indicated by avoidance of novel conspecifics. We have previously shown that systemic injection of a 5-HT2a receptor antagonist reduces the acquisition of conditioned defeat. Because neural activity in the basolateral amygdala (BLA) is critical for the acquisition of conditioned defeat and BLA 5-HT2a receptors can modulate anxiety but have a limited effect on emotional memories, we investigated whether 5-HT2a receptor modulation alters defeat-induced anxiety but not defeat-related memories. We injected the 5-HT2a receptor antagonist MDL 11,939 (0 mM, 1.7 mM or 17 mM) or the 5-HT2a receptor agonist TCB-2 (0 mM, 8 mM or 80 mM) into the BLA prior to social defeat. We found that injection of MDL 11,939 into the BLA impaired acquisition of the conditioned defeat response and blocked defeat-induced anxiety in the open field, but did not significantly impair avoidance of former opponents in the Y-maze. Furthermore, we found that injection of TCB-2 into the BLA increased the acquisition of conditioned defeat and increased anxiety-like behavior in the open field, but did not alter avoidance of former opponents. Our data suggest that 5-HT2a receptor signaling in the BLA is both necessary and sufficient for the development of conditioned defeat, likely via modulation of defeat-induced anxiety. PMID:25458113

  3. Genotype-Dependent Difference in 5-HT2C Receptor-Induced Hypolocomotion: Comparison with 5-HT2A Receptor Functional Activity

    PubMed Central

    Bazovkina, Darya V.; Kondaurova, Elena M.; Naumenko, Vladimir S.; Ponimaskin, Evgeni

    2015-01-01

    In the present study behavioral effects of the 5-HT2C serotonin receptor were investigated in different mouse strains. The 5-HT2C receptor agonist MK-212 applied intraperitoneally induced significant dose-dependent reduction of distance traveled in the open field test in CBA/Lac mice. This effect was receptor-specific because it was inhibited by the 5-HT2C receptor antagonist RS102221. To study the role of genotype in 5-HT2C receptor-induced hypolocomotion, locomotor activity of seven inbred mouse strains was measured after MK-212 acute treatment. We found that the 5-HT2C receptor stimulation by MK-212 decreased distance traveled in the open field test in CBA/Lac, C57Bl/6, C3H/He, and ICR mice, whereas it failed to affect locomotor activity in DBA/2J, Asn, and Balb/c mice. We also compared the interstrain differences in functional response to 5-HT2C and 5-HT2A receptors activation measured by the quantification of receptor-mediated head-twitches. These experiments revealed significant positive correlation between 5-HT2C and 5-HT2A receptors functional responses for all investigated mouse strains. Moreover, we found that 5-HT2A receptor activation with DOI did not change locomotor activity in CBA/Lac mice. Taken together, our data indicate the implication of 5-HT2C receptors in regulation of locomotor activity and suggest the shared mechanism for functional responses mediated by 5-HT2C and 5-HT2A receptors. PMID:26380122

  4. Genotype-Dependent Difference in 5-HT2C Receptor-Induced Hypolocomotion: Comparison with 5-HT2A Receptor Functional Activity.

    PubMed

    Bazovkina, Darya V; Kondaurova, Elena M; Naumenko, Vladimir S; Ponimaskin, Evgeni

    2015-01-01

    In the present study behavioral effects of the 5-HT2C serotonin receptor were investigated in different mouse strains. The 5-HT2C receptor agonist MK-212 applied intraperitoneally induced significant dose-dependent reduction of distance traveled in the open field test in CBA/Lac mice. This effect was receptor-specific because it was inhibited by the 5-HT2C receptor antagonist RS102221. To study the role of genotype in 5-HT2C receptor-induced hypolocomotion, locomotor activity of seven inbred mouse strains was measured after MK-212 acute treatment. We found that the 5-HT2C receptor stimulation by MK-212 decreased distance traveled in the open field test in CBA/Lac, C57Bl/6, C3H/He, and ICR mice, whereas it failed to affect locomotor activity in DBA/2J, Asn, and Balb/c mice. We also compared the interstrain differences in functional response to 5-HT2C and 5-HT2A receptors activation measured by the quantification of receptor-mediated head-twitches. These experiments revealed significant positive correlation between 5-HT2C and 5-HT2A receptors functional responses for all investigated mouse strains. Moreover, we found that 5-HT2A receptor activation with DOI did not change locomotor activity in CBA/Lac mice. Taken together, our data indicate the implication of 5-HT2C receptors in regulation of locomotor activity and suggest the shared mechanism for functional responses mediated by 5-HT2C and 5-HT2A receptors. PMID:26380122

  5. Genotype-Dependent Difference in 5-HT2C Receptor-Induced Hypolocomotion: Comparison with 5-HT2A Receptor Functional Activity.

    PubMed

    Bazovkina, Darya V; Kondaurova, Elena M; Naumenko, Vladimir S; Ponimaskin, Evgeni

    2015-01-01

    In the present study behavioral effects of the 5-HT2C serotonin receptor were investigated in different mouse strains. The 5-HT2C receptor agonist MK-212 applied intraperitoneally induced significant dose-dependent reduction of distance traveled in the open field test in CBA/Lac mice. This effect was receptor-specific because it was inhibited by the 5-HT2C receptor antagonist RS102221. To study the role of genotype in 5-HT2C receptor-induced hypolocomotion, locomotor activity of seven inbred mouse strains was measured after MK-212 acute treatment. We found that the 5-HT2C receptor stimulation by MK-212 decreased distance traveled in the open field test in CBA/Lac, C57Bl/6, C3H/He, and ICR mice, whereas it failed to affect locomotor activity in DBA/2J, Asn, and Balb/c mice. We also compared the interstrain differences in functional response to 5-HT2C and 5-HT2A receptors activation measured by the quantification of receptor-mediated head-twitches. These experiments revealed significant positive correlation between 5-HT2C and 5-HT2A receptors functional responses for all investigated mouse strains. Moreover, we found that 5-HT2A receptor activation with DOI did not change locomotor activity in CBA/Lac mice. Taken together, our data indicate the implication of 5-HT2C receptors in regulation of locomotor activity and suggest the shared mechanism for functional responses mediated by 5-HT2C and 5-HT2A receptors.

  6. Extensive Rigid Analogue Design Maps the Binding Conformation of Potent N-Benzylphenethylamine 5-HT2A Serotonin Receptor Agonist Ligands

    PubMed Central

    2012-01-01

    Based on the structure of the superpotent 5-HT2A agonist 2-(4-bromo-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine, which consists of a ring-substituted phenethylamine skeleton modified with an N-benzyl group, we designed and synthesized a small library of constrained analogues to identify the optimal arrangement of the pharmacophoric elements of the ligand. Structures consisted of diversely substituted tetrahydroisoquinolines, piperidines, and one benzazepine. Based on the structure of (S,S)-9b, which showed the highest affinity of the series, we propose an optimal binding conformation. (S,S)-9b also displayed 124-fold selectivity for the 5-HT2A over the 5-HT2C receptor, making it the most selective 5-HT2A receptor agonist ligand currently known. PMID:23336049

  7. Lack of Association between the Serotonin Transporter (5-HTT) and Serotonin Receptor (5-HT2A) Gene Polymorphisms with Smoking Behavior among Malaysian Malays

    PubMed Central

    Rozak, Nur Iwani A; Ahmad, Imran; Gan, Siew Hua; Abu Bakar, Ruzilawati

    2014-01-01

    Abstract An insertion/deletion polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) and a polymorphism (rs6313) in the serotonin 2A receptor gene (5-HT2A) have previously been linked to smoking behavior. The objective of this study was to determine the possible association of the 5-HTTLPR and 5-HT2A gene polymorphisms with smoking behavior within a population of Malaysian male smokers (n=248) and non-smokers (n=248). The 5-HTTLPR genotypes were determined using the polymerase chain reaction (PCR) and were classified as short (S) alleles or long (L) alleles. The 5HT2A genotypes were determined using PCR-restriction fragment length polymorphisms (PCR-RFLP). No significant differences in the distribution frequencies of the alleles were found between the smokers and the non-smokers for the 5-HTTLPR polymorphism (x2 = 0.72, P>0.05) or the 5HT2A polymorphism (x2 = 0.73, P>0.05). This is the first study conducted on Malaysian Malay males regarding the association of 5-HTTLPR and 5HT2A polymorphisms and smoking behavior. However, the genes were not found to be associated with smoking behavior in our population. PMID:25853073

  8. Allosteric signaling through an mGlu2 and 5-HT2A heteromeric receptor complex and its potential contribution to schizophrenia.

    PubMed

    Moreno, José L; Miranda-Azpiazu, Patricia; García-Bea, Aintzane; Younkin, Jason; Cui, Meng; Kozlenkov, Alexey; Ben-Ezra, Ariel; Voloudakis, Georgios; Fakira, Amanda K; Baki, Lia; Ge, Yongchao; Georgakopoulos, Anastasios; Morón, José A; Milligan, Graeme; López-Giménez, Juan F; Robakis, Nikolaos K; Logothetis, Diomedes E; Meana, J Javier; González-Maeso, Javier

    2016-01-12

    Heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) can form multiprotein complexes (heteromers), which can alter the pharmacology and functions of the constituent receptors. Previous findings demonstrated that the Gq/11-coupled serotonin 5-HT2A receptor and the Gi/o-coupled metabotropic glutamate 2 (mGlu2) receptor-GPCRs that are involved in signaling alterations associated with psychosis-assemble into a heteromeric complex in the mammalian brain. In single-cell experiments with various mutant versions of the mGlu2 receptor, we showed that stimulation of cells expressing mGlu2-5-HT2A heteromers with an mGlu2 agonist led to activation of Gq/11 proteins by the 5-HT2A receptors. For this crosstalk to occur, one of the mGlu2 subunits had to couple to Gi/o proteins, and we determined the relative location of the Gi/o-contacting subunit within the mGlu2 homodimer of the heteromeric complex. Additionally, mGlu2-dependent activation of Gq/11, but not Gi/o, was reduced in the frontal cortex of 5-HT2A knockout mice and was reduced in the frontal cortex of postmortem brains from schizophrenic patients. These findings offer structural insights into this important target in molecular psychiatry.

  9. Functional selectivity of hallucinogenic phenethylamine and phenylisopropylamine derivatives at human 5-hydroxytryptamine (5-HT)2A and 5-HT2C receptors.

    PubMed

    Moya, Pablo R; Berg, Kelly A; Gutiérrez-Hernandez, Manuel A; Sáez-Briones, Patricio; Reyes-Parada, Miguel; Cassels, Bruce K; Clarke, William P

    2007-06-01

    2,5-Dimethoxy-4-substituted phenylisopropylamines and phenethylamines are 5-hydroxytryptamine (serotonin) (5-HT)(2A/2C) agonists. The former are partial to full agonists, whereas the latter are partial to weak agonists. However, most data come from studies analyzing phospholipase C (PLC)-mediated responses, although additional effectors [e.g., phospholipase A(2) (PLA(2))] are associated with these receptors. We compared two homologous series of phenylisopropylamines and phenethylamines measuring both PLA(2) and PLC responses in Chinese hamster ovary-K1 cells expressing human 5-HT(2A) or 5-HT(2C) receptors. In addition, we assayed both groups of compounds as head shake inducers in rats. At the 5-HT(2C) receptor, most compounds were partial agonists for both pathways. Relative efficacy of some phenylisopropylamines was higher for both responses compared with their phenethylamine counterparts, whereas for others, no differences were found. At the 5-HT(2A) receptor, most compounds behaved as partial agonists, but unlike findings at 5-HT(2C) receptors, all phenylisopropylamines were more efficacious than their phenethylamine counterparts. 2,5-Dimethoxyphenylisopropylamine activated only the PLC pathway at both receptor subtypes, 2,5-dimethoxyphenethylamine was selective for PLC at the 5-HT(2C) receptor, and 2,5-dimethoxy-4-nitrophenethylamine was PLA(2)-specific at the 5-HT(2A) receptor. For both receptors, the rank order of efficacy of compounds differed depending upon which response was measured. The phenylisopropylamines were strong head shake inducers, whereas their phenethylamine congeners were not, in agreement with in vitro results and the involvement of 5-HT(2A) receptors in the head shake response. Our results support the concept of functional selectivity and indicate that subtle changes in ligand structure can result in significant differences in the cellular signaling profile.

  10. APD125, a Selective Serotonin 5-HT2A Receptor Inverse Agonist, Significantly Improves Sleep Maintenance in Primary Insomnia

    PubMed Central

    Rosenberg, Russell; Seiden, David J.; Hull, Steven G.; Erman, Milton; Schwartz, Howard; Anderson, Christen; Prosser, Warren; Shanahan, William; Sanchez, Matilde; Chuang, Emil; Roth, Thomas

    2008-01-01

    Introduction: Insomnia is a condition affecting 10% to 15% of the adult population and is characterized by difficulty falling asleep, difficulty staying asleep, or nonrestorative sleep, accompanied by daytime impairment or distress. This study evaluates APD125, a selective inverse agonist of the 5-HT2A receptor, for treatment of chronic insomnia, with particular emphasis on sleep maintenance. In phase 1 studies, APD125 improved sleep maintenance and was well tolerated. Methodology: Adult subjects (n = 173) with DSM-IV defined primary insomnia were randomized into a multicenter, double-blind, placebo-controlled, 3-way crossover study to compare 2 doses of APD125 (10 mg and 40 mg) with placebo. Each treatment period was 7 days with a 7- to 9-day washout period between treatments. Polysomnographic recordings were performed at the initial 2 screening nights and at nights (N) 1/2 and N 6/7 of each treatment period. Results: APD125 was associated with significant improvements in key sleep maintenance parameters measured by PSG. Wake time after sleep onset decreased (SEM) by 52.5 (3.2) min (10 mg) and 53.5 (3.5) min (40 mg) from baseline to N 1/2 vs. 37.8 (3.4) min for placebo, (P < 0.0001 for both doses vs placebo), and by 51.7 (3.4) min (P = 0.01) and 48.0 (3.6) min (P = 0.2) at N 6/7 vs. 44.0 (3.8) min for placebo. Significant APD125 effects on wake time during sleep were also seen (P < 0.0001 N 1/2, P < 0.001 N 6/7). The number of arousals and number of awakenings decreased significantly with APD125 treatment compared to placebo. Slow wave sleep showed a statistically significant dose-dependent increase. There was no significant decrease in latency to persistent sleep. No serious adverse events were reported, and no meaningful differences in adverse event profiles were observed between either dose of APD125 and placebo. APD125 was not associated with next-day psychomotor impairment as measured by Digit Span, Digit Symbol Copy, and Digit Symbol Coding Tests

  11. Involvement of 5-HT2A receptors in MDMA reinforcement and cue-induced reinstatement of MDMA-seeking behaviour.

    PubMed

    Orejarena, María Juliana; Lanfumey, Laurence; Maldonado, Rafael; Robledo, Patricia

    2011-08-01

    The serotonergic system appears crucial for (±)-3,4-methylenedioxymethamphetamine (MDMA) reinforcing properties. Current evidence indicates that serotonin 5-HT2A receptors (5-HT2ARs) modulate mesolimbic dopamine (DA) activity and several behavioural responses related to the addictive properties of psychostimulants. This study evaluated the role of 5-HT2ARs in MDMA-induced reinforcement and hyperlocomotion, and the reinstatement of MDMA-seeking behaviour. Basal and MDMA-stimulated extracellular levels of DA in the nucleus accumbens (NAc) and serotonin and noradrenaline in the prefrontal cortex were also assessed. Self-administration of MDMA was blunted in 5-HT2AR knockout (KO) mice compared to wild-type (WT) littermates at both doses tested (0.125 and 0.25 mg/kg per infusion). Horizontal locomotion was increased by MDMA (10 and 20 mg/kg i.p.) to a higher extent in KO than in WT mice. DA outflow in the NAc was lower in KO compared to WT mice under basal conditions and after MDMA (20 mg/kg) challenge. In WT mice, MDMA (5 and 10 mg/kg i.p.) priming did not reinstate MDMA-seeking behaviour, while cue-induced reinstatement was prominent. This cue-induced reinstatement was blocked by administration of the selective 5-HT2AR antagonist, SR46349B (eplivanserin) at a dose of 0.5 mg/kg, but not at 0.25 mg/kg. Our results indicate that 5-HT2ARs are crucial for MDMA-induced reinforcement and cue-induced reinstatement of MDMA-seeking behaviour. These effects are probably due to the modulation of mesolimbic dopaminergic activity.

  12. 3,4-methylenedioxymethamphetamine increases excitability in the dentate gyrus: role of 5HT2A receptor-induced PGE2 signaling.

    PubMed

    Collins, Stuart A; Huff, Courtney; Chiaia, Nicolas; Gudelsky, Gary A; Yamamoto, Bryan K

    2016-03-01

    3,4-methylenedioxymethamphetamine (MDMA) is a widely abused psychostimulant, which causes release of serotonin in various forebrain regions. Recently, we reported that MDMA increases extracellular glutamate concentrations in the dentate gyrus, via activation of 5HT2A receptors. We examined the role of prostaglandin signaling in mediating the effects of 5HT2A receptor activation on the increases in extracellular glutamate and the subsequent long-term loss of parvalbumin interneurons in the dentate gyrus caused by MDMA. Administration of MDMA into the dentate gyrus of rats increased PGE2 concentrations which was prevented by coadministration of MDL100907, a 5HT2A receptor antagonist. MDMA-induced increases in extracellular glutamate were inhibited by local administration of SC-51089, an inhibitor of the EP1 prostaglandin receptor. Systemic administration of SC-51089 during injections of MDMA prevented the decreases in parvalbumin interneurons observed 10 days later. The loss of parvalbumin immunoreactivity after MDMA exposure coincided with a decrease in paired-pulse inhibition and afterdischarge threshold in the dentate gyrus. These changes were prevented by inhibition of EP1 and 5HT2A receptors during MDMA. Additional experiments revealed an increased susceptibility to kainic acid-induced seizures in MDMA-treated rats, which could be prevented with SC51089 treatments during MDMA exposure. Overall, these findings suggest that 5HT2A receptors mediate MDMA-induced PGE2 signaling and subsequent increases in glutamate. This signaling mediates parvalbumin cell losses as well as physiologic changes in the dentate gyrus, suggesting that the lack of the inhibition provided by these neurons increases the excitability within the dentate gyrus of MDMA-treated rats. We hypothesized that the widely abused psychostimulant MDMA causes a loss of parvalbumin (PV) cells and increases excitability in the dentate gyrus. MDMA increases serotonin (5HT) release and activates 5HT2A

  13. Tolerance to LSD and DOB induced shaking behaviour: differential adaptations of frontocortical 5-HT(2A) and glutamate receptor binding sites.

    PubMed

    Buchborn, Tobias; Schröder, Helmut; Dieterich, Daniela C; Grecksch, Gisela; Höllt, Volker

    2015-03-15

    Serotonergic hallucinogens, such as lysergic acid diethylamide (LSD) and dimethoxy-bromoamphetamine (DOB), provoke stereotype-like shaking behaviour in rodents, which is hypothesised to engage frontocortical glutamate receptor activation secondary to serotonin2A (5-HT2A) related glutamate release. Challenging this hypothesis, we here investigate whether tolerance to LSD and DOB correlates with frontocortical adaptations of 5-HT2A and/or overall-glutamate binding sites. LSD and DOB (0.025 and 0.25 mg/kg, i.p.) induce a ketanserin-sensitive (0.5 mg/kg, i.p., 30-min pretreatment) increase in shaking behaviour (including head twitches and wet dog shakes), which with repeated application (7× in 4 ds) is undermined by tolerance. Tolerance to DOB, as indexed by DOB-sensitive [(3)H]spiroperidol and DOB induced [(35)S]GTP-gamma-S binding, is accompanied by a frontocortical decrease in 5-HT2A binding sites and 5-HT2 signalling, respectively; glutamate-sensitive [(3)H]glutamate binding sites, in contrast, remain unchanged. As to LSD, 5-HT2 signalling and 5-HT2A binding, respectively, are not or only marginally affected, yet [(3)H]glutamate binding is significantly decreased. Correlation analysis interrelates tolerance to DOB to the reduced 5-HT2A (r=.80) as well as the unchanged [(3)H]glutamate binding sites (r=.84); tolerance to LSD, as opposed, shares variance with the reduction in [(3)H]glutamate binding sites only (r=.86). Given that DOB and LSD both induce tolerance, one correlating with 5-HT2A, the other with glutamate receptor adaptations, it might be inferred that tolerance can arise at either level. That is, if a hallucinogen (like LSD in our study) fails to induce 5-HT2A (down-)regulation, glutamate receptors (activated postsynaptic to 5-HT2A related glutamate release) might instead adapt and thus prevent further overstimulation of the cortex. PMID:25513973

  14. Tolerance to LSD and DOB induced shaking behaviour: differential adaptations of frontocortical 5-HT(2A) and glutamate receptor binding sites.

    PubMed

    Buchborn, Tobias; Schröder, Helmut; Dieterich, Daniela C; Grecksch, Gisela; Höllt, Volker

    2015-03-15

    Serotonergic hallucinogens, such as lysergic acid diethylamide (LSD) and dimethoxy-bromoamphetamine (DOB), provoke stereotype-like shaking behaviour in rodents, which is hypothesised to engage frontocortical glutamate receptor activation secondary to serotonin2A (5-HT2A) related glutamate release. Challenging this hypothesis, we here investigate whether tolerance to LSD and DOB correlates with frontocortical adaptations of 5-HT2A and/or overall-glutamate binding sites. LSD and DOB (0.025 and 0.25 mg/kg, i.p.) induce a ketanserin-sensitive (0.5 mg/kg, i.p., 30-min pretreatment) increase in shaking behaviour (including head twitches and wet dog shakes), which with repeated application (7× in 4 ds) is undermined by tolerance. Tolerance to DOB, as indexed by DOB-sensitive [(3)H]spiroperidol and DOB induced [(35)S]GTP-gamma-S binding, is accompanied by a frontocortical decrease in 5-HT2A binding sites and 5-HT2 signalling, respectively; glutamate-sensitive [(3)H]glutamate binding sites, in contrast, remain unchanged. As to LSD, 5-HT2 signalling and 5-HT2A binding, respectively, are not or only marginally affected, yet [(3)H]glutamate binding is significantly decreased. Correlation analysis interrelates tolerance to DOB to the reduced 5-HT2A (r=.80) as well as the unchanged [(3)H]glutamate binding sites (r=.84); tolerance to LSD, as opposed, shares variance with the reduction in [(3)H]glutamate binding sites only (r=.86). Given that DOB and LSD both induce tolerance, one correlating with 5-HT2A, the other with glutamate receptor adaptations, it might be inferred that tolerance can arise at either level. That is, if a hallucinogen (like LSD in our study) fails to induce 5-HT2A (down-)regulation, glutamate receptors (activated postsynaptic to 5-HT2A related glutamate release) might instead adapt and thus prevent further overstimulation of the cortex.

  15. A comparison of the behavioural effects of 5-HT2A and 5-HT2C receptor agonists in the pigeon.

    PubMed

    Wolff, M C; Leander, J D

    2000-08-01

    Activity at the 5-HT2A receptor versus that of the 5-HT2C receptor was studied in three behavioural paradigms. In pigeons trained to discriminate 0.32 mg/kg of 1-(2,5-diemethoxy-4-iodophenyl)-2-aminopropane (DOI) (a mixed 5-HT2A/C receptor agonist) from vehicle, quipazine (0.1-1 mg/kg) and m-chlorophenylpiperazine (mCPP) (1-3 mg/kg) substituted for DOI in a dose-related manner, and this generalization was blocked by MDL100907 (0.0001-0.01 mg/kg), a selective 5-HT2A receptor antagonist. RO60-0175 (a relatively selective 5-HT2C agonist) induced partial substitution at 3 mg/kg that was antagonized by both MDL100907 and by 3 mg/kg of SB242084, a relatively selective 5-HT2C antagonist. MK212 (a mixed 5-HT2C/A agonist) induced partial substitution that was antagonized by SB242084, but not by MDL100907. On a progressive ratio 5 operant schedule (PR5) for food reinforcement, DOI, quipazine, mCPP, MK212 and R060-0175 decreased the break point; mCPP, DOI, MK212 and quipazine also induced vomiting. Although MDL100907 antagonized both the reductions of break point and vomiting, SB242084 only partially attenuated the decrease in break point observed with MK212 and DOI, and was unable to eliminate vomiting. Thus pharmacological activity at the 5-HT2A receptor can be behaviourally distinguished from pharmacological activity at the 5-HT2C receptor in the pigeon. Furthermore, the decrease in the break point of a PR5 schedule induced by 5-HT2C receptor agonists may be related to decreased appetite, whereas that induced by 5-HT2A receptor agonists may be due to unrelated factors, such as emesis. PMID:11103887

  16. The role of the 5-HT2A and 5-HT2C receptors in the stimulus effects of hallucinogenic drugs. I: Antagonist correlation analysis.

    PubMed

    Fiorella, D; Rabin, R A; Winter, J C

    1995-10-01

    Investigations conducted over the past 3 decades have demonstrated that serotonergic receptors, specifically the 5-HT2A and 5-HT2C subtypes, play an important role in the behavioral effects of hallucinogenic compounds. The present study was designed to determine the respective significance of these two receptors in the stimulus effects of LSD and (-)DOM in the rat. Specifically, the interactions of a series of serotonergic antagonists (risperidone, pirenpirone, metergoline, ketanserin, loxapine, LY53857, pizotyline, spiperone, cyprohepatadine, mesulergine, promethazine, and thioridazine) with the LSD stimulus and the (-)DOM stimulus in LSD-trained subjects was defined. From these data, IC50 values were determined for the inhibition of the LSD-appropriate responding elicited by either 0.1 mg/kg LSD (15-min pretreatment time) or 0.4 mg/kg (-)DOM (75-min pretreatment). In addition, the affinities of these antagonists for 5-HT2A and 5-HT2C receptors were determined in radioligand competition studies, 5-HT2A affinity correlated significantly with IC50 values for the blockade of the LSD (r = +0.75, P < 0.05) and (-)DOM (r = +0.95, P < 0.001) stimuli in the LSD trained subjects. 5-HT2C affinity did not correlate significantly with either series of IC50 values. These data indicate that (1) the stimulus effects of LSD, and (2) the substitution of (-)DOM for the LSD stimulus are mediated by agonist activity at 5-HT2A receptors.

  17. Effect of fluvoxamine on platelet 5-HT2A receptors as studied by [3H]lysergic acid diethylamide ([3H]LSD) binding in healthy volunteers.

    PubMed

    Spigset, O; Mjörndal, T

    1997-09-01

    Alterations in platelet 5-HT2A receptor characteristics have been reported in major depression as well as in other psychiatric diseases, and some effort has been made to utilize platelet 5-HT2A receptor status as a biological correlate to antidepressant drug response. In order to investigate whether treatment with a selective serotonin reuptake inhibitor affects platelet 5-HT2A receptors, we have studied platelet [3H]lysergic acid diethylamide ([3H]LSD) binding in healthy subjects treated with fluvoxamine in increasing dosage once weekly for 4 weeks. After 1 week of fluvoxamine treatment (25 mg/day), both Bmax and Kd were significantly lower than before the start of the treatment (19.9 versus 25.5 fmol/mg protein, P = 0.005 for Bmax; 0.45 versus 0.93 nM, P = 0.006 for Kd). Bmax returned to baseline during week 2, whereas Kd was lower than the baseline value throughout the treatment period. After discontinuation of fluvoxamine treatment, there was a significant increase in Kd (0.50 nM before discontinuation vs. 1.14 nM after discontinuation; P = 0.001), but not in Bmax. The study demonstrates that fluvoxamine affects platelet 5-HT2A receptor status irrespective of underlying psychiatric disease, and that this effect is evident already after 1 week at a subtherapeutic fluvoxamine dose.

  18. Exploring the relationship between binding modes of 9-(aminomethyl)-9,10-dihydroanthracene and cyproheptadine analogues at the 5-HT2A serotonin receptor.

    PubMed

    Westkaemper, R B; Runyon, S P; Savage, J E; Roth, B L; Glennon, R A

    2001-02-26

    Comparison of the serotonin 5-HT2A receptor affinities of a parallel series of structural analogues of the novel ligand 9-aminomethyl-9,10-dihydroanthracene (AMDA) and a structurally similar prototypical tricyclic amine cyproheptadine suggests that the two agents bind to the receptor in different fashions. Examination of ligand-receptor model complexes supports the experimental data and suggests a potential origin for the differences in binding modes.

  19. MDMA-induced loss of parvalbumin interneurons within the dentate gyrus is mediated by 5HT2A and NMDA receptors.

    PubMed

    Collins, Stuart A; Gudelsky, Gary A; Yamamoto, Bryan K

    2015-08-15

    MDMA is a widely abused psychostimulant which causes a rapid and robust release of the monoaminergic neurotransmitters dopamine and serotonin. Recently, it was shown that MDMA increases extracellular glutamate concentrations in the dorsal hippocampus, which is dependent on serotonin release and 5HT2A/2C receptor activation. The increased extracellular glutamate concentration coincides with a loss of parvalbumin-immunoreactive (PV-IR) interneurons of the dentate gyrus region. Given the known susceptibility of PV interneurons to excitotoxicity, we examined whether MDMA-induced increases in extracellular glutamate in the dentate gyrus are necessary for the loss of PV cells in rats. Extracellular glutamate concentrations increased in the dentate gyrus during systemic and local administration of MDMA. Administration of the NMDA receptor antagonist, MK-801, during systemic injections of MDMA, prevented the loss of PV-IR interneurons seen 10 days after MDMA exposure. Local administration of MDL100907, a selective 5HT2A receptor antagonist, prevented the increases in glutamate caused by reverse dialysis of MDMA directly into the dentate gyrus and prevented the reduction of PV-IR. These findings provide evidence that MDMA causes decreases in PV within the dentate gyrus through a 5HT2A receptor-mediated increase in glutamate and subsequent NMDA receptor activation.

  20. Development of a Multiplex Assay for Studying Functional Selectivity of Human Serotonin 5-HT2A Receptors and Identification of Active Compounds by High-Throughput Screening.

    PubMed

    Iglesias, Alba; Lage, Sonia; Cadavid, Maria Isabel; Loza, Maria Isabel; Brea, José

    2016-09-01

    G protein-coupled receptors (GPCRs) exist as collections of conformations in equilibrium, and the efficacy of drugs has been proposed to be associated with their absolute and relative affinities for these different conformations. The serotonin 2A (5-HT2A) receptor regulates multiple physiological functions, is involved in the pathophysiology of schizophrenia, and serves as an important target of atypical antipsychotic drugs. This receptor was one of the first GPCRs for which the functional selectivity phenomenon was observed, with its various ligands exerting differential effects on the phospholipase A2 (PLA2) and phospholipase C (PLC) signaling pathways. We aimed to develop a multiplex functional assay in 96-well plates for the simultaneous measurement of the PLA2 and PLC pathways coupled to 5-HT2A receptors; this approach enables the detection of either functional selectivity or cooperativity phenomena in early drug screening stages. The suitability of the method for running screening campaigns was tested using the Prestwick Chemical Library, and 22 confirmed hits with activities of more than 90% were identified; 11 of these hits produced statistically significant differences between the two effector pathways. Thus, we have developed a miniaturized multiplex assay in 96-well plates to measure functional selectivity for 5-HT2A receptors in the early stages of the drug discovery process. PMID:27095818

  1. Synthesis and in vitro evaluation of [18F]FECIMBI-36: A potential agonist PET ligand for 5-HT2A/2C receptors

    PubMed Central

    Prabhakaran, Jaya; Underwood, Mark D.; Dileep Kumar, J. S.; Simpson, Norman R.; Kassir, Suham A.; Bakalian, Mihran J.; Mann, J. John; Arango, Victoria

    2016-01-01

    Radiosynthesis and in vitro evaluation of [18F]-2-(4-bromo-2,5-dimethoxyphenyl)-N-(2-(2-fluoroethoxy)benzyl)ethanamine, ([18F]FECIMBI-36) or ([18F]1), a potential agonist PET imaging agent for 5-HT2A/2C receptors is described. Syntheses of reference standard 1 and the corresponding des-fluoroethyl radiolabeling precursor (2) were achieved with 75% and 65% yields, respectively. In vitro pharmacology assay of FECIMBI-36 by [3H]-ketanserin competition binding assay obtained from NIMH-PDSP showed high affinities to 5-HT2AR (Ki = 1 nM) and 5-HT2CR (Ki = 1.7 nM). Radiolabeling of FECIMBI-36 was achieved from the boc-protected precursor 2 using [18F]-fluoroethyltosylate in presence of Cs2CO3 in DMSO followed by removal of the protective group. [18F]1 was isolated using RP-HPLC in 25 ± 5% yield, purity ≥95% and specific activity 1–2 Ci/μmol (N = 6). In vitro autoradiography studies demonstrate that [18F]1 selectively label 5-HT2A and 5-HT2C receptors in slide-mounted sections of postmortem human brain using phosphor imaging. Our results indicate the potential of [18F]1 for imaging 5-HT2A/2C receptors in the high affinity state in vivo using PET imaging. PMID:26253634

  2. Synthesis and in vitro evaluation of [18F]FECIMBI-36: A potential agonist PET ligand for 5-HT2A/2C receptors.

    PubMed

    Prabhakaran, Jaya; Underwood, Mark D; Kumar, J S Dileep; Simpson, Norman R; Kassir, Suham A; Bakalian, Mihran J; Mann, J John; Arango, Victoria

    2015-09-15

    Radiosynthesis and in vitro evaluation of [(18)F]-2-(4-bromo-2,5-dimethoxyphenyl)-N-(2-(2-fluoroethoxy)benzyl)ethanamine, ([(18)F]FECIMBI-36) or ([(18)F]1), a potential agonist PET imaging agent for 5-HT2A/2C receptors is described. Syntheses of reference standard 1 and the corresponding des-fluoroethyl radiolabeling precursor (2) were achieved with 75% and 65% yields, respectively. In vitro pharmacology assay of FECIMBI-36 by [(3)H]-ketanserin competition binding assay obtained from NIMH-PDSP showed high affinities to 5-HT2AR (Ki = 1nM) and 5-HT2CR (Ki=1.7 nM). Radiolabeling of FECIMBI-36 was achieved from the boc-protected precursor 2 using [(18)F]-fluoroethyltosylate in presence of Cs2CO3 in DMSO followed by removal of the protective group. [(18)F]1 was isolated using RP-HPLC in 25 ± 5% yield, purity > 95% and specific activity 1-2Ci/μmol (N = 6). In vitro autoradiography studies demonstrate that [(18)F]1 selectively label 5-HT2A and 5-HT2C receptors in slide-mounted sections of postmortem human brain using phosphor imaging. Our results indicate the potential of [(18)F]1 for imaging 5-HT2A/2C receptors in the high affinity state in vivo using PET imaging.

  3. Role of 5-HT2A and 5-HT2C receptors in the stimulus effects of hallucinogenic drugs. II: Reassessment of LSD false positives.

    PubMed

    Fiorella, D; Rabin, R A; Winter, J C

    1995-10-01

    In the context of animal studies of hallucinogens, an LSD-false positive is defined as a drug known to be devoid of hallucinogenic activity in humans but which nonetheless fully mimics LSD in animals. Quipazine, MK-212, lisuride, and yohimbine have all been reported to be LSD false positives. The present study was designed to determine whether these compounds also substitute for the stimulus effects of the more pharmacologically selective hallucinogen (-)DOM (0.56 mg/kg, 75-min pretreatment time). The LSD and (-)DOM stimuli fully generalized to quipazine (3.0 mg/kg) and lisuride (0.2 mg/kg), but only partially generalized to MK-212 (0.1-1.0 mg/kg) and yohimbine (2-20 mg/kg). In combination tests, pirenpirone (0.08 mg/kg), a compound with both D2 and 5-HT2A affinity, blocked the substitution of quipazine and lisuride for the (-)DOM stimulus. Ketanserin (2.5 mg/kg), an antagonist with greater than 1 order of magnitude higher affinity for 5-HT2A receptors than either 5-HT2C or D2 receptors, also fully blocked the substitution of these compounds for the (-)DOM stimulus, while the selective D2 antagonist thiothixene (0.1-1.0 mg/kg) failed to block the substitution of lisuride for the (-)DOM stimulus. These results suggest that quipazine and lisuride substitute for the stimulus properties of the phenylalkglamine hallucinogen (-)DOM via agonist activity at 5-HT2A receptors. In addition, these results suggest that 5-HT2A agonist activity may be required, but is not in itself sufficient, for indolamine and phenylalkglamine compounds to elicit hallucinations in humans. Finally, it is concluded that MK-212 and yohimbine are neither LSD nor (-)DOM false positives.

  4. Implication of 5-HT2A subtype receptors in DOI activity in the four-plates test-retest paradigm in mice.

    PubMed

    Ripoll, Nadège; Hascoët, Martine; Bourin, Michel

    2006-01-01

    The four-plates test (FPT) is an animal model of anxiety which allows the detection of anxiolytic effect not only of benzodiazepines (BZDs) but also of other non-BZDs anxiolytic compounds such as antidepressants (ADs). Furthermore, DOI, a 5-HT(2A/2C) agonist, has been shown to exert an anxiolytic-like effect in this model. Retesting mice in animal models of anxiety (test-retest paradigm) induces an anxiogenic-like and a loss of anxiolytic-like effects in response to BZDs and ADs. On the contrary, DOI has been reported to oppose the fear potentiation induced by trial 1 in the FPT. Despite DOI is considered as one of the most selective 5-HT(2A) available, it acts as agonist at all three 5-HT(2) receptor subtypes (5-HT(2A), 5-HT(2B) and 5-HT(2C)). The aim of this study was thus to investigate in the FPT test-retest paradigm, which 5-HT(2) receptor subtype(s) was involved in the DOI-induced effect in experienced mice. The effect of DOI (0.25-4 mg/kg) and the agonists, 5-HT(2B), BW 723C86 (1-16 mg/kg) and 5-HT(2C), RO 60-0175 (0.25-4 mg/kg) have also been studied. Then, antagonism studies were conducted combinating the 5-HT(2A) receptor antagonist SR 46349B, the 5-HT(2B/2C) receptor antagonist SB 206553 or the selective 5-HT(2C) receptor antagonist RS 10-2221 (at the doses of 0.1 and 1 mg/kg) with the DOI (1 mg/kg). Our study shows that the BW 723C86 had no effect on retesting mice, whereas it exerted an anxiolytic-like effect in naive mice. By contrast to DOI, the RO 60-0175 had no effect neither in naive nor experienced mice. Furthermore, only the SR 46349B antagonized the DOI-induced anti-punishment effect. Diazepam included as a positive control also increased in each case the number of punished passages in naive mice. Our findings altogether also suggest that DOI exerts its anxiolytic-like effect in the FPT test-retest paradigm through 5-HT(2A) receptors.

  5. Participation of 5-HT1-like and 5-HT2A receptors in the contraction of human temporal artery by 5-hydroxytryptamine and related drugs.

    PubMed Central

    Verheggen, R.; Freudenthaler, S.; Meyer-Dulheuer, F.; Kaumann, A. J.

    1996-01-01

    1. We investigated the hypothesis that, as in some other large human arteries, 5-HT-induced contraction of the temporal artery is mediated through two co-existing receptor populations, 5-HT1-like- and 5-HT2A. Temporal arterial segments were obtained from patients undergoing brain surgery and rings prepared set up to contract with 5-HT and related agents. Fractions of maximal 5-HT responses mediated through 5-HT1-like and 5-HT2A receptors, f1 and f2 = 1-f1, were estimated by use of the 5-HT2A-selective antagonist ketanserin. 2. In rings with intact endothelium 5-HT evoked contractions with a -log EC50, M of 7.0. Ketanserin (10-1000 nM) antagonized part of the 5-HT-induced contractions. Ketanserin-resistant components of 5-HT-induced contractions were found with -log EC50, M of 6.9 and f1 of 0.17 (100 nM ketanserin) and -log EC50, M of 6.4 and f1 of 0.20 (1000 nM ketanserin). 3. In rings with endothelial function attenuated by enzymatic treatment, 5-HT caused contractions with a -log EC50, M of 7.2 that were partially blocked by ketanserin. Ketanserin-resistant components of 5-HT-induced contractions were found with -log EC50, M 7.4 and f1 of 0.16 (100 nM ketanserin) and -log EC50, M of 7.5 and f1 of 0.14 (1000 nM ketanserin). 4. The ketanserin-resistant component of 5-HT-evoked contraction was blocked by methiothepin (100-1000 nM) consistent with mediation through 5-HT1-like receptors. 5. In rings with intact endothelium the 5-HT1-like-selective agonist, sumatriptan, caused small contractions with a -log EC50, M of 6.5 and intrinsic activity of 0.21 with respect to 5-HT that were resistant to blockade by 1000 nM ketanserin but antagonized by 100 nM methiothepin. 6. In rings with intact endothelium the 5-HT2A receptor partial agonist SK&F 103829 (2,3,4,5-tetrahydro-8[methyl sulphonyl]-1H3-benzazepin-7-ol methensulphonate) contracted rings with a -log EC50, M of 5.0 and an intrinsic activity of 0.49 with respect to 5-HT; the effects were antagonized by ketanserin 1000

  6. Evidence for a 5-HT2A receptor mode of action in the anxiolytic-like properties of DOI in mice.

    PubMed

    Nic Dhonnchadha, Bríd Aine; Hascoët, Martine; Jolliet, Pascale; Bourin, Michel

    2003-12-17

    DOI [(+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane] displays a high affinity for the rat 5-HT2A, 5-HT2B and 5-HT2C receptors (pKi 7.3, 7.4 and 7.8, respectively) and acts as an agonist. DOI (0.5-4 mg/kg, i.p. 30 min pre-test) increased the number of punished passages in the mouse four plates test (FPT). The anti-punishment action of DOI (1 mg/kg, i.p. 30 min pre-test) was abolished by prior treatment with the selective 5-HT2A receptor antagonist SR 46949B (0.1 and 1 mg/kg, i.p. 45 min pre-test) but not by the selective 5-HT2C receptor antagonist RS 10-2221 (0.1 and 1 mg/kg, i.p. 45 min pre-test) nor the selective 5-HT2C/2B receptor antagonist SB 206553 (0.1 and 1 mg/kg, i.p. 45 min pre-test). An anxiolytic-like action was also observed for DOI (1 mg/kg) in the elevated plus maze (EPM). The anxiolytic-like action of DOI (1 mg/kg, i.p. 30 min pre-test) was antagonised by pre-treatment with SR 46949B (0.125 and 0.5 mg/kg, i.p. 45 min pre-test) but not by RS 10-2221 (0.1 and 1 mg/kg, i.p. 45 min pre-test) nor SB 206553 (0.1 and 1 mg/kg, i.p. 45 min pre-test). In conclusion, DOI produced an anxiolytic-like profile in the mouse FPT and EPM. These effects are likely to be 5-HT2A receptor mediated.

  7. A Model of Post-Infection Fatigue Is Associated with Increased TNF and 5-HT2A Receptor Expression in Mice.

    PubMed

    Couch, Yvonne; Xie, Qin; Lundberg, Louise; Sharp, Trevor; Anthony, Daniel C

    2015-01-01

    It is well documented that serotonin (5-HT) plays an important role in psychiatric illness. For example, myalgic encephalomyelitis (ME/CFS), which is often provoked by infection, is a disabling illness with an unknown aetiology and diagnosis is based on symptom-specific criteria. However, 5-HT2A receptor expression and peripheral cytokines are known to be upregulated in ME. We sought to examine the relationship between the 5-HT system and cytokine expression following systemic bacterial endotoxin challenge (LPS, 0.5 mg/kg i.p.), at a time when the acute sickness behaviours have largely resolved. At 24 hours post-injection mice exhibit no overt changes in locomotor behaviour, but do show increased immobility in a forced swim test, as well as decreased sucrose preference and reduced marble burying activity, indicating a depressive-like state. While peripheral IDO activity was increased after LPS challenge, central activity levels remained stable and there was no change in total brain 5-HT levels or 5-HIAA/5-HT. However, within the brain, levels of TNF and 5-HT2A receptor mRNA within various regions increased significantly. This increase in receptor expression is reflected by an increase in the functional response of the 5-HT2A receptor to agonist, DOI. These data suggest that regulation of fatigue and depressive-like moods after episodes of systemic inflammation may be regulated by changes in 5-HT receptor expression, rather than by levels of enzyme activity or cytokine expression in the CNS. PMID:26147001

  8. A Model of Post-Infection Fatigue Is Associated with Increased TNF and 5-HT2A Receptor Expression in Mice

    PubMed Central

    Couch, Yvonne; Xie, Qin; Lundberg, Louise; Sharp, Trevor; Anthony, Daniel C.

    2015-01-01

    It is well documented that serotonin (5-HT) plays an important role in psychiatric illness. For example, myalgic encephalomyelitis (ME/CFS), which is often provoked by infection, is a disabling illness with an unknown aetiology and diagnosis is based on symptom-specific criteria. However, 5-HT2A receptor expression and peripheral cytokines are known to be upregulated in ME. We sought to examine the relationship between the 5-HT system and cytokine expression following systemic bacterial endotoxin challenge (LPS, 0.5mg/kg i.p.), at a time when the acute sickness behaviours have largely resolved. At 24 hours post-injection mice exhibit no overt changes in locomotor behaviour, but do show increased immobility in a forced swim test, as well as decreased sucrose preference and reduced marble burying activity, indicating a depressive-like state. While peripheral IDO activity was increased after LPS challenge, central activity levels remained stable and there was no change in total brain 5-HT levels or 5-HIAA/5-HT. However, within the brain, levels of TNF and 5-HT2A receptor mRNA within various regions increased significantly. This increase in receptor expression is reflected by an increase in the functional response of the 5-HT2A receptor to agonist, DOI. These data suggest that regulation of fatigue and depressive-like moods after episodes of systemic inflammation may be regulated by changes in 5-HT receptor expression, rather than by levels of enzyme activity or cytokine expression in the CNS. PMID:26147001

  9. Multiple conformations of 5-HT2A and 5-HT 2C receptors in rat brain: an autoradiographic study with [125I](±)DOI.

    PubMed

    López-Giménez, Juan F; Vilaró, M Teresa; Palacios, José M; Mengod, Guadalupe

    2013-10-01

    Earlier autoradiographic studies with the 5-HT2 receptor agonist [(125)I](±)DOI in human brain showed unexpected biphasic competition curves for various 5-HT2A antagonists. We have performed similar studies in rat brain regions with selective 5-HT2A (M100907) and 5-HT2C (SB242084) antagonists together with ketanserin and mesulergine. The effect of GTP analogues on antagonist competition was also studied. Increasing concentrations of Gpp(NH)p or GTPγS resulted in a maximal inhibition of [(125)I](±)DOI-specific binding of approximately 50 %. M100907 competed biphasically in all regions. In the presence of 100 μM Gpp(NH)p, M100907 still displaced biphasically the remaining [(125)I](±)DOI binding. Ketanserin showed biphasic curves in some regions and monophasic curves in others. In the latter, Gpp(NH)p evidenced an additional high-affinity site. SB242084 competed biphasically in brainstem nuclei and monophasically in the other regions. In most areas, SB242084 affinities were not notably altered by Gpp(NH)p. Mesulergine competed monophasically in all regions without alteration by Gpp(NH)p. These results conform with the extended ternary complex model of receptor action: receptor exists as an equilibrium of multiple conformations, i.e. ground (R), partly activated (R*) and activated G-protein-coupled (R*G) conformation/s. Thus, [(125)I](±)DOI would label multiple conformations of both 5-HT2A and 5-HT2C receptors in rat brain, and M100907 and ketanserin would recognise these conformations with different affinities.

  10. Differential effects of neonatal handling on anxiety, corticosterone response to stress, and hippocampal glucocorticoid and serotonin (5-HT)2A receptors in Lewis rats.

    PubMed

    Durand, M; Sarrieau, A; Aguerre, S; Mormède, P; Chaouloff, F

    1998-05-01

    Neonatal handling (during the first 3 weeks of age) has been reported by others to diminish the hypothalamo-pituitary-adrenal (HPA) responsivity to stress in adult Long Evans rats, an effect involving a serotonin (5-HT)2A receptor-mediated increase in glucocorticoid receptor (GR) gene expression in the frontal cortex and the hippocampus. In addition, handled animals may also display enduring reductions in anxiety-related behaviours, including in the elevated plus-maze. We have thus analysed the aforementioned neuroendocrine and behavioural consequences of neonatal stress in male and female adult Lewis rats, a strain characterised by its high anxiety and its hyporesponsive HPA axis. Plasma corticosterone, but not behavioural, responses to an elevated plus-maze test were decreased in handled rats. Besides, hippocampal mineralocorticoid receptor (MR) and GR binding capacities were not different between handled and non-handled Lewis rats, an observation which could be extended to our adult Long Evans rats. Lastly, neither hippocampal nor cortical 5-HT2A receptor binding capacities in adult Lewis rats were affected by prior handling. In keeping with the failure to detect early handling-induced increases in hippocampal GR binding in 3-week old Lewis and Long Evans rats, the present study reinforces past findings indicating that environmental and genetic factors are crucial variables in the neonatal handling paradigm.

  11. Role for serotonin2A (5-HT2A) and 2C (5-HT2C) receptors in experimental absence seizures.

    PubMed

    Venzi, Marcello; David, François; Bellet, Joachim; Cavaccini, Anna; Bombardi, Cristiano; Crunelli, Vincenzo; Di Giovanni, Giuseppe

    2016-09-01

    Absence seizures (ASs) are the hallmark of childhood/juvenile absence epilepsy. Monotherapy with first-line anti-absence drugs only controls ASs in 50% of patients, indicating the need for novel therapeutic targets. Since serotonin family-2 receptors (5-HT2Rs) are known to modulate neuronal activity in the cortico-thalamo-cortical loop, the main network involved in AS generation, we investigated the effect of selective 5-HT2AR and 5-HT2CR ligands on ASs in the Genetic Absence Epilepsy Rats from Strasbourg (GAERS), a well established polygenic rat model of these non-convulsive seizures. GAERS rats were implanted with fronto-parietal EEG electrodes under general anesthesia, and their ASs were later recorded under freely moving conditions before and after intraperitoneal administration of various 5-HT2AR and 5-HT2CR ligands. The 5-HT2A agonist TCB-2 dose-dependently decreased the total time spent in ASs, an effect that was blocked by the selective 5-HT2A antagonist MDL11,939. Both MDL11,939 and another selective 5-HT2A antagonist (M100,907) increased the length of individual seizures when injected alone. The 5-HT2C agonists lorcaserin and CP-809,101 dose-dependently suppressed ASs, an effect blocked by the selective 5-HT2C antagonist SB 242984. In summary, 5-HT2ARs and 5-HT2CRs negatively control the expression of experimental ASs, indicating that selective agonists at these 5-HT2R subtypes might be potential novel anti-absence drugs.

  12. Role for serotonin2A (5-HT2A) and 2C (5-HT2C) receptors in experimental absence seizures.

    PubMed

    Venzi, Marcello; David, François; Bellet, Joachim; Cavaccini, Anna; Bombardi, Cristiano; Crunelli, Vincenzo; Di Giovanni, Giuseppe

    2016-09-01

    Absence seizures (ASs) are the hallmark of childhood/juvenile absence epilepsy. Monotherapy with first-line anti-absence drugs only controls ASs in 50% of patients, indicating the need for novel therapeutic targets. Since serotonin family-2 receptors (5-HT2Rs) are known to modulate neuronal activity in the cortico-thalamo-cortical loop, the main network involved in AS generation, we investigated the effect of selective 5-HT2AR and 5-HT2CR ligands on ASs in the Genetic Absence Epilepsy Rats from Strasbourg (GAERS), a well established polygenic rat model of these non-convulsive seizures. GAERS rats were implanted with fronto-parietal EEG electrodes under general anesthesia, and their ASs were later recorded under freely moving conditions before and after intraperitoneal administration of various 5-HT2AR and 5-HT2CR ligands. The 5-HT2A agonist TCB-2 dose-dependently decreased the total time spent in ASs, an effect that was blocked by the selective 5-HT2A antagonist MDL11,939. Both MDL11,939 and another selective 5-HT2A antagonist (M100,907) increased the length of individual seizures when injected alone. The 5-HT2C agonists lorcaserin and CP-809,101 dose-dependently suppressed ASs, an effect blocked by the selective 5-HT2C antagonist SB 242984. In summary, 5-HT2ARs and 5-HT2CRs negatively control the expression of experimental ASs, indicating that selective agonists at these 5-HT2R subtypes might be potential novel anti-absence drugs. PMID:27085605

  13. The 5-HT(2A) receptor and serotonin transporter in Asperger's disorder: A PET study with [¹¹C]MDL 100907 and [¹¹C]DASB.

    PubMed

    Girgis, Ragy R; Slifstein, Mark; Xu, Xiaoyan; Frankle, W Gordon; Anagnostou, Evdokia; Wasserman, Stacey; Pepa, Lauren; Kolevzon, Alexander; Abi-Dargham, Anissa; Laruelle, Marc; Hollander, Eric

    2011-12-30

    Evidence from biochemical, imaging, and treatment studies suggest abnormalities of the serotonin system in autism spectrum disorders, in particular in frontolimbic areas of the brain. We used the radiotracers [(11)C]MDL 100907 and [(11)C]DASB to characterize the 5-HT(2A) receptor and serotonin transporter in Asperger's Disorder. Seventeen individuals with Asperger's Disorder (age=34.3 ± 11.1 years) and 17 healthy controls (age=33.0 ± 9.6 years) were scanned with [(11)C]MDL 100907. Of the 17 patients, eight (age=29.7 ± 7.0 years) were also scanned with [¹¹C]DASB, as were eight healthy controls (age=28.7 ± 7.0 years). Patients with Asperger's Disorder and healthy control subjects were matched for age, gender, and ethnicity, and all had normal intelligence. Metabolite-corrected arterial plasma inputs were collected and data analyzed by two-tissue compartment modeling. The primary outcome measure was regional binding potential BP(ND). Neither regional [¹¹C]MDL 100907 BP(ND) nor [¹¹C]DASB BP(ND) was statistically different between the Asperger's and healthy subjects. This study failed to find significant alterations in binding parameters of 5-HT(2A) receptors and serotonin transporters in adult subjects with Asperger's disorder.

  14. A double dissociation in the effects of 5-HT2A and 5-HT2C receptors on the acquisition and expression of conditioned defeat in Syrian hamsters

    PubMed Central

    Harvey, Marquinta L.; Swallows, Cody L.; Cooper, Matthew A.

    2012-01-01

    Previous research indicates that serotonin enhances the development of stress-induced changes in behavior, although it is unclear which serotonin receptors mediate this effect. 5-HT2 receptors are potential candidates because activation at these receptors is associated with increased fear and anxiety. In this study we investigated whether pharmacological treatments targeting 5-HT2 receptors would alter the acquisition and expression of conditioned defeat. Conditioned defeat is a social defeat model in Syrian hamsters in which individuals display increased submissive and defensive behavior and a loss of territorial aggression when tested with a novel intruder 24 hours after an acute social defeat. The nonselective 5-HT2 receptor agonist mCPP (0.0, 0.3, 1.0 or 3.0 mg/kg) was injected either prior to social defeat training or prior to conditioned defeat testing. Also, the 5-HT2A receptor antagonist MDL 11,939 (0.0, 0.5 or 2.0 mg/kg) was injected either prior to social defeat training or prior to conditioned defeat testing. Injection of mCPP prior to testing increased the expression of conditioned defeat, but injection of mCPP prior to training did not alter the acquisition of conditioned defeat. Conversely, injection of MDL 11,939 prior to training reduced the acquisition of conditioned defeat, but injection of MDL 11,939 prior to testing did not alter the expression of conditioned defeat. Our data suggest that mCPP activates 5-HT2C receptors during testing to enhance the display of submissive and defensive behavior, whereas MDL 11,939 blocks 5-HT2A receptors during social defeat to disrupt the development of the conditioned defeat response. In sum, these results suggest that serotonin acts at separate 5-HT2 receptors to facilitate the acquisition and expression of defeat-induced changes in social behavior. PMID:22708954

  15. Cardiac baroreflex facilitation evoked by hypothalamus and prefrontal cortex stimulation: role of the nucleus tractus solitarius 5-HT2A receptors.

    PubMed

    Sévoz-Couche, C; Comet, M A; Bernard, J F; Hamon, M; Laguzzi, R

    2006-10-01

    We previously showed that serotonin (5-HT2) receptor activation in the nucleus of the tractus solitarius (NTS) produced hypotension, bradycardia, and facilitation of the baroreflex bradycardia. Activation of the preoptic area (POA) of the hypothalamus, which is involved in shock-evoked passive behaviors, induces similar modifications. In addition, previous studies showed that blockade of the infralimbic (IL) part of the medial prefrontal cortex, which sends projections to POA, produced an inhibitory influence on the baroreflex cardiac response. Thus, to assess the possible implication of NTS 5-HT2 receptors in passive cardiovascular responses, we analyzed in anesthetized rats the effects of NTS inhibition and NTS 5-HT2 receptor blockade on the cardiovascular modifications induced by chemical (0.3 M D,L-homocysteic acid) and electrical (50 Hz, 150-200 microA) stimulation of IL or POA. Intra-NTS microinjections of muscimol, a GABAA receptor agonist, prevented the decreases in blood pressure and heart rate normally evoked by IL or POA activation. In addition, we found that intra-NTS microinjection of R(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidine-methanol, a specific 5-HT2A receptor antagonist, did not affect the decreases in cardiovascular baseline parameters induced by IL or POA stimulation but prevented the facilitation of the aortic baroreflex bradycardia normally observed during IL (+65 and +60%) or POA (+70 and +69%) electrical and chemical stimulation, respectively. These results show that NTS 5-HT2A receptors play a key role in the enhancement of the cardiac response of the baroreflex but not in the changes in basal heart rate and blood pressure induced by IL or POA stimulation. PMID:16763082

  16. Effects of imipramine and bupropion on the duration of immobility of ACTH-treated rats in the forced swim test: involvement of the expression of 5-HT2A receptor mRNA.

    PubMed

    Kitamura, Yoshihisa; Fujitani, Yoshika; Kitagawa, Kouhei; Miyazaki, Toshiaki; Sagara, Hidenori; Kawasaki, Hiromu; Shibata, Kazuhiko; Sendo, Toshiaki; Gomita, Yutaka

    2008-02-01

    We examined the effect of chronic administration of imipramine and bupropion, monoamine reuptake inhibitors, on the duration of immobility in the forced swim test and serotonin (5-HT)(2A) receptor function in the form of 5-HT(2A) receptor mRNA levels in rats chronically treated with adrenocorticotropic hormone (ACTH). The immobility-decreasing effect of bupropion without imipramine did not influence the chronic ACTH treatment. The effect on the expression of 5-HT(2A) receptor mRNA of chronic ACTH treatment was decreased by bupropion, but not imipramine. These results suggest that bupropion has the effect of reducing immobility time in the forced swim test in the tricyclic antidepressant-resistant depressive model induced by chronic ACTH treatment in rats, and that decreased 5-HT(2A) receptor mRNA levels may be involved in this phenomenon.

  17. In Vivo Quantification of 5-HT2A Brain Receptors in Mdr1a KO Rats with 123I-R91150 Single-Photon Emission Computed Tomography.

    PubMed

    Dumas, Noé; Moulin-Sallanon, Marcelle; Fender, Pascal; Tournier, Benjamin B; Ginovart, Nathalie; Charnay, Yves; Millet, Philippe

    2015-01-01

    Our goal was to identify suitable image quantification methods to image 5-hydroxytryptamine2A (5-HT2A) receptors in vivo in Mdr1a knockout (KO) rats (i.e., P-glycoprotein KO) using 123I-R91150 single-photon emission computed tomography (SPECT). The 123I-R91150 binding parameters estimated with different reference tissue models (simplified reference tissue model [SRTM], Logan reference tissue model, and tissue ratio [TR] method) were compared to the estimates obtained with a comprehensive three-tissue/seven-parameter (3T/7k)-based model. The SRTM and Logan reference tissue model estimates of 5-HT2A receptor (5-HT2AR) nondisplaceable binding potential (BPND) correlated well with the absolute receptor density measured with the 3T/7k gold standard (r > .89). Quantification of 5-HT2AR using the Logan reference tissue model required at least 90 minutes of scanning, whereas the SRTM required at least 110 minutes. The TR method estimates were also highly correlated to the 5-HT2AR density (r > .91) and only required a single 20-minute scan between 100 and 120 minutes postinjection. However, a systematic overestimation of the BPND values was observed. The Logan reference tissue method is more convenient than the SRTM for the quantification of 5-HT2AR in Mdr1a KO rats using 123I-R91150 SPECT. The TR method is an interesting and simple alternative, despite its bias, as it still provides a valid index of 5-HT2AR density. PMID:26105563

  18. Serotonin contracts the rat mesenteric artery by inhibiting 4-aminopyridine-sensitive Kv channels via the 5-HT2A receptor and Src tyrosine kinase.

    PubMed

    Sung, Dong Jun; Noh, Hyun Ju; Kim, Jae Gon; Park, Sang Woong; Kim, Bokyung; Cho, Hana; Bae, Young Min

    2013-01-01

    Serotonin (5-hydroxytryptamine (5-HT)) is a neurotransmitter that regulates a variety of functions in the nervous, gastrointestinal and cardiovascular systems. Despite such importance, 5-HT signaling pathways are not entirely clear. We demonstrated previously that 4-aminopyridine (4-AP)-sensitive voltage-gated K(+) (Kv) channels determine the resting membrane potential of arterial smooth muscle cells and that the Kv channels are inhibited by 5-HT, which depolarizes the membranes. Therefore, we hypothesized that 5-HT contracts arteries by inhibiting Kv channels. Here we studied 5-HT signaling and the detailed role of Kv currents in rat mesenteric arteries using patch-clamp and isometric tension measurements. Our data showed that inhibiting 4-AP-sensitive Kv channels contracted arterial rings, whereas inhibiting Ca(2+)-activated K(+), inward rectifier K(+) and ATP-sensitive K(+) channels had little effect on arterial contraction, indicating a central role of Kv channels in the regulation of resting arterial tone. 5-HT-induced arterial contraction decreased significantly in the presence of high KCl or the voltage-gated Ca(2+) channel (VGCC) inhibitor nifedipine, indicating that membrane depolarization and the consequent activation of VGCCs mediate the 5-HT-induced vasoconstriction. The effects of 5-HT on Kv currents and arterial contraction were markedly prevented by the 5-HT2A receptor antagonists ketanserin and spiperone. Consistently, α-methyl 5-HT, a 5-HT2 receptor agonist, mimicked the 5-HT action on Kv channels. Pretreatment with a Src tyrosine kinase inhibitor, 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine, prevented both the 5-HT-mediated vasoconstriction and Kv current inhibition. Our data suggest that 4-AP-sensitive Kv channels are the primary regulator of the resting tone in rat mesenteric arteries. 5-HT constricts the arteries by inhibiting Kv channels via the 5-HT2A receptor and Src tyrosine kinase pathway. PMID:24336234

  19. Serotonin (5-HT) and 5-HT2A receptor agonists suppress lipolysis in primary rat adipose cells.

    PubMed

    Hansson, Björn; Medina, Anya; Fryklund, Claes; Fex, Malin; Stenkula, Karin G

    2016-05-27

    Serotonin (5-HT) is a biogenic monoamine that functions both as a neurotransmitter and a circulating hormone. Recently, the metabolic effects of 5-HT have gained interest and peripheral 5-HT has been proposed to influence lipid metabolism in various ways. Here, we investigated the metabolic effects of 5-HT in isolated, primary rat adipose cells. Incubation with 5-HT suppressed β-adrenergically stimulated glycerol release and decreased phosphorylation of protein kinase A (PKA)-dependent substrates, hormone sensitive lipase (Ser563) and perilipin (Ser522). The inhibitory effect of 5-HT on lipolysis enhanced the anti-lipolytic effect of insulin, but sustained in the presence of phosphodiesterase inhibitors, OPC3911 and isobuthylmethylxanthine (IBMX). The relative expression of 5-HT1A, -2B and -4 receptor class family were significantly higher in adipose tissue compared to adipose cells, whereas 5-HT1D, -2A and -7 were highly expressed in isolated adipose cells. Similar to 5-HT, 5-HT2 receptor agonists reduced lipolysis while 5-HT1 receptor agonists rather decreased non-stimulated and insulin-stimulated glucose uptake. Together, these data provide evidence of a direct effect of 5-HT on adipose cells, where 5-HT suppresses lipolysis and glucose uptake, which could contribute to altered systemic lipid- and glucose metabolism. PMID:27109474

  20. 5-HT2A and 5-HT2C receptors as hypothalamic targets of developmental programming in male rats

    PubMed Central

    Martin-Gronert, Malgorzata S.; Stocker, Claire J.; Wargent, Edward T.; Cripps, Roselle L.; Garfield, Alastair S.; Jovanovic, Zorica; D'Agostino, Giuseppe; Yeo, Giles S. H.; Cawthorne, Michael A.; Arch, Jonathan R. S.; Heisler, Lora K.; Ozanne, Susan E.

    2016-01-01

    ABSTRACT Although obesity is a global epidemic, the physiological mechanisms involved are not well understood. Recent advances reveal that susceptibility to obesity can be programmed by maternal and neonatal nutrition. Specifically, a maternal low-protein diet during pregnancy causes decreased intrauterine growth, rapid postnatal catch-up growth and an increased risk for diet-induced obesity. Given that the synthesis of the neurotransmitter 5-hydroxytryptamine (5-HT) is nutritionally regulated and 5-HT is a trophic factor, we hypothesised that maternal diet influences fetal 5-HT exposure, which then influences development of the central appetite network and the subsequent efficacy of 5-HT to control energy balance in later life. Consistent with our hypothesis, pregnant rats fed a low-protein diet exhibited elevated serum levels of 5-HT, which was also evident in the placenta and fetal brains at embryonic day 16.5. This increase was associated with reduced levels of 5-HT2CR, the primary 5-HT receptor influencing appetite, in the fetal, neonatal and adult hypothalamus. As expected, a reduction of 5-HT2CR was associated with impaired sensitivity to 5-HT-mediated appetite suppression in adulthood. 5-HT primarily achieves effects on appetite by 5-HT2CR stimulation of pro-opiomelanocortin (POMC) peptides within the arcuate nucleus of the hypothalamus (ARC). We show that 5-HT2ARs are also anatomically positioned to influence the activity of ARC POMC neurons and that mRNA encoding 5-HT2AR is increased in the hypothalamus of in utero growth-restricted offspring that underwent rapid postnatal catch-up growth. Furthermore, these animals at 3 months of age are more sensitive to appetite suppression induced by 5-HT2AR agonists. These findings not only reveal a 5-HT-mediated mechanism underlying the programming of susceptibility to obesity, but also provide a promising means to correct it, by treatment with a 5-HT2AR agonist. PMID:26769798

  1. Potential Modes of Interaction of 9-Aminomethyl-9,10-dihydroanthracene (AMDA) Derivatives with the 5-HT2A Receptor: A Ligand Structure-Affinity Relationship, Receptor Mutagenesis and Receptor Modeling Investigation⊕

    PubMed Central

    Runyon, Scott P.; Mosier, Philip D.; Roth, Bryan L.; Glennon, Richard A.; Westkaemper, Richard B.

    2011-01-01

    The effects of 3-position substitution of 9-aminomethyl-9,10-dihydroanthracene (AMDA) on 5-HT2A receptor affinity were determined and compared to a parallel series of DOB-like 1-(2,5-dimethoxyphenyl)-2-aminopropanes substituted at the 4-position. The results were interpreted within the context of 5-HT2A receptor models that suggest that members of the DOB-like series can bind to the receptor in two distinct modes that correlate with the compounds’ functional activity. Automated ligand docking and molecular dynamics suggest that all of the AMDA derivatives, the parent of which is a 5-HT2A antagonist, bind in a fashion analogous to that for the sterically demanding antagonist DOB-like compounds. The failure of the F3406.52L mutation to adversely affect the affinity of AMDA and the 3-bromo derivative is consistent with the proposed modes of orientation. Evaluation of ligand-receptor complex models suggest that a valine/threonine exchange between the 5-HT2A and D2 receptors may be the origin of selectivity for AMDA and two substituted derivatives. PMID:18847250

  2. Synthesis and structure-affinity relationships of novel small molecule natural product derivatives capable of discriminating between serotonin 5-HT1A, 5-HT2A, 5-HT2C receptor subtypes

    PubMed Central

    Cummings, David F.; Canseco, Diana C.; Sheth, Pratikkumar; Johnson, James E.; Schetz, John A.

    2010-01-01

    Efforts to develop ligands that distinguish between clinically relevant 5-HT2A and 5-HT2C serotonin receptor subtypes have been challenging, because their sequences have high homology. Previous studies reported that a novel aplysinopsin belonging to a chemical class of natural products isolated from a marine sponge was selective for the 5-HT2C over the 5-HT2A receptor subtype. Our goal was to explore the 5-HT2A/2C receptor structure-affinity relationships of derivatives based on the aplysinopsin natural product pharmacophore. Twenty aplysinopsin derivatives were synthesized, purified and tested for their affinities for cloned human serotonin 5-HT1A, 5-HT2A and 5-HT2C receptor subtypes. Four compounds in this series had >30-fold selectivity for 5-HT2A or 5-HT2C receptors. The compound (E)-5-((5,6-dichloro-1H-indol-3-yl)methylene)-2-imino-1,3-dimethylimidazolidin-4-one (UNT-TWU-22, 16) had approximately 2100-fold selectivity for the serotonin 5-HT2C receptor subtype: an affinity for 5-HT2C equal to 46 nM and no detectable affinity for the 5-HT1A or 5-HT2A receptor subtypes. The two most important factors controlling 5-HT2A or 5-HT2C receptor subtype selectivity were the combined R1, R3-alkylation of the imidazolidinone ring and the type and number of halogens on the indole ring of the aplysinopsin pharmacophore. PMID:20570529

  3. Metabotropic glutamate mGlu2 receptor is necessary for the pharmacological and behavioral effects induced by hallucinogenic 5-HT2A receptor agonists.

    PubMed

    Moreno, José L; Holloway, Terrell; Albizu, Laura; Sealfon, Stuart C; González-Maeso, Javier

    2011-04-15

    Hallucinogenic drugs, including mescaline, psilocybin and lysergic acid diethylamide (LSD), act at serotonin 5-HT2A receptors (5-HT2ARs). Metabotropic glutamate receptor 2/3 (mGluR2/3) ligands show efficacy in modulating the responses induced by activation of 5-HT2ARs. The formation of a 5-HT2AR-mGluR2 complex suggests a functional interaction that affects the hallucinogen-regulated cellular signaling pathways. Here, we tested the cellular and behavioral effects of hallucinogenic 5-HT2AR agonists in mGluR2 knockout (mGluR2-KO) mice. Mice were intraperitoneally injected with the hallucinogens DOI (2 mg/kg) and LSD (0.24 mg/kg), or vehicle. Head-twitch behavioral response, expression of c-fos, which is induced by all 5-HT2AR agonists, and expression of egr-2, which is hallucinogen-specific, were determined in wild type and mGluR2-KO mice. [(3)H]Ketanserin binding displacement curves by DOI were performed in mouse frontal cortex membrane preparations. Head twitch behavior was abolished in mGluR2-KO mice. The high-affinity binding site of DOI was undetected in mGluR2-KO mice. The hallucinogen DOI induced c-fos in both wild type and mGluR2-KO mice. However, the induction of egr-2 by DOI was eliminated in mGlu2-KO mice. These findings suggest that the 5-HT2AR-mGluR2 complex is necessary for the neuropsychological responses induced by hallucinogens.

  4. Potentiation of 5-methoxy-N,N-dimethyltryptamine-induced hyperthermia by harmaline and the involvement of activation of 5-HT1A and 5-HT2A receptors.

    PubMed

    Jiang, Xi-Ling; Shen, Hong-Wu; Yu, Ai-Ming

    2015-02-01

    5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) and harmaline are serotonin (5-HT) analogs often abused together, which alters thermoregulation that may indicate the severity of serotonin toxicity. Our recent studies have revealed that co-administration of monoamine oxidase inhibitor harmaline leads to greater and prolonged exposure to 5-HT agonist 5-MeO-DMT that might be influenced by cytochrome P450 2D6 (CYP2D6) status. This study was to define the effects of harmaline and 5-MeO-DMT on thermoregulation in wild-type and CYP2D6-humanized (Tg-CYP2D6) mice, as well as the involvement of 5-HT receptors. Animal core body temperatures were monitored noninvasively in the home cages after implantation of telemetry transmitters and administration of drugs. Harmaline (5 and 15 mg/kg, i.p.) alone was shown to induce hypothermia that was significantly affected by CYP2D6 status. In contrast, higher doses of 5-MeO-DMT (10 and 20 mg/kg) alone caused hyperthermia. Co-administration of harmaline (2, 5 or 15 mg/kg) remarkably potentiated the hyperthermia elicited by 5-MeO-DMT (2 or 10 mg/kg), which might be influenced by CYP2D6 status at certain dose combination. Interestingly, harmaline-induced hypothermia was only attenuated by 5-HT1A receptor antagonist WAY-100635, whereas 5-MeO-DMT- and harmaline-5-MeO-DMT-induced hyperthermia could be suppressed by either WAY-100635 or 5-HT2A receptor antagonists (MDL-100907 and ketanserin). Moreover, stress-induced hyperthermia under home cage conditions was not affected by WAY-100635 but surprisingly attenuated by MDL-100907 and ketanserin. Our results indicate that co-administration of monoamine oxidase inhibitor largely potentiates 5-MeO-DMT-induced hyperthermia that involves the activation of both 5-HT1A and 5-HT2A receptors. These findings shall provide insights into development of anxiolytic drugs and new strategies to relieve the lethal hyperthermia in serotonin toxicity.

  5. Serotonin 5-HT2A receptor binding in platelets from healthy subjects as studied by [3H]-lysergic acid diethylamide ([3H]-LSD): intra- and interindividual variability.

    PubMed

    Spigset, O; Mjörndal, T

    1997-04-01

    In studies on platelet 5-HT2A receptor binding in patients with neuropsychiatric disorders, there has been a marked variability and a considerable overlap of values between patients and controls. The causes of the large variability in 5-HT2A receptor parameters is still unsettled. In the present study, we have quantified the intra- and interindividual variability of platelet 5-HT2A receptor binding in 112 healthy subjects and explored factors that may influence 5-HT2A receptor binding, using [3H]-lysergic acid diethylamide as radioligand. Age, gender, blood pressure, and metabolic capacity of the liver enzymes CYP2D6 and CYP2C19 did not influence Bmax and Kd values. Body weight and body mass index (BMI) showed a negative correlation with Kd (p = .04 and .03, respectively), but not with Bmax. Bmax was significantly lower in the light half of the year than in the dark half of the year (p = .001), and Kd was significantly lower in the fall than in the summer and winter (p < .001). In females, there was a significant increase in Bmax from week 1 to week 2 of the menstrual cycle (p = .03). Females taking contraceptive pills had significantly higher Kd than drug-free females in weeks 1 and 4 of the menstrual cycle (p = .04). This study shows that a number of factors should be taken into account when using platelet 5-HT2A receptor binding in studies of neuropsychiatric disorders.

  6. Cognitive Impairment Induced by Delta9-tetrahydrocannabinol Occurs through Heteromers between Cannabinoid CB1 and Serotonin 5-HT2A Receptors

    PubMed Central

    Lanfumey, Laurence; Cordomí, Arnau; Pastor, Antoni; de La Torre, Rafael; Gasperini, Paola; Navarro, Gemma; Howell, Lesley A.; Pardo, Leonardo; Lluís, Carmen; Canela, Enric I.; McCormick, Peter J.; Maldonado, Rafael; Robledo, Patricia

    2015-01-01

    Activation of cannabinoid CB1 receptors (CB1R) by delta9-tetrahydrocannabinol (THC) produces a variety of negative effects with major consequences in cannabis users that constitute important drawbacks for the use of cannabinoids as therapeutic agents. For this reason, there is a tremendous medical interest in harnessing the beneficial effects of THC. Behavioral studies carried out in mice lacking 5-HT2A receptors (5-HT2AR) revealed a remarkable 5-HT2AR-dependent dissociation in the beneficial antinociceptive effects of THC and its detrimental amnesic properties. We found that specific effects of THC such as memory deficits, anxiolytic-like effects, and social interaction are under the control of 5-HT2AR, but its acute hypolocomotor, hypothermic, anxiogenic, and antinociceptive effects are not. In biochemical studies, we show that CB1R and 5-HT2AR form heteromers that are expressed and functionally active in specific brain regions involved in memory impairment. Remarkably, our functional data shows that costimulation of both receptors by agonists reduces cell signaling, antagonist binding to one receptor blocks signaling of the interacting receptor, and heteromer formation leads to a switch in G-protein coupling for 5-HT2AR from Gq to Gi proteins. Synthetic peptides with the sequence of transmembrane helices 5 and 6 of CB1R, fused to a cell-penetrating peptide, were able to disrupt receptor heteromerization in vivo, leading to a selective abrogation of memory impairments caused by exposure to THC. These data reveal a novel molecular mechanism for the functional interaction between CB1R and 5-HT2AR mediating cognitive impairment. CB1R-5-HT2AR heteromers are thus good targets to dissociate the cognitive deficits induced by THC from its beneficial antinociceptive properties. PMID:26158621

  7. Antidepressant-like activity of Tagetes lucida Cav. is mediated by 5-HT(1A) and 5-HT(2A) receptors.

    PubMed

    Bonilla-Jaime, H; Guadarrama-Cruz, G; Alarcon-Aguilar, F J; Limón-Morales, O; Vazquez-Palacios, G

    2015-10-01

    It has been demonstrated that the aqueous extract of Tagetes lucida Cav. shows an antidepressant-like effect on the forced swimming test (FST) in rats. The aim of this study was to analyze the participation of the serotoninergic system in the antidepressant-like effect of the aqueous extract of T. lucida. Different doses of the extract of T. lucida were administered at 72, 48, 24, 18 and 1 h before FST. The animals were pretreated with a 5-HT1A receptor antagonist (WAY-100635, 0.5 mg/kg), a 5-HT2A receptor antagonist (ketanserin, 5 mg/kg), a β-noradrenergic receptor antagonist (propranolol, 200 mg/kg), and with a α2-noradrenergic receptor antagonist (yohimbine, 1 mg/kg) alone or combined with the extract and pretreated with a serotonin synthesis inhibitor (PCPA) before treatment with 8-OH-DPAT + the extract of T. lucida. In addition, suboptimal doses of the 5-HT1A agonist (8-OH-DPAT) + non-effective dose of extract was analyzed in the FST. To determine the presence of flavonoids, the aqueous extract of T. lucida (20 µl, 4 mg/ml) was injected in HPLC; however, a quercetin concentration of 7.72 mg/g of extract weight was detected. A suboptimal dose of 8-OH-DPAT + extract of T. lucida decreased immobility and increased swimming and climbing. An antidepressant-like effect with the aqueous extract of T. lucida at doses of 100 and 200 mg/kg was observed on the FST with decreased immobility behavior and increased swimming; however, this effect was blocked by WAY-100635, ketanserin and PCPA but not by yohimbine and propranolol, suggesting that the extract of T. lucida could be modulating the release/reuptake of serotonin.

  8. Examination of the hippocampal contribution to serotonin 5-HT2A receptor-mediated facilitation of object memory in C57BL/6J mice.

    PubMed

    Zhang, Gongliang; Cinalli, David; Cohen, Sarah J; Knapp, Kristina D; Rios, Lisa M; Martínez-Hernández, José; Luján, Rafael; Stackman, Robert W

    2016-10-01

    The rodent hippocampus supports non-spatial object memory. Serotonin 5-HT2A receptors (5-HT2AR) are widely expressed throughout the hippocampus. We previously demonstrated that the activation of 5-HT2ARs enhanced the strength of object memory assessed 24 h after a limited (i.e., weak memory) training procedure. Here, we examined the subcellular distribution of 5-HT2ARs in the hippocampal CA1 region and underlying mechanisms of 5-HT2AR-mediated object memory consolidation. Analyses with immuno-electron microscopy revealed the presence of 5-HT2ARs on the dendritic spines and shafts of hippocampal CA1 neurons, and presynaptic terminals in the CA1 region. In an object recognition memory procedure that places higher demand on the hippocampus, only post-training systemic or intrahippocampal administration of the 5-HT2AR agonist TCB-2 enhanced object memory. Object memory enhancement by TCB-2 was blocked by the 5-HT2AR antagonist, MDL 11,937. The memory-enhancing dose of systemic TCB-2 increased extracellular glutamate levels in hippocampal dialysate samples, and increased the mean in vivo firing rate of hippocampal CA1 neurons. In summary, these data indicate a pre- and post-synaptic distribution of 5-HT2ARs, and activation of 5-HT2ARs selectively enhanced the consolidation of object memory, without affecting encoding or retrieval. The 5-HT2AR-mediated facilitation of hippocampal memory may be associated with an increase in hippocampal neuronal firing and glutamate efflux during a post-training time window in which recently encoded memories undergo consolidation.

  9. Molecular Pharmacology and Ligand Docking Studies Reveal a Single Amino Acid Difference between Mouse and Human Serotonin 5-HT2A Receptors That Impacts Behavioral Translation of Novel 4-Phenyl-2-dimethylaminotetralin Ligands

    PubMed Central

    Cordova-Sintjago, Tania; Liu, Yue; Kim, Myong S.; Morgan, Drake; Booth, Raymond G.

    2013-01-01

    During translational studies to develop 4-phenyl-2-dimethylaminotetralin (PAT) compounds for neuropsychiatric disorders, the (2R,4S)-trans-(+)- and (2S,4R)-trans-(−)-enantiomers of the analog 6-hydroxy-7-chloro-PAT (6-OH-7-Cl-PAT) demonstrated unusual pharmacology at serotonin (5-HT) 5-HT2 G protein–coupled receptors (GPCRs). The enantiomers had similar affinities (Ki) at human (h) 5-HT2A receptors (∼70 nM). In an in vivo mouse model of 5-HT2A receptor activation [(±)-(2,5)-dimethoxy-4-iodoamphetamine (DOI)–elicited head twitch], however, (−)-6-OH-7-Cl-PAT was about 5-fold more potent than the (+)-enantiomer at attenuating the DOI-elicited response. It was discovered that (+)-6-OH-7-Cl-PAT (only) had ∼40-fold-lower affinity at mouse (m) compared with h5-HT2A receptors. Molecular modeling and computational ligand docking studies indicated that the 6-OH moiety of (+)- but not (−)-6-OH-7-Cl-PAT could form a hydrogen bond with serine residue 5.46 of the h5-HT2A receptor. The m5-HT2A as well as m5-HT2B, h5-HT2B, m5-HT2C, and h5-HT2C receptors have alanine at position 5.46, obviating this interaction; (+)-6-OH-7-Cl-PAT also showed ∼50-fold lower affinity than (−)-6-OH-7-Cl-PAT at m5-HT2C and h5-HT2C receptors. Mutagenesis studies confirmed that 5-HT2A S5.46 is critical for (+)- but not (−)-6-OH-7-Cl-PAT binding, as well as function. The (+)-6-OH-7-Cl-PAT enantiomer showed partial agonist effects at h5-HT2A wild-type (WT) and m5-HT2A A5.46S point-mutated receptors but did not activate m5-HT2A WT and h5-HT2A S5.46A point-mutated receptors, or h5-HT2B, h5-HT2C, and m5-HT2C receptors; (−)-6-OH-7-Cl-PAT did not activate any of the 5-HT2 receptors. Experiments also included the (2R,4S)-trans-(+)- and (2S,4R)-trans-(−)-enantiomers of 6-methoxy-7-chloro-PAT to validate hydrogen bonding interactions proposed for the corresponding 6-OH analogs. Results indicate that PAT ligand three-dimensional structure impacts target receptor binding and translational

  10. Blonanserin Ameliorates Phencyclidine-Induced Visual-Recognition Memory Deficits: the Complex Mechanism of Blonanserin Action Involving D3-5-HT2A and D1-NMDA Receptors in the mPFC

    PubMed Central

    Hida, Hirotake; Mouri, Akihiro; Mori, Kentaro; Matsumoto, Yurie; Seki, Takeshi; Taniguchi, Masayuki; Yamada, Kiyofumi; Iwamoto, Kunihiro; Ozaki, Norio; Nabeshima, Toshitaka; Noda, Yukihiro

    2015-01-01

    Blonanserin differs from currently used serotonin 5-HT2A/dopamine-D2 receptor antagonists in that it exhibits higher affinity for dopamine-D2/3 receptors than for serotonin 5-HT2A receptors. We investigated the involvement of dopamine-D3 receptors in the effects of blonanserin on cognitive impairment in an animal model of schizophrenia. We also sought to elucidate the molecular mechanism underlying this involvement. Blonanserin, as well as olanzapine, significantly ameliorated phencyclidine (PCP)-induced impairment of visual-recognition memory, as demonstrated by the novel-object recognition test (NORT) and increased extracellular dopamine levels in the medial prefrontal cortex (mPFC). With blonanserin, both of these effects were antagonized by DOI (a serotonin 5-HT2A receptor agonist) and 7-OH-DPAT (a dopamine-D3 receptor agonist), whereas the effects of olanzapine were antagonized by DOI but not by 7-OH-DPAT. The ameliorating effect was also antagonized by SCH23390 (a dopamine-D1 receptor antagonist) and H-89 (a protein kinase A (PKA) inhibitor). Blonanserin significantly remediated the decrease in phosphorylation levels of PKA at Thr197 and of NR1 (an essential subunit of N-methyl-D-aspartate (NMDA) receptors) at Ser897 by PKA in the mPFC after a NORT training session in the PCP-administered mice. There were no differences in the levels of NR1 phosphorylated at Ser896 by PKC in any group. These results suggest that the ameliorating effect of blonanserin on PCP-induced cognitive impairment is associated with indirect functional stimulation of the dopamine-D1-PKA-NMDA receptor pathway following augmentation of dopaminergic neurotransmission due to inhibition of both dopamine-D3 and serotonin 5-HT2A receptors in the mPFC. PMID:25120077

  11. Combined serotonin (5-HT)1A agonism, 5-HT(2A) and dopamine D₂ receptor antagonism reproduces atypical antipsychotic drug effects on phencyclidine-impaired novel object recognition in rats.

    PubMed

    Oyamada, Yoshihiro; Horiguchi, Masakuni; Rajagopal, Lakshmi; Miyauchi, Masanori; Meltzer, Herbert Y

    2015-05-15

    Subchronic administration of an N-methyl-D-aspartate receptor (NMDAR) antagonist, e.g. phencyclidine (PCP), produces prolonged impairment of novel object recognition (NOR), suggesting they constitute a hypoglutamate-based model of cognitive impairment in schizophrenia (CIS). Acute administration of atypical, e.g. lurasidone, but not typical antipsychotic drugs (APDs), e.g. haloperidol, are able to restore NOR following PCP (acute reversal model). Furthermore, atypical APDs, when co-administered with PCP, have been shown to prevent development of NOR deficits (prevention model). Most atypical, but not typical APDs, are more potent 5-HT(2A) receptor inverse agonists than dopamine (DA) D2 antagonists, and have been shown to enhance cortical and hippocampal efflux and to be direct or indirect 5-HT(1A) agonists in vivo. To further clarify the importance of these actions to the restoration of NOR by atypical APDs, sub-effective or non-effective doses of combinations of the 5-HT(1A) partial agonist (tandospirone), the 5-HT(2A) inverse agonist (pimavanserin), or the D2 antagonist (haloperidol), as well as the combination of all three agents, were studied in the acute reversal and prevention PCP models of CIS. Only the combination of all three agents restored NOR and prevented the development of PCP-induced deficit. Thus, this triple combination of 5-HT(1A) agonism, 5-HT(2A) antagonism/inverse agonism, and D2 antagonism is able to mimic the ability of atypical APDs to prevent or ameliorate the PCP-induced NOR deficit, possibly by stimulating signaling cascades from D1 and 5-HT(1A) receptor stimulation, modulated by D2 and 5-HT(2A) receptor antagonism. PMID:25448429

  12. Changes in the 5-HT2A receptor system in the pre-mammillary hypothalamus of the ewe are related to regulation of LH pulsatile secretion by an endogenous circannual rhythm

    PubMed Central

    Chemineau, Philippe; Daveau, Agnès; Pelletier, Jean; Malpaux, Benoît; Karsch, Fred J; Viguié, Catherine

    2003-01-01

    Background We wanted to determine if changes in the expression of serotonin 2A receptor (5HT2A receptor) gene in the premammillary hypothalamus are associated with changes in reproductive neuroendocrine status. Thus, we compared 2 groups of ovariectomized-estradiol-treated ewes that expressed high vs low LH pulsatility in two different paradigms (2 groups per paradigm): (a) refractoriness (low LH secretion) or not (high LH secretion) to short days in pineal-intact Ile-de-France ewes (RSD) and (b) endogenous circannual rhythm (ECR) in free-running pinealectomized Suffolk ewes in the active or inactive stage of their reproductive rhythm. Results In RSD ewes, density of 5HT2A receptor mRNA (by in situ hybridization) was significantly higher in the high LH group (25.3 ± 1.4 vs 21.4 ± 1.5 grains/neuron, P < 0.05) and 3H-Ketanserin binding (a specific radioligand) of the median part of the premammillary hypothalamus tended to be higher in the high group (29.1 ± 4.0 vs 24.6 ± 4.2 fmol/mg tissu-equivalent; P < 0.10). In ECR ewes, density of 5HT2A receptor mRNA and 3H-Ketanserin binding were both significantly higher in the high LH group (20.8 ± 1.6 vs 17.0 ± 1.5 grains/neuron, P < 0.01, and 19.7 ± 5.0 vs 7.4 ± 3.4 fmol/mg tissu-equivalent; P < 0.05, respectively). Conclusions We conclude that these higher 5HT2A receptor gene expression and binding activity of 5HT2A receptor in the premammillary hypothalamus are associated with stimulation of LH pulsatility expressed before the development of refractoriness to short days and prior to the decline of reproductive neuroendocrine activity during expression of the endogenous circannual rhythm. PMID:12553884

  13. The antidepressant-like activity of 6-methoxy-2-[4-(2-methoxyphenyl)piperazin-1-yl]-9H-xanthen-9-one involves serotonergic 5-HT(1A) and 5-HT(2A/C) receptors activation.

    PubMed

    Pytka, Karolina; Walczak, Maria; Kij, Agnieszka; Rapacz, Anna; Siwek, Agata; Kazek, Grzegorz; Olczyk, Adrian; Gałuszka, Adam; Waszkielewicz, Anna; Marona, Henryk; Sapa, Jacek; Filipek, Barbara

    2015-10-01

    Xanthone derivatives have been shown to posses many biological properties. Some of them act within the central nervous system and show neuroprotective or antidepressant-like properties. Taking this into account we investigated antidepressant-like activity in mice and the possible mechanism of action of 6-methoxy-2-[4-(2-methoxyphenyl)piperazin-1-yl]-9H-xanthen-9-one (HBK-11) - a new xanthone derivative. We demonstrated that HBK-11 produced antidepressant-like effects in the forced swim test and tail suspension test, comparable to that of venlafaxine. The combined treatment with sub-effective doses of HBK-11 and fluoxetine (but not reboxetine or bupropion) significantly reduced the immobility in the forced swim test. Moreover, the antidepressant-like activity of HBK-11 in the aforementioned test was blocked by p-chlorophenylalanine, and significantly reduced by serotonergic 5HT1A receptor antagonist - WAY-1006335 and 5HT2A/C receptor antagonist - ritanserin. As none of the above treatments influenced the spontaneous locomotor activity, it can be concluded that HBK-11 mediates its activity through a serotonergic system, and its antidepressant-like effect involves 5HT1A and 5HT2A/C receptor activation. Furthermore, at antidepressant-like doses HBK-11 did not cause the mice to display locomotor deficits in rotarod or chimney tests. Considering the pharmacokinetic profile, HBK-11 demonstrated rapid absorption after i.p. administration, high clearance value, short terminal half-life, very high volume of distribution and incomplete bioavailability. The compound studied had good penetration into the brain tissue of mice. Since studied xanthone derivative seems to present interesting, untypical mechanism of antidepressant-like action i.e. 5HT2A/C receptor activation, it may have a potential in the treatment of depressive disorders, and surely requires further studies. PMID:26210317

  14. Inhibition of SNL-induced upregulation of CGRP and NPY in the spinal cord and dorsal root ganglia by the 5-HT(2A) receptor antagonist ketanserin in rats.

    PubMed

    Wang, Dongmei; Chen, Tingjun; Gao, Yun; Quirion, Rémi; Hong, Yanguo

    2012-05-01

    Our previous study has demonstrated that topical and systemic administration of the 5-HT(2A) receptor antagonist ketanserin attenuates neuropathic pain. To explore the mechanisms involved, we examined whether ketanserin reversed the plasticity changes associated with calcitonin gene-related peptides (CGRP) and neuropeptide Y (NPY) which may reflect distinct mechanisms: involvement and compensatory protection. Behavioral responses to thermal and tactile stimuli after spinal nerve ligation (SNL) at L5 demonstrated neuropathic pain and its attenuation in the vehicle- and ketanserin-treated groups, respectively. SNL surgery induced an increase in CGRP and NPY immunoreactivity (IR) in laminae I-II of the spinal cord. L5 SNL produced an expression of NPY-IR in large, medium and small diameter neurons in dorsal root ganglion (DRG) only at L5, but not adjacent L4 and L6. Daily injection of ketanserin (0.3 mg/kg, s.c.) for two weeks suppressed the increase in CGRP-IR and NPY-IR in the spinal cord or DRG. The present study demonstrated that: (1) the expression of CGRP was enhanced in the spinal dorsal horn and NPY was expressed in the DRG containing injured neurons, but not in the adjacent DRG containing intact neurons, following L5 SNL; (2) the maladaptive changes in CGRP and NPY expression in the spinal cord and DRG mediated the bioactivity of 5-HT/5-HT(2A) receptors in neuropathic pain and (3) the blockade of 5-HT(2A) receptors by ketanserin reversed the evoked upregulation of both CGRP and NPY in the spinal cord and DRG contributing to the inhibition of neuropathic pain.

  15. The highly selective 5-hydroxytryptamine (5-HT)2A receptor antagonist, EMD 281014, significantly increases swimming and decreases immobility in male congenital learned helpless rats in the forced swim test.

    PubMed

    Patel, Jignesh G; Bartoszyk, Gerd D; Edwards, Emmeline; Ashby, Charles R

    2004-04-01

    We examined the effect of the highly selective 5-hydroxytryptamine (5-HT)(2A) receptor antagonist 7-[4-[2-(4-fluoro-phenyl)-ethyl]-piperazine-1-carbonyl]-1H-indole-3-carbonitrile HCl (EMD 281014) in congenital learned helpless male rats in the forced swim test. The administration of EMD-281014 (0.3-30 mg/kg i.p.) to congenital learned helpless rats dose-dependently and significantly (at 10 and 30 mg/kg) decreased immobility and increased swimming compared to vehicle-treated animals. Thus, EMD 281014 produces effects in the forced swim test resembling those of antidepressants.

  16. The role of the 5-HT2A and 5-HT2C receptors in the stimulus effects of hallucinogenic drugs. III: The mechanistic basis for supersensitivity to the LSD stimulus following serotonin depletion.

    PubMed

    Fiorella, D; Helsley, S; Lorrain, D S; Rabin, R A; Winter, J C

    1995-10-01

    The present study was designed to determine the effects of p-chlorophenylalanine (PCPA) and p-chloroamphetamine (PCA) administration on (1) the levels of serotonin (5-hydroxytryptamine, 5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) in rat brain, (2) the sensitivity of LSD-trained rats to the stimulus effects of LSD, and (3) the maximal levels of 5-HT2A and 5-HT2C receptor mediated phosphoinositide (PI) hydrolysis in rat brain. PCA and PCPA both produced a significant depletion of whole brain 5-HT and 5-HIAA concentrations. The depletion of serotonin with PCPA, but not PCA, resulted in supersensitivity of LSD-trained subjects to the stimulus effects of LSD. Neither PCPA nor PCA treatment altered the maximal level of 5-HT2A receptor-mediated PI hydrolysis. However, PCPA, but not PCA, treatment resulted in a significant upregulation (46%, P < 0.05) of the maximal level of 5-HT2C receptor mediated PI hydrolysis. These data suggest that upregulation of the 5-HT2C receptor mediates the supersensitivity to LSD discriminative stimulus which follows the depletion of central nervous system serotonin by PCPA.

  17. Binding of [(3)H]lysergic acid diethylamide to serotonin 5-HT(2A) receptors and of [(3)H]paroxetine to serotonin uptake sites in platelets from healthy children, adolescents and adults.

    PubMed

    Sigurdh, J; Spigset, O; Allard, P; Mjörndal, T; Hägglöf, B

    1999-11-01

    Possible age effects on binding of [(3)H]lysergic acid diethylamide ([(3)H]LSD) to serotonin 5-HT(2A) receptors and of [(3)H]paroxetine to serotonin uptake sites were studied in platelets from healthy children (11-12 years of age), adolescents (16-17 years of age) and adults. Significant overall age effects were found both for the number of binding sites (B(max)) for [(3)H]LSD binding (p < 0.001), the affinity constant (K(d)) for [(3)H]LSD binding (p < 0.001), B(max) for [(3)H]paroxetine binding (p < 0.001) and K(d) for [(3)H] paroxetine binding (p = 0.006). In general, there was a decrease in B(max) with increasing age, which predominantly occurred between the ages 11-12 years and 16-17 years for the 5-HT(2A) receptor, and after 16-17 years of age for the serotonin uptake site. These developmental changes might have an impact on the effect of treatment with serotonergic drugs in children and adolescents. When the platelet serotonin variables investigated are employed in studies in children or adolescents, age matching or, alternatively, introduction of age control in the statistical analysis should be performed.

  18. 5-HT(2A) and mGlu2 receptor binding levels are related to differences in impulsive behavior in the Roman Low- (RLA) and High- (RHA) avoidance rat strains.

    PubMed

    Klein, A B; Ultved, L; Adamsen, D; Santini, M A; Tobeña, A; Fernandez-Teruel, A; Flores, P; Moreno, M; Cardona, D; Knudsen, G M; Aznar, S; Mikkelsen, J D

    2014-03-28

    The Roman Low- and High-Avoidance rat strains (RLA-I vs RHA-I) have been bidirectionally selected and bred according to their performance in the two-way active avoidance response in the shuttle-box test. Numerous studies have reported a pronounced divergence in emotionality between the two rat strains including differences in novelty seeking, anxiety, stress coping, and susceptibility to addictive substances. However, the underlying molecular mechanisms behind these divergent phenotypes are not known. Here, we determined impulsivity using the 5-choice serial reaction time task and levels of serotonin transporter (SERT), 5-HT(2A) and 5-HT(1A) receptor binding using highly specific radioligands ((3)H-escitalopram, (3)H-MDL100907 and (3)H-WAY100635) and mGlu2/3 receptor binding ((3)H-LY341495) using receptor autoradiography in fronto-cortical sections from RLA-I (n=8) and RHA-I (n=8) male rats. In the more impulsive RHA-I rats, 5-HT(2A), 5-HT(1A) and SERT binding in the frontal cortex was significantly higher compared to RLA-I rats. In contrast, mGlu2/3 receptor binding was decreased by 40% in RHA-I rats compared to RLA-I rats. To differentiate between mGlu2 and mGlu3 receptor protein levels, these were further studied using western blotting, which showed non-detectable levels of mGlu2 receptor protein in RHA rats, while no differences were observed for mGlu3 receptor protein levels. Collectively, these data show general congenital differences in the serotonergic system and a pronounced difference in mGlu2 receptor protein levels. We suggest that the differences in the serotonergic system may mediate some of the phenotypic characteristics in this strain such as hyper-impulsivity and susceptibility to drug addiction. PMID:24412375

  19. The Combination of Marketed Antagonists of α1b-Adrenergic and 5-HT2A Receptors Inhibits Behavioral Sensitization and Preference to Alcohol in Mice: A Promising Approach for the Treatment of Alcohol Dependence

    PubMed Central

    Trovero, Fabrice; David, Sabrina; Bernard, Philippe; Puech, Alain; Bizot, Jean-Charles; Tassin, Jean-Pol

    2016-01-01

    Alcohol-dependence is a chronic disease with a dramatic and expensive social impact. Previous studies have indicated that the blockade of two monoaminergic receptors, α1b-adrenergic and 5-HT2A, could inhibit the development of behavioral sensitization to drugs of abuse, a hallmark of drug-seeking and drug-taking behaviors in rodents. Here, in order to develop a potential therapeutic treatment of alcohol dependence in humans, we have blocked these two monoaminergic receptors by a combination of antagonists already approved by Health Agencies. We show that the association of ifenprodil (1 mg/kg) and cyproheptadine (1 mg/kg) (α1-adrenergic and 5-HT2 receptor antagonists marketed as Vadilex ® and Periactine ® in France, respectively) blocks behavioral sensitization to amphetamine in C57Bl6 mice and to alcohol in DBA2 mice. Moreover, this combination of antagonists inhibits alcohol intake in mice habituated to alcohol (10% v/v) and reverses their alcohol preference. Finally, in order to verify that the effect of ifenprodil was not due to its anti-NMDA receptors property, we have shown that a combination of prazosin (0.5 mg/kg, an α1b-adrenergic antagonist, Mini-Press ® in France) and cyproheptadine (1 mg/kg) could also reverse alcohol preference. Altogether these findings strongly suggest that combined prazosin and cyproheptadine could be efficient as a therapy to treat alcoholism in humans. Finally, because α1b-adrenergic and 5-HT2A receptors blockade also inhibits behavioral sensitization to psychostimulants, opioids and tobacco, it cannot be excluded that this combination will exhibit some efficacy in the treatment of addiction to other abused drugs. PMID:26968030

  20. A Novel Aminotetralin-Type Serotonin (5-HT) 2C Receptor-Specific Agonist and 5-HT2A Competitive Antagonist/5-HT2B Inverse Agonist with Preclinical Efficacy for Psychoses

    PubMed Central

    Morgan, Drake; Felsing, Daniel; Kondabolu, Krishnakanth; Rowland, Neil E.; Robertson, Kimberly L.; Sakhuja, Rajeev; Booth, Raymond G.

    2014-01-01

    Development of 5-HT2C agonists for treatment of neuropsychiatric disorders, including psychoses, substance abuse, and obesity, has been fraught with difficulties, because the vast majority of reported 5-HT2C selective agonists also activate 5-HT2A and/or 5-HT2B receptors, potentially causing hallucinations and/or cardiac valvulopathy. Herein is described a novel, potent, and efficacious human 5-HT2C receptor agonist, (−)-trans-(2S,4R)-4-(3′[meta]-bromophenyl)-N,N-dimethyl-1,2,3,4-tetrahydronaphthalen-2-amine (−)-MBP), that is a competitive antagonist and inverse agonist at human 5-HT2A and 5-HT2B receptors, respectively. (−)-MBP has efficacy comparable to the prototypical second-generation antipsychotic drug clozapine in three C57Bl/6 mouse models of drug-induced psychoses: the head-twitch response elicited by [2,5]-dimethoxy-4-iodoamphetamine; hyperlocomotion induced by MK-801 [(5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (dizocilpine maleate)]; and hyperlocomotion induced by amphetamine. (−)-MBP, however, does not alter locomotion when administered alone, distinguishing it from clozapine, which suppresses locomotion. Finally, consumption of highly palatable food by mice was not increased by (−)-MBP at a dose that produced at least 50% maximal efficacy in the psychoses models. Compared with (−)-MBP, the enantiomer (+)-MBP was much less active across in vitro affinity and functional assays using mouse and human receptors and also translated in vivo with comparably lower potency and efficacy. Results indicate a 5-HT2C receptor-specific agonist, such as (−)-MBP, may be pharmacotherapeutic for psychoses, without liability for obesity, hallucinations, heart disease, sedation, or motoric disorders. PMID:24563531

  1. Effects of the 5-HT₆ receptor antagonists SB-399885 and RO-4368554 and of the 5-HT(2A) receptor antagonist EMD 281014 on sleep and wakefulness in the rat during both phases of the light-dark cycle.

    PubMed

    Monti, Jaime M; Jantos, Héctor

    2011-01-01

    The effects of the 5-HT₆ receptor antagonists SB-399885 (2.5, 5 and 10 mg/kg) and RO-4368554 (2.5, 5 and 10 mg/kg) and of the 5-HT(2A) receptor antagonist EMD 281014 (2.5, 5 and 10 mg/kg) were studied in rats implanted for chronic sleep procedures. Administration of 10 mg/kg SB-399885, i.p., to rats 2 h after the beginning of the light phase of the light-dark cycle caused a significant increase of wakefulness (W) and a reduction of slow wave sleep (SWS), REM sleep (REMS) and the number of REM periods during 6-h recording sessions. Light sleep was increased after the whole range of doses. The increase of W and reduction of SWS and REMS occurred predominantly during the first 2-h period whereas light sleep was augmented over the first and the second 2-h recording periods. Injection of RO-4368554 (10 mg/kg, i.p.) 2 h after the beginning of the light period significantly increased W and reduced SWS and REMS during the first 2-h recording period. Administration of EMD 281014 (10 mg/kg, i.p.) during the light phase significantly increased SWS and reduced light sleep during 6-h sessions. REMS and the number of REM period were reduced with the entire range of doses. The reduction of REMS and light sleep and the increase of SWS occurred predominantly during the first and the second 2-h of recording, respectively. Injection of SB-399885 (10 mg/kg, i.p.) 2 h after the beginning of the dark period induced a significant reduction of REMS during the first 2-h of recording. In contrast, RO-4368554 did not modify values corresponding to sleep variables during the dark period. Treatment with EMD 281014 (2.5-10 mg/kg, i.p.) during the dark phase significantly increased SWS during the second 2-h period. Our study supports the proposal that blockade of postsynaptic 5-HT₆ receptors with systemic administration of SB-399885 and RO-4368554 increases W and reduces SWS and REMS during the light phase of the sleep-wake cycle. SB-399885 also induces a suppression of REMS during the dark

  2. Distinct effect of 5-HT1A and 5-HT2A receptors in the medial nucleus of the amygdala on tonic immobility behavior.

    PubMed

    de Paula, Bruna Balbino; Leite-Panissi, Christie Ramos Andrade

    2016-07-15

    The tonic immobility (TI) response is an innate fear behavior associated with intensely dangerous situations, exhibited by many species of invertebrate and vertebrate animals. In humans, it is possible that TI predicts the severity of posttraumatic stress disorder symptoms. This behavioral response is initiated and sustained by the stimulation of various groups of neurons distributed in the telencephalon, diencephalon and brainstem. Previous research has found the highest Fos-IR in the posteroventral part of the medial nucleus of the amygdala (MEA) during TI behavior; however, the neurotransmission of this amygdaloid region involved in the modulation of this innate fear behavior still needs to be clarified. Considering that a major drug class used for the treatment of psychopathology is based on serotonin (5-HT) neurotransmission, we investigated the effects of serotonergic receptor activation in the MEA on the duration of TI. The results indicate that the activation of the 5HT1A receptors or the blocking of the 5HT2 receptors of the MEA can promote a reduction in fear and/or anxiety, consequently decreasing TI duration in guinea pigs. In contrast, blocking the 5HT1A receptors or activating the 5HT2 receptors in this amygdalar region increased the TI duration, suggesting an increase in fear and/or anxiety. These alterations do not appear to be due to a modification of spontaneous motor activity, which might non-specifically affect TI duration. Thus, these results suggest a distinct role of the 5HT receptors in the MEA in innate fear modulation. PMID:27150816

  3. Hallucinogen-like effects of 2-([2-(4-cyano-2,5-dimethoxyphenyl) ethylamino]methyl)phenol (25CN-NBOH), a novel N-benzylphenethylamine with 100-fold selectivity for 5-HT2A receptors, in mice

    PubMed Central

    Gray, Bradley W.; Bailey, Jessica M.; Smith, Douglas; Hansen, Martin; Kristensen, Jesper L.

    2014-01-01

    Rationale 2-([2-(4-cyano-2,5-dimethoxyphenyl)ethylamino]methyl)phenol (25CN-NBOH) is structurally similar to N-benzyl substituted phenethylamine hallucinogens currently emerging as drugs of abuse. 25CN-NBOH exhibits dramatic selectivity for 5-HT2A receptors in vitro, but has not been behaviorally characterized. Objective 25CN-NBOH was compared to the traditional phenethylamine hallucinogen R(−)-2,5-dimethoxy-4-iodoamphetamine (DOI) using mouse models of drug-elicited head twitch behavior and drug discrimination. Methods Drug-elicited head twitches were quantified for 10 min following administration of various doses of either DOI or 25CN-NBOH, with and without pretreatments of 0.01 mg/kg 5-HT2A antagonist M100907 or 3.0 mg/kg 5-HT2C antagonist RS102221. The capacity of 25CN-NBOH to attenuate DOI-elicited head twitch was also investigated. Mice were trained to discriminate DOI or M100907 from saline, and 25CN-NBOH was tested for generalization. Results 25CN-NBOH induced a head twitch response in the mouse that was lower in magnitude than that of DOI, blocked by M100907, but not altered by RS102221. DOI-elicited head twitch was dose-dependently attenuated by 25CN-NBOH pretreatment. 25CN-NBOH produced an intermediate degree of generalization (55%) for the DOI training dose, and these interoceptive effects were attenuated by M100907. Finally, 25CN-NBOH did not generalize to M100907 at any dose, but ketanserin fully substituted in these animals. Conclusions 25CN-NBOH was behaviorally active, but less effective than DOI in two mouse models of hallucinogenic effects. The effectiveness with which M100907 antagonized the behavioral actions of 25CN-NBOH strongly suggests that the 5-HT2A receptor is an important site of agonist action for this compound in vivo. PMID:25224567

  4. Effects of central activation of serotonin 5-HT2A/2C or dopamine D2/3 receptors on the acute and repeated effects of clozapine in the conditioned avoidance response test

    PubMed Central

    Feng, Min; Gao, Jun; Sui, Nan; Li, Ming

    2014-01-01

    Rationale: Acute administration of clozapine (a gold standard of atypical antipsychotics) disrupts avoidance response in rodents, while repeated administration often causes a tolerance effect. Objective: The present study investigated the neuroanatomical basis and receptor mechanisms of acute and repeated effects of clozapine treatment in the conditioned avoidance response test in male Sprague-Dawley rats. Methods: DOI (2,5-dimethoxy-4-iodo-amphetamine, a preferential 5-HT2A/2C agonist) or quinpirole (a preferential dopamine D2/3 agonist) was microinjected into the medial prefrontal cortex (mPFC) or nucleus accumbens shell (NAs), and their effects on the acute and long-term avoidance-disruptive effect of clozapine were tested. Results: Intra-mPFC microinjection of quinpirole enhanced the acute avoidance disruptive effect of clozapine (10 mg/kg, sc), while DOI microinjections reduced it marginally. Repeated administration of clozapine (10 mg/kg, sc) daily for 5 days caused a progressive decrease in its inhibition of avoidance responding, indicating tolerance development. Intra-mPFC microinjection of DOI at 25.0 (but not 5.0) μg/side during this period completely abolished the expression of clozapine tolerance. This was indicated by the finding that clozapine-treated rats centrally infused with 25.0 μg/side DOI did not show higher levels of avoidance responses than the vehicle-treated rats in the clozapine challenge test. Microinjection of DOI into the mPFC immediately before the challenge test also decreased the expression of clozapine tolerance. Conclusions: Acute behavioral effect of clozapine can be enhanced by activation of the D2/3 receptors in the mPFC. Clozapine tolerance expression relies on the neuroplasticity initiated by its antagonist action against 5-HT2A/2C receptors in the mPFC. PMID:25288514

  5. D-serine deficiency attenuates the behavioral and cellular effects induced by the hallucinogenic 5-HT(2A) receptor agonist DOI.

    PubMed

    Santini, Martin A; Balu, Darrick T; Puhl, Matthew D; Hill-Smith, Tiffany E; Berg, Alexandra R; Lucki, Irwin; Mikkelsen, Jens D; Coyle, Joseph T

    2014-02-01

    Both the serotonin and glutamate systems have been implicated in the pathophysiology of schizophrenia, as well as in the mechanism of action of antipsychotic drugs. Psychedelic drugs act through the serotonin 2A receptor (5-HT2AR), and elicit a head-twitch response (HTR) in mice, which directly correlates to 5-HT2AR activation and is absent in 5-HT2AR knockout mice. The precise mechanism of this response remains unclear, but both an intrinsic cortico-cortical pathway and a thalamo-cortical pathway involving glutamate release have been proposed. Here, we used a genetic model of NMDAR hypofunction, the serine racemase knockout (SRKO) mouse, to explore the role of glutamatergic transmission in regulating 5-HT2AR-mediated cellular and behavioral responses. SRKO mice treated with the 5-HT2AR agonist (±)-2,5-dimethoxy-4-iodoamphetamine (DOI) showed a clearly diminished HTR and lower induction of c-fos mRNA. These altered functional responses in SRKO mice were not associated with changes in cortical or hippocampal 5-HT levels or in 5-HT2AR and metabotropic glutamate-2 receptor (mGluR2) mRNA and protein expression. Together, these findings suggest that D-serine-dependent NMDAR activity is involved in mediating the cellular and behavioral effects of 5-HT2AR activation.

  6. Dual role of serotonin in the acquisition and extinction of reward-driven learning: involvement of 5-HT1A, 5-HT2A and 5-HT3 receptors.

    PubMed

    Frick, Luciana Romina; Bernardez-Vidal, Micaela; Hocht, Christian; Zanutto, Bonifacio Silvano; Rapanelli, Maximiliano

    2015-01-15

    Serotonin (5-HT) has been proposed as a possible encoder of reward. Nevertheless, the role of this neurotransmitter in reward-based tasks is not well understood. Given that the major serotonergic circuit in the rat brain comprises the dorsal raphe nuclei and the medial prefrontal cortex (mPFC), and because the latter structure is involved in the control of complex behaviors and expresses 1A (5-HT1A), 2A (5-HT2A), and 3 (5-HT3) receptors, the aim was to study the role of 5-HT and of these receptors in the acquisition and extinction of a reward-dependent operant conditioning task. Long Evans rats were trained in an operant conditioning task while receiving fluoxetine (serotonin reuptake inhibitor, 10mg/kg), tianeptine (serotonin reuptake enhancer, 10mg/kg), buspirone (5-HT1A partial agonist, 10mg/kg), risperidone (5-HT2A antagonist, 1mg/kg), ondansetron (5-HT3 antagonist, 2mg/kg) or vehicle. Then, animals that acquired the operant conditioning without any treatment were trained to extinct the task in the presence of the pharmacological agents. Fluoxetine impaired acquisition but improved extinction. Tianeptine administration induced the opposite effects. Buspirone induced a mild deficit in acquisition and had no effects during the extinction phase. Risperidone administration resulted in learning deficits during the acquisition phase, although it promoted improved extinction. Ondansetron treatment showed a deleterious effect in the acquisition phase and an overall improvement in the extinction phase. These data showed a differential role of 5-HT in the acquisition and extinction of an operant conditioning task, suggesting that it may have a dual function in reward encoding. PMID:24949809

  7. Binding of [3H]paroxetine to serotonin uptake sites and of [3H]lysergic acid diethylamide to 5-HT2A receptors in platelets from women with premenstrual dysphoric disorder during gonadotropin releasing hormone treatment.

    PubMed

    Bixo, M; Allard, P; Bäckström, T; Mjörndal, T; Nyberg, S; Spigset, O; Sundström-Poromaa, I

    2001-08-01

    Changes in serotonergic parameters have been reported in psychiatric conditions such as depression but also in the premenstrual dysphoric disorder (PMDD). In addition, hormonal effects on serotonergic activity have been established. In the present study, binding of [3H]paroxetine to platelet serotonin uptake sites and binding of [3H]lysergic acid diethylamide ([3H]LSD) to platelet serotonin (5-HT)2A receptors were studied in patients with PMDD treated with a low dose of a gonadotropin releasing hormone (GnRH) agonist (buserelin) or placebo and compared to controls. The PMDD patients were relieved of premenstrual symptoms like depression and irritability during buserelin treatment. The number of [3H]paroxetine binding sites (Bmax) were significantly higher in the follicular phase in untreated PMDD patients compared to controls. When treated with buserelin the difference disappeared. No differences in [3H]LSD binding between the three groups were shown. The present study demonstrated altered platelet [3H]paroxetine binding characteristics in women with PMDD compared to controls. Furthermore, [3H]paroxetine binding was affected by PMDD treatment with a low dose of buserelin. The results are consistent with the hypothesis that changes in serotonergic transmission could be a trait in the premenstrual dysphoric disorder.

  8. Extending David Horrobin's membrane phospholipid theory of schizophrenia: overactivity of cytosolic phospholipase A(2) in the brain is caused by overdrive of coupled serotonergic 5HT(2A/2C) receptors in response to stress.

    PubMed

    Eggers, Arnold E

    2012-12-01

    David Horrobin's membrane phospholipid theory of schizophrenia has held up well over time because his therapeutic prediction that dietary supplementation with eicosapentaenoic acid (EPA) would have a therapeutic effect has been partially verified and undergoes continued testing. In the final version of his theory, he hypothesized that there was hyperactivity of phosphoslipase A(2) (PLA(2)) or a related enzyme but did not explain how the hyperactivity came about. It is known that serotonergic 5HT(2A/2C) receptors are coupled to PLA(2), which hydrolyzes both arachidonic acid (AA) and EPA from diacylglycerides at the sn-2 position. In this paper, Horrobin's theory is combined with a previously published theory of chronic stress in which it was hypothesized that a disinhibited dorsal raphe nucleus, the principal nucleus of the serotonergic system, can organize the neuropathology of diseases such as migraine, hypertension, and the metabolic syndrome. The new or combined theory is that schizophrenia is a disease of chronic stress in which a disinhibited DRN causes widespread serotonergic overdrive in the cerebral cortex. This in turn causes overdrive of cPLA(2) and both central and peripheral depletion of AA and EPA. Because EPA is present in smaller amounts, it falls below threshold for maintaining an intracellular balance between AA-derived and EPA-derived second messenger cascades, which leads to abnormal patterns of neuronal firing. There are two causes of neuronal dysfunction: the disinhibited DRN and EPA depletion. Schizophrenia is statistically associated with metabolic syndrome, hypertension, and migraine because they form a cluster of diseases with similar pathophysiology. The theory provides an explanation for both the central and peripheral phospholipid abnormalities in schizophrenia. It also explains the role of stress in schizophrenia, elevated serum PLA(2) activity in schizophrenia, the relationship between untreated schizophrenia and metabolic syndrome

  9. The serotonergic hallucinogen 5-methoxy-N,N-dimethyltryptamine disrupts cortical activity in a regionally-selective manner via 5-HT(1A) and 5-HT(2A) receptors.

    PubMed

    Riga, Maurizio S; Bortolozzi, Analia; Campa, Letizia; Artigas, Francesc; Celada, Pau

    2016-02-01

    5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a natural hallucinogen, acting as a non-selective serotonin 5-HT(1A)/5-HT(2A)-R agonist. Psychotomimetic agents such as the non-competitive NMDA-R antagonist phencyclidine and serotonergic hallucinogens (DOI and 5-MeO-DMT) disrupt cortical synchrony in the low frequency range (<4 Hz) in rat prefrontal cortex (PFC), an effect reversed by antipsychotic drugs. Here we extend these observations by examining the effect of 5-MeO-DMT on low frequency cortical oscillations (LFCO, <4 Hz) in PFC, visual (V1), somatosensory (S1) and auditory (Au1) cortices, as well as the dependence of these effects on 5-HT(1A)-R and 5-HT(2A)-R, using wild type (WT) and 5-HT(2A)-R knockout (KO2A) anesthetized mice. 5-MeO-DMT reduced LFCO in the PFC of WT and KO2A mice. The effect in KO2A mice was fully prevented by the 5-HT(1A)-R antagonist WAY-100635. Systemic and local 5-MeO-DMT reduced 5-HT release in PFC mainly via 5-HT(1A)-R. Moreover, 5-MeO-DMT reduced LFCO in S1, Au1 and V1 of WT mice and only in V1 of KO2A mice, suggesting the involvement of 5-HT(1A)-R activation in the 5-MeO-DMT-induced disruption of V1 activity. In addition, antipsychotic drugs reversed 5-MeO-DMT effects in WT mice. The present results suggest that the hallucinogen action of 5-MeO-DMT is mediated by simultaneous alterations of the activity of sensory (S1, Au1, V1) and associative (PFC) cortical areas, also supporting a role of 5-HT(1A)-R stimulation in V1 and PFC, in addition to the well-known action on 5-HT(2A)-R. Moreover, the reversal by antipsychotic drugs of 5-MeO-DMT effects adds to previous literature supporting the usefulness of the present model in antipsychotic drug development.

  10. Synthesis and Structure–Activity Relationships of N-Benzyl Phenethylamines as 5-HT2A/2C Agonists

    PubMed Central

    2014-01-01

    N-Benzyl substitution of 5-HT2A receptor agonists of the phenethylamine structural class of psychedelics (such as 4-bromo-2,5-dimethoxyphenethylamine, often referred to as 2C-B) confer a significant increase in binding affinity as well as functional activity of the receptor. We have prepared a series of 48 compounds with structural variations in both the phenethylamine and N-benzyl part of the molecule to determine the effects on receptor binding affinity and functional activity at 5-HT2A and 5-HT2C receptors. The compounds generally had high affinity for the 5-HT2A receptor with 8b having the highest affinity at 0.29 nM but with several other compounds also exhibiting subnanomolar binding affinities. The functional activity of the compounds was distributed over a wider range with 1b being the most potent at 0.074 nM. Most of the compounds exhibited low to moderate selectivity (1- to 40-fold) for the 5-HT2A receptor in the binding assays, although one compound 6b showed an impressive 100-fold selectivity for the 5-HT2A receptor. In the functional assay, selectivity was generally higher with 1b being more than 400-fold selective for the 5-HT2A receptor. PMID:24397362

  11. Heterocomplex formation of 5-HT2A-mGlu2 and its relevance for cellular signaling cascades.

    PubMed

    Delille, Hannah K; Becker, Judith M; Burkhardt, Sabrina; Bleher, Barbara; Terstappen, Georg C; Schmidt, Martin; Meyer, Axel H; Unger, Liliane; Marek, Gerard J; Mezler, Mario

    2012-06-01

    Dopamine, serotonin and glutamate play a role in the pathophysiology of schizophrenia. In the brain a functional crosstalk between the serotonin receptor 5-HT(2A) and the metabotropic glutamate receptor mGlu(2) has been demonstrated. Such a crosstalk may be mediated indirectly through neuronal networks or directly by receptor oligomerization. A direct link of the 5-HT(2A)-mGlu(2) heterocomplex formation to receptor function, i.e. to intracellular signaling, has not been fully demonstrated yet. Here we confirm the formation of 5-HT(2A)-mGlu(2) heterocomplexes using quantitative Snap/Clip-tag based HTRF methods. Additionally, mGlu(2) formed complexes with 5-HT(2B) and mGlu(5) but not 5-HT(2C) indicating that complex formation is not specific to the 5-HT(2A)-mGlu(2) pair. We studied the functional consequences of the 5-HT(2A)-mGlu(2) heterocomplex addressing cellular signaling pathways. Co-expression of receptors in HEK-293 cells had no relevant effects on signaling mediated by the individual receptors when mGlu(2) agonists, antagonists and PAMs, or 5-HT(2A) hallucinogenic and non-hallucinogenic agonists and antagonists were used. Hallucinogenic 5-HT(2A) agonists induced signaling through G(q/11), but not G(i) and thus did not lead to modulation of intracellular cAMP levels. In membranes of the medial prefrontal cortex [(3)H]-LY341495 binding competition of mGlu(2/3) agonist LY354740 was not influenced by 2,5-dimethoxy-4-iodoamphetamine (DOI). Taken together, the formation of GPCR heterocomplexes does not necessarily translate into second messenger effects. These results do not put into question the well-documented functional cross-talk of the two receptors in the brain, but do challenge the biological relevance of the 5-HT(2A)-mGlu(2) heterocomplex.

  12. The influence of 5-HT(2A) activity on a 5-HT(2C) specific in vivo assay used for early identification of multiple acting SERT and 5-HT(2C) receptor ligands.

    PubMed

    Éliás, Olivér; Nógrádi, Katalin; Domány, György; Szakács, Zoltán; Kóti, János; Szántay, Csaba; Tarcsay, Ákos; Keserű, György M; Gere, Anikó; Kiss, Béla; Kurkó, Dalma; Kolok, Sándor; Némethy, Zsolt; Kapui, Zoltán; Hellinger, Éva; Vastag, Mónika; Sághy, Katalin; Kedves, Rita; Gyertyán, István

    2016-02-01

    As a result of our exploratory programme aimed at elaborating dually acting compounds towards the serotonin (5-HT) transporter (SERT) and the 5-HT2C receptor a novel series of 3-amino-1-phenylpropoxy substituted diphenylureas was identified. From that collection two promising compounds (2 and 3) exhibiting highest 5-HT2C receptor affinity strongly inhibited the 5-HT2C receptor agonist 1-(3-chlorophenyl)piperazine (mCPP) induced hypomotility in mice. In further pursuance of that objective (2-aminoethyl)(benzyl)sulfamoyl diphenylureas and diphenylpiperazines have also been elaborated. Herein we report the synthesis of potent multiple-acting compounds from this new class. However, when two optimized representatives (6 and 14) possessing the desired in vitro profile were tested neither reduced the motor activity of mCPP treated animals. Comparative albeit limited in vitro structure-activity relationship (SAR) analysis and detailed in vivo studies are discussed and explanation for their intricate behaviour is proposed.

  13. 4-Fluorosulfonylpiperidines: selective 5-HT2A ligands for the treatment of insomnia.

    PubMed

    Fish, L Rebecca; Gilligan, Myra T; Humphries, Alexander C; Ivarsson, Magnus; Ladduwahetty, Tammy; Merchant, Kevin J; O'Connor, Desmond; Patel, Smita; Philipps, Elisabeth; Vargas, Hugo M; Hutson, Peter H; MacLeod, Angus M

    2005-08-15

    Incorporation of fluorine at the 4-position of an existing series of sulfonyl piperidine 5-HT2A antagonists gave compounds with increased selectivity over the IKr potassium channel. This work led to the identification of 3b, a compound that gave no increase in QTc in the anesthetized dog up to plasma levels as high as 148 microM. Furthermore, 3b has been shown to increase slow-wave sleep bout duration and to decrease the number of awakenings in rats, indicating the potential utility of 5-HT2A antagonists in the treatment of insomnia.

  14. Molecular Determinants for Ligand Binding at Serotonin 5-HT2A and 5-HT2C GPCRs: Experimental Affinity Results Analyzed by Molecular Modeling and Ligand Docking Studies

    PubMed Central

    Sakhuja, Rajeev; Kondabolu, Krishnakanth; Canal, Clinton E.; Booth, Raymond G.

    2013-01-01

    Ligands that activate the serotonin 5-HT2C G protein-coupled receptor (GPCR) may be therapeutic for psychoses, addiction, and other neuropsychiatric disorders. Ligands that are antagonists at the closely related 5-HT2A GPCR also may treat neuropsychiatric disorders; in contrast, 5-HT2A activation may cause hallucinations. 5-HT2C-specific agonist drug design is challenging because 5-HT2 GPCRs share 80% transmembrane (TM) homology, same second messenger signaling, and no crystal structures are reported. To help delineate molecular determinants underlying differential binding and activation of 5-HT2 GPCRs, 5-HT2A, and 5-HT2C homology models were built from the β2-adrenergic GPCR crystal structure and equilibrated in a lipid phosphatidyl choline bilayer performing molecular dynamics simulations. Ligand docking studies at the 5-HT2 receptor models were conducted with the (2R, 4S)- and (2S, 4R)-enantiomers of the novel 5-HT2C agonist/5-HT2A/2B antagonist trans-4-phenyl-N,N-dimethyl-2-aminotetralin (PAT) and its 4′-chlorophenyl congners. Results indicate PAT–5-HT2 molecular interactions especially in TM domain V are important for the (2R, 4S) enantiomer, whereas, TM domain VI and VII interactions are more important for the (2S, 4R) enantiomer. PMID:23913978

  15. 1,4-Disubstituted aromatic piperazines with high 5-HT2A/D2 selectivity: Quantitative structure-selectivity investigations, docking, synthesis and biological evaluation.

    PubMed

    Möller, Dorothee; Salama, Ismail; Kling, Ralf C; Hübner, Harald; Gmeiner, Peter

    2015-09-15

    Simultaneous targeting of dopamine D2 and 5-HT2A receptors for the treatment of schizophrenia is one key feature of typical and atypical antipsychotics. In most of the top-selling antipsychotic drugs like aripiprazole and risperidone, high affinity to both receptors can be attributed to the presence of 1,4-disubstituted aromatic piperazines or piperidines as primary receptor recognition elements. Taking advantage of our in-house library of phenylpiperazine-derived dopamine receptor ligands and experimental data, we established highly significant CoMFA and CoMSIA models for the prediction of 5-HT2A over D2 selectivity. Subsequently, the models were applied to identify the selective candidates 55-57 from our newly synthesized library of GPCR ligands comprising a pyrazolo[1,5-a]pyridine head group and a 1,2,3-triazole based linker unit. The test compound 57 showed subnanomolar a Ki value (0.64 nM) for 5-HT2A and more than 10- and 30-fold selectivity over the dopamine receptor isoforms D2S and D2L, respectively. PMID:26299826

  16. Hallucinogenic 5-HT2AR agonists LSD and DOI enhance dopamine D2R protomer recognition and signaling of D2-5-HT2A heteroreceptor complexes.

    PubMed

    Borroto-Escuela, Dasiel O; Romero-Fernandez, Wilber; Narvaez, Manuel; Oflijan, Julia; Agnati, Luigi F; Fuxe, Kjell

    2014-01-01

    Dopamine D2LR-serotonin 5-HT2AR heteromers were demonstrated in HEK293 cells after cotransfection of the two receptors and shown to have bidirectional receptor-receptor interactions. In the current study the existence of D2L-5-HT2A heteroreceptor complexes was demonstrated also in discrete regions of the ventral and dorsal striatum with in situ proximity ligation assays (PLA). The hallucinogenic 5-HT2AR agonists LSD and DOI but not the standard 5-HT2AR agonist TCB2 and 5-HT significantly increased the density of D2like antagonist (3)H-raclopride binding sites and significantly reduced the pKiH values of the high affinity D2R agonist binding sites in (3)H-raclopride/DA competition experiments. Similar results were obtained in HEK293 cells and in ventral striatum. The effects of the hallucinogenic 5-HT2AR agonists on D2R density and affinity were blocked by the 5-HT2A antagonist ketanserin. In a forskolin-induced CRE-luciferase reporter gene assay using cotransfected but not D2R singly transfected HEK293 cells DOI and LSD but not TCB2 significantly enhanced the D2LR agonist quinpirole induced inhibition of CRE-luciferase activity. Haloperidol blocked the effects of both quinpirole alone and the enhancing actions of DOI and LSD while ketanserin only blocked the enhancing actions of DOI and LSD. The mechanism for the allosteric enhancement of the D2R protomer recognition and signalling observed is likely mediated by a biased agonist action of the hallucinogenic 5-HT2AR agonists at the orthosteric site of the 5-HT2AR protomer. This mechanism may contribute to the psychotic actions of LSD and DOI and the D2-5-HT2A heteroreceptor complex may thus be a target for the psychotic actions of hallunicogenic 5-HT2A agonists.

  17. Effects of the 5-HT2A agonist psilocybin on mismatch negativity generation and AX-continuous performance task: implications for the neuropharmacology of cognitive deficits in schizophrenia.

    PubMed

    Umbricht, Daniel; Vollenweider, Franz X; Schmid, Liselotte; Grübel, Claudia; Skrabo, Anja; Huber, Theo; Koller, Rene

    2003-01-01

    Previously the NMDA (N-methyl-D-aspartate) receptor (NMDAR) antagonist ketamine was shown to disrupt generation of the auditory event-related potential (ERP) mismatch negativity (MMN) and the performance of an 'AX'-type continuous performance test (AX-CPT)--measures of auditory and visual context-dependent information processing--in a similar manner as observed in schizophrenia. This placebo-controlled study investigated effects of the 5-HT(2A) receptor agonist psilocybin on the same measures in 18 healthy volunteers. Psilocybin administration induced significant performance deficits in the AX-CPT, but failed to reduce MMN generation significantly. These results indirectly support evidence that deficient MMN generation in schizophrenia may be a relatively distinct manifestation of deficient NMDAR functioning. In contrast, secondary pharmacological effects shared by NMDAR antagonists and the 5-HT(2A) agonist (ie disruption of glutamatergic neurotransmission) may be the mechanism underlying impairments in AX-CPT performance observed during both psilocybin and ketamine administration. Comparable deficits in schizophrenia may result from independent dysfunctions of 5-HT(2A) and NMDAR-related neurotransmission.

  18. 5-HT2A Gene Variants Moderate the Association between PTSD and Reduced Default Mode Network Connectivity.

    PubMed

    Miller, Mark W; Sperbeck, Emily; Robinson, Meghan E; Sadeh, Naomi; Wolf, Erika J; Hayes, Jasmeet P; Logue, Mark; Schichman, Steven A; Stone, Angie; Milberg, William; McGlinchey, Regina

    2016-01-01

    The default mode network (DMN) has been used to study disruptions of functional connectivity in a wide variety of psychiatric and neurological conditions, including posttraumatic stress disorder (PTSD). Studies indicate that the serotonin system exerts a modulatory influence on DMN connectivity; however, no prior study has examined associations between serotonin receptor gene variants and DMN connectivity in either clinical or healthy samples. We examined serotonin receptor single nucleotide polymorphisms (SNPs), PTSD, and their interactions for association with DMN connectivity in 134 White non-Hispanic veterans. We began by analyzing candidate SNPs identified in prior meta-analyses of relevant psychiatric traits and found that rs7997012 (an HTR2A SNP), implicated previously in anti-depressant medication response in the Sequenced Treatment Alternatives for Depression study (STAR(*)D; McMahon et al., 2006), interacted with PTSD to predict reduced connectivity between the posterior cingulate cortex (PCC) and the right medial prefrontal cortex and right middle temporal gyrus (MTG). rs130058 (HTR1B) was associated with connectivity between the PCC and right angular gyrus. We then expanded our analysis to 99 HTR1B and HTR2A SNPs and found two HTR2A SNPs (rs977003 and rs7322347) that significantly moderated the association between PTSD severity and the PCC-right MTG component of the DMN after correcting for multiple testing. Finally, to obtain a more precise localization of the most significant SNP × PTSD interaction, we performed a whole cortex vertex-wise analysis of the rs977003 effect. This analysis revealed the locus of the pre-frontal effect to be in portions of the superior frontal gyrus, while the temporal lobe effect was centered in the middle and inferior temporal gyri. These findings point to the influence of HTR2A variants on DMN connectivity and advance knowledge of the role of 5-HT2A receptors in the neurobiology of PTSD. PMID:27445670

  19. 5-HT2A Gene Variants Moderate the Association between PTSD and Reduced Default Mode Network Connectivity

    PubMed Central

    Miller, Mark W.; Sperbeck, Emily; Robinson, Meghan E.; Sadeh, Naomi; Wolf, Erika J.; Hayes, Jasmeet P.; Logue, Mark; Schichman, Steven A.; Stone, Angie; Milberg, William; McGlinchey, Regina

    2016-01-01

    The default mode network (DMN) has been used to study disruptions of functional connectivity in a wide variety of psychiatric and neurological conditions, including posttraumatic stress disorder (PTSD). Studies indicate that the serotonin system exerts a modulatory influence on DMN connectivity; however, no prior study has examined associations between serotonin receptor gene variants and DMN connectivity in either clinical or healthy samples. We examined serotonin receptor single nucleotide polymorphisms (SNPs), PTSD, and their interactions for association with DMN connectivity in 134 White non-Hispanic veterans. We began by analyzing candidate SNPs identified in prior meta-analyses of relevant psychiatric traits and found that rs7997012 (an HTR2A SNP), implicated previously in anti-depressant medication response in the Sequenced Treatment Alternatives for Depression study (STAR*D; McMahon et al., 2006), interacted with PTSD to predict reduced connectivity between the posterior cingulate cortex (PCC) and the right medial prefrontal cortex and right middle temporal gyrus (MTG). rs130058 (HTR1B) was associated with connectivity between the PCC and right angular gyrus. We then expanded our analysis to 99 HTR1B and HTR2A SNPs and found two HTR2A SNPs (rs977003 and rs7322347) that significantly moderated the association between PTSD severity and the PCC-right MTG component of the DMN after correcting for multiple testing. Finally, to obtain a more precise localization of the most significant SNP × PTSD interaction, we performed a whole cortex vertex-wise analysis of the rs977003 effect. This analysis revealed the locus of the pre-frontal effect to be in portions of the superior frontal gyrus, while the temporal lobe effect was centered in the middle and inferior temporal gyri. These findings point to the influence of HTR2A variants on DMN connectivity and advance knowledge of the role of 5-HT2A receptors in the neurobiology of PTSD. PMID:27445670

  20. Effect of GABAergic ligands on the anxiolytic-like activity of DOI (a 5-HT(2A/2C) agonist) in the four-plate test in mice.

    PubMed

    Massé, Fabienne; Hascoët, Martine; Bourin, Michel

    2007-01-01

    5-HTergic and GABAergic systems are involved in neurobiology of anxiety. Precedent studies have demonstrated that SSRIs possessed an anxiolytic-like effect in the four-plate test (FPT) at doses that did not modify spontaneous locomotor activity. This effect seems to be mediated through the activation of 5-HT(2A) postsynaptic receptors. The purpose of the present study was to examine the implication of GABA system in the anxiolytic-like activity of DOI in the FPT. To achieve this, the co-administration of DOI (5-HT(2A/2C) receptor agonists) with GABA(A) and GABA(B) receptor ligands was evaluated in the FPT. Alprazolam, diazepam and muscimol (for higher dose) potentiated the anxiolytic-like effect of DOI. Bicuculline, picrotoxin and baclofen inhibited the anxiolytic-like effect of DOI. Flumazenil and CGP 35348 had no effect on the anxiolytic-like activity of DOI. These results suggest that the GABA system seems to be strongly implicated in the anxiolytic-like activity of DOI in the FPT.

  1. Evidence for a common biological basis of the Absorption trait, hallucinogen effects, and positive symptoms: epistasis between 5-HT2a and COMT polymorphisms.

    PubMed

    Ott, Ulrich; Reuter, Martin; Hennig, Juergen; Vaitl, Dieter

    2005-08-01

    Absorption represents a disposition to experience altered states of consciousness characterized by intensively focused attention. It is correlated with hypnotic susceptibility and includes phenomena ranging from vivid perceptions and imaginations to mystical experiences. Based on the assumption that drug-induced and naturally occurring mystical experiences share common neural mechanisms, we hypothesized that Absorption is influenced by the T102C polymorphism affecting the 5-HT2a receptor, which is known to be an important target site of hallucinogens like LSD. Based on the pivotal role ascribed to the prefrontal executive control network for absorbed attention and positive symptoms in schizophrenia, it was further hypothesized that Absorption is associated with the VAL158MET polymorphism of the catechol-O-methyltransferase (COMT) gene affecting the dopaminergic neurotransmitter system. The Tellegen Absorption Scale was administered to 336 subjects (95 male, 241 female). Statistical analysis revealed that the group with the T/T genotype of the T102C polymorphism, implying a stronger binding potential of the 5-HT2a receptor, indeed had significantly higher Absorption scores (F = 10.00, P = 0.002), while no main effect was found for the COMT polymorphism. However, the interaction between T102C and COMT genotypes yielded significance (F = 3.89; P = 0.049), underlining the known functional interaction between the 5-HT and the dopaminergic system. These findings point to biological foundations of the personality trait of Absorption.

  2. Contrasting mechanisms of action and sensitivity to antipsychotics of phencyclidine versus amphetamine: importance of nucleus accumbens 5-HT2A sites for PCP-induced locomotion in the rat.

    PubMed

    Millan, M J; Brocco, M; Gobert, A; Joly, F; Bervoets, K; Rivet, J; Newman-Tancredi, A; Audinot, V; Maurel, S

    1999-12-01

    In the present study, the comparative mechanisms of action of phencyclidine (PCP) and amphetamine were addressed employing the parameter of locomotion in rats. PCP-induced locomotion (PLOC) was potently blocked by the selective serotonin (5-HT)2A vs. D2 antagonists, SR46349, MDL100,907, ritanserin and fananserin, which barely affected amphetamine-induced locomotion (ALOC). In contrast, the selective D2 vs. 5-HT2A antagonists, eticlopride, raclopride and amisulpride, preferentially inhibited ALOC vs. PLOC. The potency of these drugs and 12 multireceptorial antipsychotics in inhibiting PLOC vs. ALOC correlated significantly with affinities at 5-HT2A vs. D2 receptors, respectively. Amphetamine and PCP both dose dependently increased dialysate levels of dopamine (DA) and 5-HT in the nucleus accumbens, striatum and frontal cortex (FCX) of freely moving rats, but PCP was proportionally more effective than amphetamine in elevating levels of 5-HT vs. DA in the accumbens. Further, whereas microinjection of PCP into the accumbens elicited locomotion, its introduction into the striatum or FCX was ineffective. The action of intra-accumbens PCP, but not intra-accumbens amphetamine, was abolished by SR46349 and clozapine. Parachloroamphetamine, which depleted accumbens pools of 5-HT but not DA, likewise abolished PLOC without affecting ALOC. In contrast, intra-accumbens 6-hydroxydopamine (6-OHDA), which depleted DA but not 5-HT, abolished ALOC but only partially attenuated PLOC. In conclusion, PLOC involves (indirect) activation of accumbens-localized 5-HT2A receptors by 5-HT. PLOC is, correspondingly, more potently blocked than ALOC by antipsychotics displaying marked affinity at 5-HT2A receptors.

  3. The effects of the preferential 5-HT2A agonist psilocybin on prepulse inhibition of startle in healthy human volunteers depend on interstimulus interval.

    PubMed

    Vollenweider, Franz X; Csomor, Philipp A; Knappe, Bernhard; Geyer, Mark A; Quednow, Boris B

    2007-09-01

    Schizophrenia patients exhibit impairments in prepulse inhibition (PPI) of the startle response. Hallucinogenic 5-HT(2A) receptor agonists are used for animal models of schizophrenia because they mimic some symptoms of schizophrenia in humans and induce PPI deficits in animals. Nevertheless, one report indicates that the 5-HT(2A) receptor agonist psilocybin increases PPI in healthy humans. Hence, we investigated these inconsistent results by assessing the dose-dependent effects of psilocybin on PPI in healthy humans. Sixteen subjects each received placebo or 115, 215, and 315 microg/kg of psilocybin at 4-week intervals in a randomized and counterbalanced order. PPI at 30-, 60-, 120-, 240-, and 2000-ms interstimulus intervals (ISIs) was measured 90 and 165 min after drug intake, coinciding with the peak and post-peak effects of psilocybin. The effects of psilocybin on psychopathological core dimensions and sustained attention were assessed by the Altered States of Consciousness Rating Scale (5D-ASC) and the Frankfurt Attention Inventory (FAIR). Psilocybin dose-dependently reduced PPI at short (30 ms), had no effect at medium (60 ms), and increased PPI at long (120-2000 ms) ISIs, without affecting startle reactivity or habituation. Psilocybin dose-dependently impaired sustained attention and increased all 5D-ASC scores with exception of Auditory Alterations. Moreover, psilocybin-induced impairments in sustained attention performance were positively correlated with reduced PPI at the 30 ms ISI and not with the concomitant increases in PPI observed at long ISIs. These results confirm the psilocybin-induced increase in PPI at long ISIs and reveal that psilocybin also produces a decrease in PPI at short ISIs that is correlated with impaired attention and consistent with deficient PPI in schizophrenia.

  4. The effect of intrahippocampal injections of ritanserin (5HT2A/2C antagonist) and granisetron (5HT3 antagonist) on learning as assessed in the spatial version of the water maze.

    PubMed

    Naghdi, Nasser; Harooni, Hooman E

    2005-02-28

    5HT(2A/2C) and 5HT(3) receptors have an important role in cognitive behavior specially in spatial learning and memory but the literature concerning the role of these receptors in hippocampus in cognition remains controversial. In the present study a 5HT(2A/2C) antagonist ritanserin (0, 2, 4, 8 microg/0.5 microl) and a 5HT(3) antagonist granisetron (0.0, 0.05, 0.25, 0.5 microg/0.5 microl) were injected bilaterally into the CA1 region of rat hippocampus, 20 min before each training session in Morris Water Maze (MWM) task. Compare with control group, ritanserin (4 microg/0.5 microl) significantly reduced the escape latency and traveled distance of swimming to platform, but granisetron (0.25 microg/0.5 microl) significantly increased those parameters. Both drugs had no effect on escape latency and traveled distance of a non-spatial visual discrimination task. These results suggest a differential role of 5HT(2A/2C) and 5HT(3) receptors during spatial learning that ritanserin improves rat performance in spatial discrimination task whereas granisetron impairs it.

  5. Association study of T102C 5-HT2A polymorphism in schizophrenic patients: diagnosis, psychopathology, and suicidal behavior

    PubMed Central

    Correa, Humberto; De Marco, Luiz; Boson, Wolfanga; Nicolato, Rodrigo; Teixeira, Antó L.; Campo, Valdir R.; Romano-Silva, Marco A.

    2007-01-01

    The objective of this study was to examine the association between the serotonin (5-HT)2A gene polymorphism (102T/C) and suicidal behavior in schizophrenic inpatients. We studied 129 subjects who met the diagnostic criteria for schizophrenia according to a structured clinicai interview (MINI-PLUS), Patients underwent a semistructured interview to assess suicide attempt history and its characteristics, in addition, at least one close relative of the patient was interviewed to assess prohand and family suicidal behavior. Healthy controls were students and hospital staff members free of psychiatric and medical illness. Genotypes were determined after polymerase chain reaction amplification of the region of 5-HT2A/T102C containing the polymorphic site and digestion with the restriction enzyme Hpall, We found no association between suicidal attempt history and suicide attempt characteristics and genotypic or aileie frequencies. Suicidal behavior was also not associated with demographic or psychopathological characteristics. These results suggest that the S-HT2A gene polymorphism (102T/C) is not involved in genetic susceptibility to suicidal behavior, but further studies in a larger sample are needed. PMID:17506229

  6. Pharmacogenetic Study of Serotonin Transporter and 5HT2A Genotypes in Autism

    PubMed Central

    Najjar, Fedra; Owley, Thomas; Mosconi, Matthew W.; Jacob, Suma; Hur, Kwan; Guter, Stephen J.; Sweeney, John A.; Gibbons, Robert D; Bishop, Jeffrey R.

    2015-01-01

    Abstract Objective: The purpose of this study was to determine whether polymorphisms in the serotonin transporter (SLC6A4) and serotonin-2A receptor (HTR2A) genes are associated with response to escitalopram in patients with autism spectrum disorder (ASD). Methods: Forty-four participants with ASD were enrolled in a 6 week, forced titration, open label examination of the selective serotonin reuptake inhibitor (SSRI) escitalopram. Doses increased at weekly intervals starting at 2.5mg daily with a maximum possible dose of 20 mg daily achieved by the end of the study. If adverse events were experienced, participants subsequently received the previously tolerated dose for the duration of study. SLC6A4 (5-HTTLPR) and HTR2A (rs7997012) genotype groups were assessed in relation to treatment outcomes and drug doses. Results: Insistence on sameness and irritability symptoms significantly improved over the course of the 6 week treatment period (p<0.0001) in this open-label trial. There were no significant differences observed in the rate of symptom improvement over time across genotype groups. Similarly, dosing trajectory was not significantly associated with genotype groups. Conclusions: Previous studies have identified SLC6A4 and HTR2A associations with SSRI response in patients with depression and 5-HTTLPR (SLC6A4) associations with escitalopram response in ASD. We did not observe evidence for similar relationships in this ASD study. PMID:26262902

  7. Clonidine potentiates the effects of 5-HT1A, 5-HT1B and 5-HT2A/2C antagonists and 8-OH-DPAT in the mouse forced swimming test.

    PubMed

    Redrobe, J P; Bourin, M

    1998-08-01

    The present study was undertaken to identify the receptor subtypes involved in clonidine's ability to enhance the effects of antidepressant drugs in the mouse forced swimming test. Clonidine (0.06 mg/kg, i.p.) significantly enhanced the antidepressant-like effects of subactive doses of the 5-HT1A receptor agonist, 8-OH-DPAT (1 mg/kg, i.p.; P<0.01); the 5-HT1A receptor antagonist, NAN 190 (0.5 mg/kg, i.p.; P<0.01); the 5-HT1A/1B autoreceptor antagonist, (+/-) pindolol (32 mg/kg, i.p.; P<0.01); the 5-HT2A/2C receptor antagonist, ritanserin (4 mg/kg, i.p.; P<0.01). Pretreatment with clonidine failed to increase mobility when administered in combination with the 5-HT1B receptor agonist, RU 24969 (1 mg/kg, i.p.) or the 5-HT2A receptor antagonist, ketanserin (8 mg/kg, i.p.). In conclusion, clonidine-induced anti-immobility effects are more likely mediated by 5-HT1A and 5-HT2C receptors, as well as alpha-2-adrenergic autoreceptors situated on noradrenergic neurones. The results of the present study also demonstrate that serotonergic receptor function can influence alpha-2-adrenoreceptor mediated responses in the mouse forced swimming test.

  8. Modulating the rate and rhythmicity of perceptual rivalry alternations with the mixed 5-HT2A and 5-HT1A agonist psilocybin.

    PubMed

    Carter, Olivia L; Pettigrew, John D; Hasler, Felix; Wallis, Guy M; Liu, Guang B; Hell, Daniel; Vollenweider, Franz X

    2005-06-01

    Binocular rivalry occurs when different images are presented simultaneously to corresponding points within the left and right eyes. Under these conditions, the observer's perception will alternate between the two perceptual alternatives. Motivated by the reported link between the rate of perceptual alternations, symptoms of psychosis and an incidental observation that the rhythmicity of perceptual alternations during binocular rivalry was greatly increased 10 h after the consumption of LSD, this study aimed to investigate the pharmacology underlying binocular rivalry and to explore the connection between the timing of perceptual switching and psychosis. Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine, PY) was chosen for the study because, like LSD, it is known to act as an agonist at serotonin (5-HT)1A and 5-HT2A receptors and to produce an altered state sometimes marked by psychosis-like symptoms. A total of 12 healthy human volunteers were tested under placebo, low-dose (115 microg/kg) and high-dose (250 microg/kg) PY conditions. In line with predictions, under both low- and high-dose conditions, the results show that at 90 min postadministration (the peak of drug action), rate and rhythmicity of perceptual alternations were significantly reduced from placebo levels. Following the 90 min testing period, the perceptual switch rate successively increased, with some individuals showing increases well beyond pretest levels at the final testing, 360 min postadministration. However, as some subjects had still not returned to pretest levels by this time, the mean phase duration at 360 min was not found to differ significantly from placebo. Reflecting the drug-induced changes in rivalry phase durations, subjects showed clear changes in psychological state as indexed by the 5D-ASC (altered states of consciousness) rating scales. This study suggests the involvement of serotonergic pathways in binocular rivalry and supports the previously proposed role of a brainstem

  9. Angiotensin II Receptor Blockers and Cancer Risk

    PubMed Central

    Zhao, Yun-Tao; Li, Peng-Yang; Zhang, Jian-Qiang; Wang, Lei; Yi, Zhong

    2016-01-01

    Abstract Angiotensin II receptor blockers (ARB) are widely used drugs that are proven to reduce cardiovascular disease events; however, several recent meta-analyses yielded conflicting conclusions regarding the relationship between ARB and cancer incidence, especially when ARB are combined with angiotensin-converting enzyme inhibitors (ACEI). We investigated the risk of cancer associated with ARB at different background ACEI levels. Search of PubMed and EMBASE (1966 to December 17, 2015) without language restriction. Randomized, controlled trials (RCTs) had at least 12 months of follow-up data and reported cancer incidence was included. Study characteristics, quality, and risk of bias were assessed by 2 reviewers independently. Nineteen RCTs including 148,334 patients were included in this study. Random-effects model meta-analyses were used to estimate the risk ratio (RR) of cancer risk. No excessive cancer risk was observed in our analyses of ARB alone versus placebo alone without background ACEI use (risk ratio [RR] 1.08, 95% confidence interval [CI] 1.00–1.18, P = 0.05); ARB alone versus ACEI alone (RR 1.03, 95%CI 0.94–1.14, P = 0.50); ARB plus partial use of ACEI versus placebo plus partial use of ACEI (RR 0.97, 95%CI 0.90–1.04, P = 0.33); and ARB plus ACEI versus ACEI (RR 0.99, 95%CI 0.79–1.24, P = 0.95). Lack of long-term data, inadequate reporting of safety data, significant heterogeneity in underlying study populations, and treatment regimens. ARB have a neutral effect on cancer incidence in randomized trials. We observed no significant differences in cancer incidence when we compared ARB alone with placebo alone, ARB alone with ACEI alone, ARB plus partial use of ACEI with placebo plus partial use of ACEI, or ARB plus ACEI combination with ACEI. PMID:27149494

  10. Aldosterone receptor blockers spironolactone and canrenone: two multivalent drugs.

    PubMed

    Armanini, Decio; Sabbadin, Chiara; Donà, Gabriella; Clari, Giulio; Bordin, Luciana

    2014-05-01

    Canrenone is a derivative of spironolactone with lower antiandrogen activity. The drug is used only in few countries and can block all the side effects of aldosterone (ALDO). The drug is effective even in the presence of normal concentrations of ALDO. Mineralcorticoid receptor antagonists block the inflammatory activity of ALDO at the level of target tissues as heart, vessels and mononuclear leukocytes. Canrenone reduces the progression of insulin resistance and of microalbuminuria in type 2 diabetes and other related diseases. Both canrenone and hydrochlorothiazide can enhance the effect of treatment with ACE inhibitors and angiotensin II receptor blockers on microalbuminuria, but ALDO receptor blockers are more active. This different action is due to the fact that only canrenone blocks mineralocorticoid receptors. Serum potassium and renal function should be monitored before and during the treatment. ALDO receptor blockers are recommended in addition to polytherapy for resistant hypertension, but there are no studies on the effect of the drug as first-choice therapy. PMID:24617854

  11. Fimasartan: A New Angiotensin Receptor Blocker.

    PubMed

    Lee, Hae-Young; Oh, Byung-Hee

    2016-07-01

    Fimasartan is the ninth, and most recent, angiotensin II receptor antagonist approved as an antihypertensive agent. Fimasartan, a pyrimidin-4(3H)-one derivative of losartan with the imidazole ring replaced, which enables higher potency and longer duration than losartan. Fecal elimination and biliary excretion are the predominant elimination pathways of fimasartan and the urinary excretion was found to be less than 3 % 24 h after administration. Fimasartan is primarily catabolized by cytochrome P450 isoform 3A and no significant drug interaction was observed when used in combination with hydrochlorothiazide, amlodipine, warfarin, or digoxin. Fimasartan at a dosage range of 60-120 mg once daily showed an antihypertensive effect over 24 h. In a large, population-based observational study, fimasartan showed an excellent safety profile. Anti-inflammatory and organ-protecting effects of fimasartan have been shown in various preclinical studies, including aortic balloon injury, myocardial infarct ischemia/reperfusion, doxorubicin cardiotoxicity, and ischemic stroke models. PMID:27272555

  12. [Effects of aldosterone receptor blocker therapy on cardiac remodeling].

    PubMed

    Boccanelli, A; Battagliese, A

    2006-01-01

    Cardiac remodeling is a physiologic or pathologic condition that occurs after myocardial infarction, pressure overload, myocardial inflammatory diseases, idiopathic dilated cardiomyopathy or volume overload. In spite of different etiologies, molecular, biochemical and mechanical processes are the same. The change in left ventricular function brings about a complex neuro-hormonal disorder, and disease progression is due to the combined action of several biological factors with toxic effects on the heart and vessels. The renin-angiotensin-aldosterone system (RAAS) is very important in this process, through the effects on hydro-saline balance or through direct processes on myocardium. A direct effect of aldosterone in myocardial fibrosis after the detection of heart tissue aldosterone production has been demonstrated. In the past, the attention of physicians and researchers was focused on angiotensin II inhibition; and therefore, on angiotensin-converting enzyme (ACE) inhibitors, considering them sufficient to antagonize the effects of aldosterone. Nevertheless, this theory has been confuted in recent studies, with the evidence of elevated plasmatic aldosterone levels in patients treated with ACE-inhibitors and angiotensin receptor blockers. This phenomenon probably is due to the activation of secondary ACTH mediated pathways of trial aldosterone production. It has been demonstrated that aldosterone receptor inhibition is effective in reducing cardiac remodeling and mortality. AREA-IN CHF is the first multicentric, double blind, randomized, placebo control study to compare canrenone, an aldosterone receptor blocker, with placebo. The primary end point is the echocardiographic evaluation of left ventricular remodeling. Secondary end points are left ventricular end-systolic volume, ejection fraction, diastolic filling patterns, NYHA functional class, and mortality and hospitalizations of cardiac origin. In addition, bio-humoral effects of aldosterone receptor blocker

  13. Use of Angiotensin Receptor Blockers In Cardiovascular Protection

    PubMed Central

    Munger, Mark A.

    2011-01-01

    Objective To differentiate angiotensin II receptor blockers (ARBs) by vascular effects and outcomes in trials on cardio-protective endpoints. Data Sources MEDLINE searches were conducted from January 2003 to March 2009 using the following search terms: renin–angiotensin–aldosterone system (RAAS) blockade or inhibition; angiotensin II receptor blocker (ARBs); cardio-protection; vascular protection; end-organ protection; candesartan; eprosartan, irbesartan; losartan; olmesartan; telmisartan; and valsartan. Ongoing and recruiting clinical trials were identified via Clinicaltrials.gov (July 2008). Study Selection and Data Abstraction Pertinent basic science research and clinical trials with cardiovascular endpoints and information from reviews, American Heart Association 2009 statistics, and The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure guidelines were included in this review. Data Synthesis ARBs differ in their vascular protective pleiotropic effects and pharmacokinetic properties, which may contribute to their pharmacological protection to reduce cardiovascular morbidity and mortality, independently of their blood pressure (BP)–lowering effects. Conclusion Emerging data show that ARBs are effective in hypertension, left ventricular hypertrophy, postmyocardial infarction, and heart failure. To what extent their pleiotropic effects, independent of BP lowering, contribute to these outcomes will be the focus of research in the coming years. Well-designed, comparative-effectiveness studies are needed to clinically differentiate this class of agents. The future will be marked by multifunctional ARBs that will pharmacologically do more than antagonize the angiotensin type I (AT1) receptor. PMID:21386934

  14. Prostate effect in dogs with the aldosterone receptor blocker eplerenone.

    PubMed

    Levin, Stuart; McMahon, Ellen; John-Baptiste, Annette; Bell, Rosonald R

    2013-02-01

    Eplerenone (Inspra) is an aldosterone receptor antagonist approved for the treatment of hypertension and heart failure after a myocardial infarction. In vitro receptor binding and transactivation studies showed eplerenone had high selectivity for the mineralocorticoid receptor over other steroid receptors (glucocorticoid, androgen, and progesterone). The most sensitive off-target effect of orally administered eplerenone preclinically was prostate atrophy in dogs. Dose-related prostate atrophy was observed at eplerenone dosages ≥15 mg/kg/day for 13 weeks or longer. The no observed adverse effect level (NOAEL) for the prostate effect in dogs was 5 mg/kg/day. The maximal effect was seen by 13 weeks and the atrophy was reversible even after 1 year of daily treatment. An additional study demonstrated dogs with eplerenone-induced prostate atrophy (confirmed by intrarectal ultrasound) had slightly decreased semen volume but no compound-related effects on libido, semen protein content, sperm motility, daily sperm production, or epididymal sperm transit time. Four possible mechanisms for prostate effect were investigated: (1) inhibition of testosterone synthesis and secretion; (2) inhibition of 5α-reductase, the enzyme within the prostate that converts testosterone into the more active growth factor dihydrotestosterone (DHT); (3) competitive antagonism of the androgen receptor; and (4) inhibition of 5α-reductase or competitive antagonism of the androgen receptor by aldosterone, which increased in dogs treated with eplerenone. Data from these studies supported blockade of androgen receptors at suprapharmacological concentrations of eplerenone. Another mineralocorticoid blocker, spironolactone, had greater antiandrogenic activity than eplerenone both in vivo and in vitro, and it has well known clinically significant antiandrogenic effects in humans, whereas eplerenone does not.

  15. Calcium channel blockers, angiotensin receptor blockers, and angiotensin-converting enzyme inhibitors: Effectiveness in combination with diuretics or β-blockers for treating hypertension

    PubMed Central

    Bisognano, John D; McLaughlin, Trent; Roberts, Craig S; Tang, Simon SK

    2007-01-01

    This retrospective database analysis compared the effectiveness of dihydropyridine calcium channel blockers (DHPs), angiotensin-converting enzyme (ACE) inhibitors, and angiotensin receptor blockers (ARBs) added to diuretics or β-blockers. Adults with hypertension treated with diuretic or β-blocker monotherapy between 1998 and 2001 were identified from a large US electronic medical records database of primary care practices. Patients were required to have a baseline blood pressure (BP) ≥140/90 mmHg (≥130/80 mmHg for diabetes mellitus) and recorded BP measurements within 6 months before and 1–12 months following index date. Patients were matched 1:1:1 by propensity score to correct for differences in baseline characteristics. 1875 patients met study criteria and 660 (220 in each cohort) were matched based on propensity scores. Matched cohorts had no significant differences in baseline characteristics. Mean changes in systolic/diastolic BP were −17.5/−8.8, −15.7/−6.3, and −13.0/−8.0 mmHg with DHPs, ACE inhibitors, and ARBs, respectively. Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High BP 6/7 goal attainment for each regimen was 47.3%, 40.0%, and 32.2%, respectively. DHPs, ACE inhibitors, and ARBs improved BP when added to patients’ β-blocker or diuretic therapy. The greatest benefits were observed with DHPs, followed by ACE inhibitors, then ARBs. PMID:18078009

  16. Angiotensin II receptor blockers for the treatment of hypertension.

    PubMed

    See, S

    2001-11-01

    The rising incidence of stroke, congestive heart failure (CHF) and end stage renal disease (ESRD) has signalled a need to increase awareness, treatment and control of hypertension. There continues to be a need for effective antihypertensive medications since hypertension is a major precursor to various forms of cardiovascular disease. The renin-angiotensin (AT) aldosterone system (RAAS) is a key component to the development of hypertension and can be one target of drug therapy. Angotensin II (ATII) receptor blockers (ARBs) are the most recent class of agents available to treat hypertension, which work by by inhibiting ATII at the receptor level. Currently, national consensus guidelines recommend that ARBs should be reserved for hypertensive patients who cannot tolerate angiotensin converting enzyme (ACE) inhibitors (ACEIs). ARBs, however, are moving to the forefront of therapy with a promising role in the area of renoprotection and CHF. Recent trials such as the The Renoprotective Effect of the Angiotensin-Receptor Antagonist Irbesartan in Patients with Nephropathy Due to Type 2 Diabetes Trial (IDNT), the Effect of Irbesartan on the Development of Diabetic Nephropathy in Patients with Type 2 Diabetes (IRMA2), and The Effects of Losartan on Renal and Cardiovascular Outcomes in Patients with Type 2 Diabetes and Nephropathy (RENAAL) study have demonstrated the renoprotective effects of ARBs in patients with Type 2 diabetes. The Valsartan Heart Failure Trial (Val-HeFT) adds to the growing body of evidence that ARBs may improve morbidity and mortality in CHF patients. As a class, ARBs are well tolerated and have a lower incidence of cough and angioedema compared to ACEIs. This article reviews the differences among the ARBs, existing efficacy data in hypertension, and explores the role of ARBs in CHF and renal disease.

  17. Comparing Angiotensin II Receptor Blockers on Benefits Beyond Blood Pressure

    PubMed Central

    2016-01-01

    The renin-angiotensin-aldosterone system (RAAS) is one of the main regulators of blood pressure, renal hemodynamics, and volume homeostasis in normal physiology, and contributes to the development of renal and cardiovascular (CV) diseases. Therefore, pharmacologic blockade of RAAS constitutes an attractive strategy in preventing the progression of renal and CV diseases. This concept has been supported by clinical trials involving patients with hypertension, diabetic nephropathy, and heart failure, and those after myocardial infarction. The use of angiotensin II receptor blockers (ARBs) in clinical practice has increased over the last decade. Since their introduction in 1995, seven ARBs have been made available, with approved indications for hypertension and some with additional indications beyond blood pressure reduction. Considering that ARBs share a similar mechanism of action and exhibit similar tolerability profiles, it is assumed that a class effect exists and that they can be used interchangeably. However, pharmacologic and dosing differences exist among the various ARBs, and these differences can potentially influence their individual effectiveness. Understanding these differences has important implications when choosing an ARB for any particular condition in an individual patient, such as heart failure, stroke, and CV risk reduction (prevention of myocardial infarction). A review of the literature for existing randomized controlled trials across various ARBs clearly indicates differences within this class of agents. Ongoing clinical trials are evaluating the role of ARBs in the prevention and reduction of CV rates of morbidity and mortality in high-risk patients. PMID:20524096

  18. The effect of angiotensin II receptor blockers on hyperuricemia

    PubMed Central

    Wolff, Marissa L.; Cruz, Jennifer L.; Vanderman, Adam J.; Brown, Jamie N.

    2015-01-01

    The objective of this review was to explore the efficacy of angiotensin II receptor blockers (ARBs) for the treatment of hyperuricemia in individuals diagnosed with gout or hyperuricemia defined as ⩾7 mg/dl at baseline. A literature search of MEDLINE (1946 to June 2015) and EMBASE (1947 to June 2015) was conducted. The following search terms were used: ‘uric acid’, ‘urate transporter’, ‘gout’, ‘angiotensin II receptor blockers’, ‘hyperuricemia’ and the names for individual ARBs, as well as any combinations of these terms. Studies were excluded that did not explore fractional excretion or serum uric acid as an endpoint, if patients did not have a diagnosis of gout or hyperuricemia at baseline, or if they were non-English language. A total of eight studies met the inclusion criteria. Of the eight studies identified, six explored ARB monotherapy and two studies investigated ARBs as adjunct therapy. Losartan demonstrated statistically significant reductions in serum uric acid levels or increases in fractional excretion of uric acid in all studies, whereas no other ARB reached statistical benefit. The effect of ARBs on the occurrence of gout attacks or other clinical outcomes were not represented. Four studies evaluated safety effects of these agents indicating abnormalities such as minor changes in lab values. In conclusion, losartan is the only ARB that has consistently demonstrated a significant reduction in serum uric acid levels, although the significance of impacting clinical outcomes remains unknown. Losartan appears to be a safe and efficacious agent to lower serum uric acid levels in patients with hyperuricemia. PMID:26568810

  19. Angiotensin II receptor antagonists (AT1-blockers, ARBs, sartans): similarities and differences

    PubMed Central

    van Zwieten, P.A.

    2006-01-01

    A survey is presented of the registered non-peptidergic angiotensin II receptor antagonists (AT1 blockers, ARBs, sartans) and their general properties and similarities. Accordingly, their receptor profile, pharmacokinetic and therapeutic applications are discussed. In addition, attention is paid to the individual characteristics of the AT1 blockers now available. A few components of this category offer additional potentially beneficial properties, owing to their pharmacological or metabolic characteristics. Such additional properties are critically discussed for eprosartan, losartan, telmisartan and valsartan. PMID:25696573

  20. Receptor blockers - general aspects with respect to their use in domestic animal reproduction.

    PubMed

    Hoffmann, B; Schuler, G

    2000-07-01

    Receptor blockers compete with the respective agonist for binding to a given receptor without inducing complete signal transduction. In recent years, major interest has focused on sex-steroid hormone receptor blockers (antagonists). Indications have been obtained that inadequate changes in receptor conformation and subsequent failure of transcriptional activation are major events preventing hormonal activity. However, various subtypes and variants of receptors and receptor mutations have also been identified. Expression of antihormonal effects may vary depending on the type of receptor the blocker is bound to. Hence, receptor blockers may also have an inherent agonistic activity. Aglepristone is the first antiprogestin registered for veterinary use with the indication "interruption or prevention of pregnancy"; similarly, these types of compounds were successfully used for induction of parturition in the dog and cat and for conservative treatment of pyometra in the dog. Moreover, application of antiprogestins has clearly demonstrated the role of progesterone as a major factor controlling overt pseudopregnancy in dogs. With respect to farm animals, parturition was induced in cows without an increased incidence of retained fetal membranes. Other than antiprogestins, antioestrogens and antiandrogens are still in a more experimental phase. In particular for use in humans, high-affinity blockers binding to the oxytocin/vasopressin receptor are in development; they exert distinct tocolytic activities. Also, the release of GnRH can be inhibited by respective antagonists; however, their use in reproduction is still hampered by the high dose requirement and the side effects observed.

  1. Receptor blockers - general aspects with respect to their use in domestic animal reproduction.

    PubMed

    Hoffmann, B; Schuler, G

    2000-07-01

    Receptor blockers compete with the respective agonist for binding to a given receptor without inducing complete signal transduction. In recent years, major interest has focused on sex-steroid hormone receptor blockers (antagonists). Indications have been obtained that inadequate changes in receptor conformation and subsequent failure of transcriptional activation are major events preventing hormonal activity. However, various subtypes and variants of receptors and receptor mutations have also been identified. Expression of antihormonal effects may vary depending on the type of receptor the blocker is bound to. Hence, receptor blockers may also have an inherent agonistic activity. Aglepristone is the first antiprogestin registered for veterinary use with the indication "interruption or prevention of pregnancy"; similarly, these types of compounds were successfully used for induction of parturition in the dog and cat and for conservative treatment of pyometra in the dog. Moreover, application of antiprogestins has clearly demonstrated the role of progesterone as a major factor controlling overt pseudopregnancy in dogs. With respect to farm animals, parturition was induced in cows without an increased incidence of retained fetal membranes. Other than antiprogestins, antioestrogens and antiandrogens are still in a more experimental phase. In particular for use in humans, high-affinity blockers binding to the oxytocin/vasopressin receptor are in development; they exert distinct tocolytic activities. Also, the release of GnRH can be inhibited by respective antagonists; however, their use in reproduction is still hampered by the high dose requirement and the side effects observed. PMID:10844202

  2. Interaction between positive allosteric modulators and trapping blockers of the NMDA receptor channel

    PubMed Central

    Emnett, Christine M; Eisenman, Lawrence N; Mohan, Jayaram; Taylor, Amanda A; Doherty, James J; Paul, Steven M; Zorumski, Charles F; Mennerick, Steven

    2015-01-01

    Background and Purpose Memantine and ketamine are clinically used, open-channel blockers of NMDA receptors exhibiting remarkable pharmacodynamic similarities despite strikingly different clinical profiles. Although NMDA channel gating constitutes an important difference between memantine and ketamine, it is unclear how positive allosteric modulators (PAMs) might affect the pharmacodynamics of these NMDA blockers. Experimental Approach We used two different PAMs: SGE-201, an analogue of an endogenous oxysterol, 24S-hydroxycholesterol, along with pregnenolone sulphate (PS), to test on memantine and ketamine responses in single cells (oocytes and cultured neurons) and networks (hippocampal slices), using standard electrophysiological techniques. Key Results SGE-201 and PS had no effect on steady-state block or voltage dependence of a channel blocker. However, both PAMs increased the actions of memantine and ketamine on phasic excitatory post-synaptic currents, but neither revealed underlying pharmacodynamic differences. SGE-201 accelerated the re-equilibration of blockers during voltage jumps. SGE-201 also unmasked differences among the blockers in neuronal networks – measured either by suppression of activity in multi-electrode arrays or by neuroprotection against a mild excitotoxic insult. Either potentiating NMDA receptors while maintaining the basal activity level or increasing activity/depolarization without potentiating NMDA receptor function is sufficient to expose pharmacodynamic blocker differences in suppressing network function and in neuroprotection. Conclusions and Implications Positive modulation revealed no pharmacodynamic differences between NMDA receptor blockers at a constant voltage, but did expose differences during spontaneous network activity. Endogenous modulator tone of NMDA receptors in different brain regions may underlie differences in the effects of NMDA receptor blockers on behaviour. PMID:25377730

  3. The Relationship Between Single Nucleotide Polymorphisms in 5-HT2A Signal Transduction-Related Genes and the Response Efficacy to Selective Serotonin Reuptake Inhibitor Treatments in Chinese Patients with Major Depressive Disorder

    PubMed Central

    Li, Heng-Fen; Yu, Xue; He, Cha-Ye; Kou, Shao-Jie; Cao, Su-Xia

    2012-01-01

    Objective: To explore the possible relationship between six single nucleotide polymorphisms (SNPs) (rs6311 and rs6305 of 5-HT2A, rs5443 of Gβ3, rs2230739 of ACDY9, rs1549870 of PDE1A and rs255163 of CREB1, which are all related with 5-HT2A the signal transduction pathway) and the response efficacy to selective serotonin reuptake inhibitor (SSRI) treatments in major depressive disorder (MDD) Chinese. Methods: This study included 194 depressed patients to investigate the influence of 6 polymorphisms in 5-HT2A signal transduction-related genes on the efficacy of SSRIs assessed over 1 year. The efficacies of SSRIs on 194 MDD patients were evaluated in an 8-week open-trial study. Over 1 year, a follow-up study was completed for 174 of them to observe the long-term efficacy of SSRIs. The optimal-scaling regression analysis was used for testing the relationship between the different genotypes of five SNPs and the efficacy in MDD. Results: It showed that the patients with rs5443TT and rs2230739GG have a relatively good efficacy in response to short-term SSRIs. We also found that good efficacy appeared in depressed patients with rs2230739GG in response to long-term SSRIs. Conclusions: It suggested that different genotypes of rs5443 and rs2230739 might influence the signal transduction pathways of second message and affect therapeutic efficacy. PMID:22480177

  4. BR 04-3 DEVELOPMENT OF NEW ANGIOTENSIN RECEPTOR BLOCKER.

    PubMed

    Choe, Seong-Choon

    2016-09-01

    There are several classes of anti-hypertensive agents in the world, the most recently developed agent is angiotensin receptor blocker (ARB). There are already 8 ARBs in the market, but still medical unmet need for treatment of hypertension is existed. The 'ideal' anti-hypertensive agent would have a number of characteristics: (1) effective in lowering blood pressure to recommend goals; (2) high efficacy as monotherapy; (3) rapid onset of effect; (4) convenient once-daily administration to maximize compliance; (5) sustained efficacy over 24 hours; (6) response increases with higher doses (clear dose-response effect); and (7) optimum tolerability profile. ARB is nearly closed to this kind of 'ideal' anti-hypertensive agent, but there are some issues to be resolved in order to meet current medical need. These are (1) BP lowering is not satisfactory all around the world; (2) adverse effects of anti-hypertensive agents are hurdles to be relieved; (3) sometimes 24 hour coverage is not demonstrated for optimal blood pressure control; (4) monotherapy is not usually enough; (5) safety issues may interfere the use of optimal anti-hypertensive agents; (6) combination may be helpful, but may not be helpful, even harmful to the patients.Fimasartan was developed by Korean pharmaceutical company, starting from 1999, and got market authorization right in 2010 from Korea. The compound fimasartan was developed via full clinical development pathway from first-in-human phase 1 trial in UK and subsequent phase 1 trials, proof of concept phase 2 trial, dose finding phase 2 trial and confirmatory phase 3 trial in Korea. Recently for the global clinical trial, phase 3 trials of fimasartan were executed in Mexico and Russia, will be followed in China very soon. Also the patient's convenience, the combo products of fimasartan including hydrochlorothiazide, amlodipine and rosuvastatin were developed via relevant clinical development programs.For the life cycle management, other combo

  5. Electron density topography based model to explore N-methyl-D-aspartate receptor channel blockers

    NASA Astrophysics Data System (ADS)

    Ingle, Snehal V.; Joshi, Kaustubh A.

    2016-03-01

    The dwell time of a molecule in a voltage dependent NMDA receptor channel is an important factor in defining its activity as channel blocker. A model has been designed, based on quantum chemical descriptors like geometrical parameters, charge distribution, electron density topography and global reactivity descriptors, to shed lights on the dwell time of a channel blocker. Structure and charge distribution studies indicate polarization of molecules with the electron density located at the core of the molecule. Electron density topography reveals ring critical point (ρrcp), emerging as a signature parameter to understand the dwell time of a channel blocker molecule.

  6. Angiotensin type 2 receptor actions contribute to angiotensin type 1 receptor blocker effects on kidney fibrosis

    PubMed Central

    Naito, Takashi; Ma, Li-Jun; Yang, Haichun; Zuo, Yiqin; Tang, Yiwei; Han, Jee Young; Kon, Valentina

    2010-01-01

    Angiotensin type 1 (AT1) receptor blocker (ARB) ameliorates progression of chronic kidney disease. Whether this protection is due solely to blockade of AT1, or whether diversion of angiotensin II from the AT1 to the available AT2 receptor, thus potentially enhancing AT2 receptor effects, is not known. We therefore investigated the role of AT2 receptor in ARB-induced treatment effects in chronic kidney disease. Adult rats underwent 5/6 nephrectomy. Glomerulosclerosis was assessed by renal biopsy 8 wk later, and rats were divided into four groups with equivalent glomerulosclerosis: no further treatment, ARB, AT2 receptor antagonist, or combination. By week 12 after nephrectomy, systolic blood pressure was decreased in all treatment groups, but proteinuria was decreased only with ARB. Glomerulosclerosis increased significantly in AT2 receptor antagonist vs. ARB. Kidney cortical collagen content was decreased in ARB, but increased in untreated 5/6 nephrectomy, AT2 receptor antagonist, and combined groups. Glomerular cell proliferation increased in both untreated 5/6 nephrectomy and AT2 receptor antagonist vs. ARB, and phospho-Erk2 was increased by AT2 receptor antagonist. Plasminogen activator inhibitor-1 mRNA and protein were increased at 12 wk by AT2 receptor antagonist in contrast to decrease with ARB. Podocyte injury is a key component of glomerulosclerosis. We therefore assessed effects of AT1 vs. AT2 blockade on podocytes and interaction with plasminogen activator inhibitor-1. Cultured wild-type podocytes, but not plasminogen activator inhibitor-1 knockout, responded to angiotensin II with increased collagen, an effect that was completely blocked by ARB with lesser effect of AT2 receptor antagonist. We conclude that the benefical effects on glomerular injury achieved with ARB are contributed to not only by blockade of the AT1 receptor, but also by increasing angiotensin effects transduced through the AT2 receptor. PMID:20042458

  7. Is there any difference between angiotensin converting enzyme inhibitors and angiotensin receptor blockers for heart failure?

    PubMed

    Rain, Carmen; Rada, Gabriel

    2015-07-06

    Angiotensin receptor blockers are usually considered as equivalent to angiotensin converting enzyme inhibitors for patients with heart failure and low-ejection fraction. Some guidelines even recommend the former as first line treatment given their better adverse effects profile. Searching in Epistemonikos database, which is maintained by screening 30 databases, we identified four systematic reviews including eight pertinent randomized controlled trials. We combined the evidence using meta-analysis and generated a summary of findings following the GRADE approach. We concluded angiotensin receptor blockers and angiotensin converting enzyme inhibitors probably have a similar effect on mortality, and they might be equivalent in reducing hospitalization risk too. Treatment withdrawal due to adverse effects is probably lower with angiotensin receptor blockers than with angiotensin converting enzyme inhibitors.

  8. Calcium Channel Blockers, More than Diuretics, Enhance Vascular Protective Effects of Angiotensin Receptor Blockers in Salt-Loaded Hypertensive Rats

    PubMed Central

    Yamamoto, Eiichiro; Kataoka, Keiichiro; Dong, Yi-Fei; Koibuchi, Nobutaka; Toyama, Kensuke; Sueta, Daisuke; Katayama, Tetsuji; Yasuda, Osamu; Ogawa, Hisao; Kim-Mitsuyama, Shokei

    2012-01-01

    The combination therapy of an angiotensin receptor blocker (ARB) with a calcium channel blocker (CCB) or with a diuretic is favorably recommended for the treatment of hypertension. However, the difference between these two combination therapies is unclear. The present work was undertaken to examine the possible difference between the two combination therapies in vascular protection. Salt-loaded stroke-prone spontaneously hypertensive rats (SHRSP) were divided into 6 groups, and they were orally administered (1) vehicle, (2) olmesartan, an ARB, (3) azelnidipine, a CCB, (4) hydrochlorothiazide, a diuretic, (5) olmesartan combined with azelnidipine, or (6) olmesartan combined with hydrochlorothiazide. Olmesartan combined with either azelnidipine or hydrochlorothiazide ameliorated vascular endothelial dysfunction and remodeling in SHRSP more than did monotherapy with either agent. However, despite a comparable blood pressure lowering effect between the two treatments, azelnidipine enhanced the amelioration of vascular endothelial dysfunction and remodeling by olmesartan to a greater extent than did hydrochlorothiazide in salt-loaded SHRSP. The increased enhancement by azelnidipine of olmesartan-induced vascular protection than by hydrochlorothiazide was associated with a greater amelioration of vascular nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation, superoxide, mitogen-activated protein kinase activation, and with a greater activation of the Akt/endothelial nitric oxide synthase (eNOS) pathway. These results provided the first evidence that a CCB potentiates the vascular protective effects of an ARB in salt-sensitive hypertension, compared with a diuretic, and provided a novel rationale explaining the benefit of the combination therapy with an ARB and a CCB. PMID:22720058

  9. [The action of ionotropic glutamate receptor channel blockers on effects of sleep deprivation in rats].

    PubMed

    Vataev, S I; Oganesian, G A; Lukomskaia, N Ia; Magazanik, L G

    2013-05-01

    The action of non-competitive glutamate receptor antagonists on the effects of sleep deprivation has been studied on Krushinskii-Molodkina rats having an inherited predisposition to audiogenic seizures and Wistar rats deprived to this respond. Two types of glutamate receptor open channels blockers were used: the selective blockers of NMDA-receptors (memantine and IEM-1921) and blockers of mixed type, impacting both on the NMDA- and presumably Ca(2+)-permeable AMPA/kainate receptors (IEM-1754 and IEM 1925). Rats were subjected to 12 hours long sleep deprivation. Immediatly after that memantine and IEM-1921 were injected, and during the first 3 hours the total or partial reduction of fast-wave (paradoxical) sleep and a significant increase of the representation of wakefulness at the cost of reducing the total time of slow-wave sleep were observed. These effects are most likely to be a consequence of the blockade of NMDA-receptors functioning in the systems of the rat brain responsible for the launch and maintenance of fast-wave sleep. Injection of IEM-1754 and IEM-1925 on background of sleep deprivation did not affect the organization of sleep during the first 3 hours of their action. During the second three-hour period the rebound effect was observed. The obtained results indicate the involvement of NMDA glutamate receptors in the functioning of various parts of the sleep system of both rat lines.

  10. [Effects of ionotropic glutamate receptor channel blockers ON sleep-waking organization in rats].

    PubMed

    Vataev, S I; Oganesian, G A; Gmiro, V E; Lukomskaia, N Ia; Magazanik, L G

    2012-07-01

    The effects of non-competitive glutamate receptor antagonists on sleep-waking organization have been studied on Krushinskii-Molodkina rats having an inherited predisposition to audiogenic seizures and Wistar ones which are resistant to this action of sound. Two types of blockers of glutamate receptor open channels were used: selective blockers of NMDA receptors (memantine and IEM-1921) and blockers of mixed type, impacting both on the NMDA and Ca-permeable AMPA/ kainate receptors (IEM-1754 and IEM 1925). During the first 3 hours after administration of these glutamate antagonists the total or partial deprivation of fast-wave sleep was provoked. Additionally the selective NMDA receptor blocking drugs (memantine, IEM-1921) induced in the same period a significant increase of the representation of wakefulness at the cost of reducing of the total time of slow-wave sleep. These effects are most likely to be a consequence of the blockade of NMDA receptors responsible for the launch and maintenance of wakefulness, slow- and fast-wave sleep. In the same first 3 hours period after the administration of IEM-1754 and IEM-1925 the organization of sleep was not significantly affected. The evident reduction of wakefulness, total duration and increase of slow-wave sleep impact was observed, during the second three-hour period. It, apparently, can be caused by the blockade of AMPA/kainate receptors. The obtained results indicate the involvement of NMDA and AMPA/kainate receptors in the functioning of various parts of the sleep system of rats belonging to both lines.

  11. Treating the Host Response to Ebola Virus Disease with Generic Statins and Angiotensin Receptor Blockers.

    PubMed

    Fedson, David S; Jacobson, Jeffrey R; Rordam, Ole Martin; Opal, Steven M

    2015-06-23

    Treatments targeting the Ebola virus may eventually be shown to work, but they will not have an impact on overall Ebola mortality in West Africa. Endothelial dysfunction is responsible for the fluid and electrolyte imbalances seen in Ebola patients. Because inexpensive generic statins and angiotensin receptor blockers restore endothelial barrier integrity, they can be used to treat the host response in these patients. In Sierra Leone, approximately 100 Ebola patients were treated with this combination, and reports indicate that survival was greatly improved.

  12. [Assessment of the utilization of angiotensin receptor blockers in hypertension].

    PubMed

    Peña Cabia, S; Ricote Lobera, I; Santos Mena, B; Hidalgo Correas, F J; Climent Florez, B; García Díaz, B

    2013-01-01

    Objetivo: Evaluar en nuestra área de Salud el grado en que la utilización de antagonistas de los receptores de la angiotensina II (ARA-II) se ajusta a los criterios propuestos por la Comunidad Autónoma de Madrid (CAM) antes de la instauración del «Plan de Actuación de ARA-II». Estudiar las indicaciones para las que se prescriben e identificar aquellos factores que han podido influir en su prescripción. Métodos: Estudio de utilización de medicamentos del tipo indicación- prescripción, descriptivo y transversal, en el que se seleccionaron pacientes con hipertensión arterial y en tratamiento con ARA-II ingresados en un Hospital General Universitario durante un periodo de estudio de 3 meses. De acuerdo con las situaciones clínicas recogidas en el Documento de la CAM «Criterios para establecer el lugar en la terapéutica de los antagonistas de los receptores de la angiotensina II», se calculó el porcentaje de pacientes con «prescripción adecuada» y «prescripción no adecuada» de ARA-II y se analizó si la edad y el sexo tenían influencia en el tipo de prescripción o en las principales indicaciones para las que se prescribieron. Resultados: De los 153 pacientes que se incluyeron en el estudio, el 67,3% tuvieron una «prescripción no adecuada», el 47,6% de ellos por prescripción de ARA-II como primer fármaco antagonista del sistema renina angiotensina aldosterona y el 34,0% por mal control de la tensión arterial con inhibidores de la enzima convertidora de angiotensina (IECA). No se encontraron diferencias estadísticamente significativas por edad o sexo en cuanto al tipo de prescripción o en las principales indicaciones para las que se prescribieron. Conclusiones: La adecuación a los criterios de uso del Documento de ARA-II se produjo en el 32,7% de los casos. Además, no se observó que factores como la edad y el sexo influyeran en el tipo de prescripción. Asimismo, se evidenciaron percep-

  13. Differential influence of 7 cations on 16 non-competitive NMDA receptor blockers.

    PubMed

    Berger, Michael L; Rebernik, Patrick

    2015-10-01

    The specific binding of the NMDA receptor (NR) channel ligand [(3)H]MK-801 to rat brain membranes is sensitive to positively charged buffer ingredients as to tris(hydroxymethyl)aminomethane (Tris), to Na(+), or to protons. Here we demonstrate that 16 non-competitive NR antagonists, including 5 long-chain diamines, classical NR channel blockers and several less known compounds, differ widely in their sensitivities to cationic buffer constituents. Although chemically distinguished either as extended di-cationic or as compact mono-cationic, their sensitivities to cationic buffer ingredients did not suggest this grouping. While the di-cationic compounds are known for their sensitivity to spermine (polyamine inverse agonists), also some of the mono-cationic blockers exhibited this feature. They might share as common target a recently described negatively charged extracellular GluN1/GluN2B interface.

  14. Ca sup 2+ channel blockers interact with. alpha. sub 2 -adrenergic receptors in rabbit ileum

    SciTech Connect

    Homaidan, F.R.; Donowitz, M.; Wicks, J.; Cusolito, S.; El Sabban, M.E.; Weiland, G.A.; Sharp, G.W.G. Tufts Univ. School of Medicine and New England Medical Center Hospital, Boston, MA )

    1988-04-01

    An interaction between Ca{sup 2+} channel blockers and {alpha}{sub 2}-adrenergic receptors has been demonstrated in rabbit ileum by studying the effect of clonidine on active electrolyte transport, under short-circuited conditions, in the presence and absence of several Ca{sup 2+} channel blocking agents. Clonidine, verapamil, diltiazem, cadmium, and nitrendipine all decrease short-circuit current and stimulate NaCl absorption to different extents with clonidine having the largest effect. Exposure to verapamil, diltiazem, and cadmium inhibited the effects of clonidine on transport, whereas nitrendipine had no such effect. Verapamil, diltiazem, and cadmium, but not nitrendipine, also decreased the specific binding of ({sup 3}H){alpha}{sub 2}-adrenergic agents to a preparation of ileal basolateral membranes explaining the observed decrease in the transport effects of clonidine. The effective concentrations of the Ca{sup 2+} channel blockers that inhibited the effects of clonidine on transport were fairly similar to the concentrations needed to inhibit its specific binding. The displacement of clonidine by calcium channel blockers is ascribed to a nonspecific effect of these agents, although the possibility that their effects are exerted via their binding to the calcium channels is not excluded.

  15. beta-adrenergic receptor gene polymorphisms and beta-blocker treatment outcomes in hypertension.

    PubMed

    Pacanowski, M A; Gong, Y; Cooper-Dehoff, R M; Schork, N J; Shriver, M D; Langaee, T Y; Pepine, C J; Johnson, J A

    2008-12-01

    Numerous studies have demonstrated that beta(1)- and beta(2)-adrenergic receptor gene (ADRB1 and ADRB2) variants influence cardiovascular risk and beta-blocker responses in hypertension and heart failure. We evaluated the relationship between ADRB1 and ADRB2 haplotypes, cardiovascular risk (death, nonfatal myocardial infarction (MI), and nonfatal stroke), and atenolol-based vs. verapamil sustained-release (SR)-based antihypertensive therapy in 5,895 coronary artery disease (CAD) patients. After an average of 2.8 years, death rates were higher in patients carrying the ADRB1 Ser49-Arg389 haplotype (hazard ratio (HR) 3.66, 95% confidence interval (95% CI) 1.68-7.99). This mortality risk was significant in patients randomly assigned to verapamil SR (HR 8.58, 95% CI 2.06-35.8) but not atenolol (HR 2.31, 95% CI 0.82-6.55), suggesting a protective role for the beta-blocker. ADRB2 haplotype associations were divergent within the treatment groups but did not remain significant after adjustment for multiple comparisons. ADRB1 haplotype variation is associated with mortality risk, and beta-blockers may be preferred in subgroups of patients defined by ADRB1 or ADRB2 polymorphisms.

  16. Brain structures implicated in the four-plate test in naïve and experienced Swiss mice using injection of diazepam and the 5-HT2A agonist DOI.

    PubMed

    Petit-Demoulière, Benoit; Massé, Fabienne; Cogrel, Nicolas; Hascoët, Martine; Bourin, Michel

    2009-12-01

    Four-plate test-retest (FPT-R) is a useful tool to study aversive memory and abolishment of benzodiazepine effects in experienced mice to four-plate test (FPT), namely one-trial tolerance. In the present study, we have used local injections paradigm, in order to localize structures implied in anxiolytic-like effects of two drugs in naïve and experienced mice: a benzodiazepine, diazepam that is only active in naïve mice; and a 5-HT(2A/2C) agonist, DOI that exert its anxiolytic-like effect both in naïve and experienced mice. Periacqueductal grey substance, three sub-regions of hippocampus (CA1, CA2 and CA3) and two nuclei of amygdala (BLA and LA) have been studied. Local injections did not cause any modifications of ambulatory activity. DOI injections elicit anxiolytic-like effects only when injected into CA2, in naïve and experienced mice. Diazepam had an anxiolytic-like effect in naïve mice, only when injected into lateral nucleus of amygdala; and in experienced mice when injected into PAG. These results help us to better understand the way of action of these two compounds and the structures functionally involved in their effects and in one-trial tolerance (OTT).

  17. Treating the Host Response to Ebola Virus Disease with Generic Statins and Angiotensin Receptor Blockers

    PubMed Central

    Jacobson, Jeffrey R.; Rordam, Ole Martin; Opal, Steven M.

    2015-01-01

    ABSTRACT Treatments targeting the Ebola virus may eventually be shown to work, but they will not have an impact on overall Ebola mortality in West Africa. Endothelial dysfunction is responsible for the fluid and electrolyte imbalances seen in Ebola patients. Because inexpensive generic statins and angiotensin receptor blockers restore endothelial barrier integrity, they can be used to treat the host response in these patients. In Sierra Leone, approximately 100 Ebola patients were treated with this combination, and reports indicate that survival was greatly improved. PMID:26106080

  18. The angiotensin II type 1 receptor blocker candesartan suppresses proliferation and fibrosis in gastric cancer.

    PubMed

    Okazaki, Mitsuyoshi; Fushida, Sachio; Harada, Shinichi; Tsukada, Tomoya; Kinoshita, Jun; Oyama, Katsunobu; Tajima, Hidehiro; Ninomiya, Itasu; Fujimura, Takashi; Ohta, Tetsuo

    2014-12-01

    Gastric cancer with peritoneal dissemination has poor clinical prognosis because of the presence of rich stromal fibrosis and acquired drug resistance. Recently, Angiotensin II type I receptor blockers such as candesartan have attracted attention for their potential anti-fibrotic activity. We examined whether candesartan could attenuate tumor proliferation and fibrosis through the interaction between gastric cancer cell line (MKN45) cells and human peritoneal mesothelial cells. Candesartan significantly reduced TGF-β1 expression and epithelial-to-mesenchymal transition-like change, while tumor proliferation and stromal fibrosis were impaired. Targeting the Angiotensin II signaling pathway may therefore be an efficient strategy for treatment of tumor proliferation and fibrosis. PMID:25224569

  19. 5-Hydroxytryptamine 2A receptor signaling cascade modulates adiponectin and plasminogen activator inhibitor 1 expression in adipose tissue.

    PubMed

    Uchida-Kitajima, Shoko; Yamauchi, Toshimasa; Takashina, Youko; Okada-Iwabu, Miki; Iwabu, Masato; Ueki, Kohjiro; Kadowaki, Takashi

    2008-09-01

    Knowledge of the regulatory factors associated with down-regulation of adiponectin gene expression and up-regulation of PAI-1 gene expression is crucial to understand the pathophysiological basis of obesity and metabolic diseases, and could establish new treatment strategies for these conditions. We showed that expression of 5-HT(2A) receptors was up-regulated in hypertrophic 3T3-L1 adipocytes, which exhibited decreased expression of adiponectin and increased expression of PAI-1. 5-HT(2A) receptor antagonists and suppression of 5-HT(2A) receptor gene expression enhanced adiponectin expression. Activation of Gq negatively regulated adiponectin expression, and inhibition of mitogen-activated protein kinase reversed the Gq-induced effect. Moreover, the 5-HT(2A) receptor blockade reduced PAI-1 expression. These findings indicate that antagonism of 5-HT(2A) receptors in adipocytes could improve the obesity-linked decreases in adiponectin expression and increases in PAI-1 expression.

  20. Probing of β-adrenergic receptors by novel fluorescent β-adrenergic blockers

    PubMed Central

    Atlas, Daphne; Levitzki, Alexander

    1977-01-01

    The synthesis of two high-affinity fluorescent β-adrenergic blockers is described: dl-N1-[2-hydroxy-3-(1-naphthyloxy)propyl]-N2-(9-acridyl)-1,2-propanediamine (9-aminoacridylpropanolol, 9-AAP) and dl-N-[2-hydroxy-3-(1-naphthyloxy)propyl]-N′-dansylethylenediamine (dansyl analogue of propranolol, DAPN). Both 9-AAP and DAPN inhibit competitively the l-epinephrine-dependent adenylate cyclase activity [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1] in turkey erythrocyte membranes without affecting the fluoride-stimulated adenylate cyclase activity. Similarly, 9-AAP and DAPN inhibit in a competitive manner the binding of [125I]-iodohydroxybenzylpindolol to these β-adrenergic receptors. The two fluorescent β-adrenergic blockers 9-AAP and DAPN probe specifically β-adrenergic receptors in the central nervous system as well as in other organs when injected into rats. The fluorescence pattern can be monitored by fluorescence microscopy performed on cryostat slices of these organs. The appearance of the characteristic fluorescence pattern can be blocked in a stereospecific fashion by a prior injection of l-propranolol and not by a prior injection of d-propranolol. These compounds therefore offer a powerful means to map β-adrenergic receptors in vivo. The stereospecific displacement of 9-AAP from the β-adrenergic receptors of turkey erythrocyte membranes by l-propranolol and by l-epinephrine can be detected in vitro using front-face fluorescence. The potential use of these compounds to probe β-receptors in vitro and in vivo is discussed. Images PMID:23531

  1. Angiotensin II Receptor Blockers Improve Peripheral Endothelial Function: A Meta-Analysis of Randomized Controlled Trials

    PubMed Central

    Li, Shuang; Wu, Yan; Yu, Ge; Xia, Qing; Xu, Yawei

    2014-01-01

    Objective(s) Several studies have assessed the effect of angiotensin II receptor blockers (ARBs) on peripheral endothelial dysfunction as measured by flow-mediated vasodilatation (FMD), a widely-used indicator for endothelial function. We conducted a meta-analysis to investigate the effect in comparison to placebo or no treatment and other antihypertensives. Methods MEDLINE, Cochrane library and EMBASE were searched to September 2013 for randomized controlled trials (RCTs) that assessed the effect of ARBs versus placebo or no treatment and other antihypertensives (angiotensin-converting enzyme inhibitors (ACEIs), calcium channel blockers (CCBs), β-blockers, diuretics) by forearm FMD. Furthermore, we also use meta-regression to analyze the relationship between the endothelial function and the duration of ARBs treatments. Results In 11 trials including 590 patients, ARBs (n = 315) significantly improved FMD (1.36%, 95% confidence internal [CI]:1.28 to 1.44) versus placebo or no treatment (n = 275). In 16 trials that included 1028 patients, ARBs (n = 486) had a significant effect (0.59%, 95% CI: 0.25 to 0.94) on FMD when compared with other antihypertensives (n = 542). In 8 trials, ARBs (n = 174) had no significant effect (−0.14%, 95% CI: −0.32 to 0.03) compared with ACEI (n = 173). Compared with others, the benefits of ARBs, respectively, were 1.67% (95% CI: 0.65 to 0.93) in 7 trials with CCBs, 0.79% (95% CI: 0.42 to 1.01) with β-blockers in 3 trials and 0.9% (95% CI: 0.77 to 1.03) with diuretics in 3 trials. Importantly, we found ARBs were less effective in a long time span (95% CI: −1.990 to −0.622) than the first 6 months (95% CI: −0.484 to 0.360). Conclusions This study shows that ARBs improve peripheral endothelial function and are superior to CCBs, β-blockers and diuretics. However, the effect couldn't be maintained for a long time. In addition, there was no significant difference between ARBs and ACEI. PMID:24595033

  2. The antidepressant effects of curcumin in the forced swimming test involve 5-HT1 and 5-HT2 receptors.

    PubMed

    Wang, Rui; Xu, Ying; Wu, Hong-Li; Li, Ying-Bo; Li, Yu-Hua; Guo, Jia-Bin; Li, Xue-Jun

    2008-01-01

    Curcuma longa is a main constituent of many traditional Chinese medicines, such as Xiaoyao-san, used to manage mental disorders effectively. Curcumin is a major active component of C. longa and its antidepressant-like effect has been previously demonstrated in the forced swimming test. The purpose of this study was to explore the possible contribution of serotonin (5-HT) receptors in the behavioral effects induced by curcumin in this animal model of depression. 5-HT was depleted by the tryptophan hydroxylase inhibitor p-chlorophenylalanine (PCPA, 100 mg/kg, i.p.) prior to the administration of curcumin, and the consequent results showed that PCPA blocked the anti-immobility effect of curcumin in forced swimming test, suggesting the involvement of the serotonergic system. Moreover, pre-treatment of pindolol (10 mg/kg, i.p., a beta-adrenoceptors blocker/5-HT(1A/1B) receptor antagonist), 4-(2'-methoxy-phenyl)-1-[2'-(n-2''-pyridinyl)-p-iodobenzamino-]ethyl-piperazine (p-MPPI, 1 mg/kg, s.c., a selective 5-HT(1A) receptor antagonist), or 1-(2-(1-pyrrolyl)-phenoxy)-3-isopropylamino-2-propanol (isamoltane, 2.5 mg/kg, i.p., a 5-HT(1B) receptor antagonist) was found to prevent the effect of curcumin (10 mg/kg) in forced swimming test. On the other hand, a sub-effective dose of curcumin (2.5 mg/kg, p.o.) produced a synergistic effect when given jointly with (+)-8-hydroxy-2-(di-n-propylamino)tetralin, (8-OH-DPAT, 1 mg/kg, i.p., a 5-HT(1A) receptor agonist), anpirtoline (0.25 mg/kg, i.p., a 5-HT(1B) receptor agonist) or ritanserin (4 mg/kg, i.p., a 5-HT(2A/2C) receptor antagonist), but not with ketanserin (5 mg/kg, i.p., a 5-HT(2A/2C) receptor antagonist with higher affinity to 5-HT(2A) receptor) or R(-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI, 1 mg/kg, i.p., a 5-HT(2A) receptor agonist). Taken together, these results indicate that the antidepressant-like effect of curcumin in the forced swimming test is related to serotonergic system and may be mediated by, at least

  3. In silico analysis of the binding of agonists and blockers to the β2-adrenergic receptor

    PubMed Central

    Vilar, Santiago; Karpiak, Joel; Berk, Barkin; Costanzi, Stefano

    2011-01-01

    Activation of G protein-coupled receptors (GPCRs) is a complex phenomenon. Here, we applied Induced Fit docking (IFD) in tandem with linear discriminant analysis (LDA) to generate hypotheses on the conformational changes induced to the β2-adrenergic receptor by agonist binding, preliminary to the sequence of events that characterize activation of the receptor. This analysis, corroborated by a follow-up molecular dynamics study, suggested that agonists induce subtle movements to the fifth transmembrane domain (TM5) of the receptor. Furthermore, molecular dynamics also highlighted a correlation between movements of TM5 and the second extracellular loop (EL2), suggesting that freedom of motion of EL2 is required for the agonist-induced TM5 displacement. Importantly, we also showed that the IFD/LDA procedure can be used as a computational means to distinguish agonists from blockers on the basis of the differential conformational changes induced to the receptor. In particular, the two most predictive models obtained are based on the RMSD induced to Ser207 and on the counterclockwise rotation induced to TM5. PMID:21334234

  4. Amino Acid Derivatives as Bitter Taste Receptor (T2R) Blockers*

    PubMed Central

    Pydi, Sai P.; Sobotkiewicz, Tyler; Billakanti, Rohini; Bhullar, Rajinder P.; Loewen, Michele C.; Chelikani, Prashen

    2014-01-01

    In humans, the 25 bitter taste receptors (T2Rs) are activated by hundreds of structurally diverse bitter compounds. However, only five antagonists or bitter blockers are known. In this study, using molecular modeling guided site-directed mutagenesis, we elucidated the ligand-binding pocket of T2R4. We found seven amino acids located in the extracellular side of transmembrane 3 (TM3), TM4, extracellular loop 2 (ECL2), and ECL3 to be involved in T2R4 binding to its agonist quinine. ECL2 residues Asn-173 and Thr-174 are essential for quinine binding. Guided by a molecular model of T2R4, a number of amino acid derivatives were screened for their ability to bind to T2R4. These predictions were tested by calcium imaging assays that led to identification of γ-aminobutryic acid (GABA) and Nα,Nα-bis(carboxymethyl)-l-lysine (BCML) as competitive inhibitors of quinine-activated T2R4 with an IC50 of 3.2 ± 0.3 μm and 59 ± 18 nm, respectively. Interestingly, pharmacological characterization using a constitutively active mutant of T2R4 reveals that GABA acts as an antagonist, whereas BCML acts as an inverse agonist on T2R4. Site-directed mutagenesis confirms that the two novel bitter blockers share the same orthosteric site as the agonist quinine. The signature residues Ala-90 and Lys-270 play important roles in interacting with BCML and GABA, respectively. This is the first report to characterize a T2R endogenous antagonist and an inverse agonist. The novel bitter blockers will facilitate physiological studies focused on understanding the roles of T2Rs in extraoral tissues. PMID:25059668

  5. Angiotensin II AT1 receptor blockers as treatments for inflammatory brain disorders

    PubMed Central

    SAAVEDRA, Juan M.

    2012-01-01

    The effects of brain AngII (angiotensin II) depend on AT1 receptor (AngII type 1 receptor) stimulation and include regulation of cerebrovascular flow, autonomic and hormonal systems, stress, innate immune response and behaviour. Excessive brain AT1 receptor activity associates with hypertension and heart failure, brain ischaemia, abnormal stress responses, blood–brain barrier breakdown and inflammation. These are risk factors leading to neuronal injury, the incidence and progression of neurodegerative, mood and traumatic brain disorders, and cognitive decline. In rodents, ARBs (AT1 receptor blockers) ameliorate stress-induced disorders, anxiety and depression, protect cerebral blood flow during stroke, decrease brain inflammation and amyloid-β neurotoxicity and reduce traumatic brain injury. Direct anti-inflammatory protective effects, demonstrated in cultured microglia, cerebrovascular endothelial cells, neurons and human circulating monocytes, may result not only in AT1 receptor blockade, but also from PPARγ (peroxisome-proliferator-activated receptor γ) stimulation. Controlled clinical studies indicate that ARBs protect cognition after stroke and during aging, and cohort analyses reveal that these compounds significantly reduce the incidence and progression of Alzheimer’s disease. ARBs are commonly used for the therapy of hypertension, diabetes and stroke, but have not been studied in the context of neurodegenerative, mood or traumatic brain disorders, conditions lacking effective therapy. These compounds are well-tolerated pleiotropic neuroprotective agents with additional beneficial cardiovascular and metabolic profiles, and their use in central nervous system disorders offers a novel therapeutic approach of immediate translational value. ARBs should be tested for the prevention and therapy of neurodegenerative disorders, in particular Alzheimer’s disease, affective disorders, such as co-morbid cardiovascular disease and depression, and traumatic

  6. Rationale for triple fixed-dose combination therapy with an angiotensin II receptor blocker, a calcium channel blocker, and a thiazide diuretic

    PubMed Central

    Volpe, Massimo; Tocci, Giuliano

    2012-01-01

    Hypertension is a growing global health problem, and is predicted to affect 1.56 billion people by 2025. Treatment remains suboptimal, with control of blood pressure achieved in only 20%–35% of patients, and the majority requiring two or more antihypertensive drugs to achieve recommended blood pressure goals. To improve blood pressure control, the European hypertension guidelines recommend that angiotensin II receptor blockers (ARBs) or angiotensin-converting enzyme inhibitors (ACEIs) are combined with calcium channel blockers (CCBs) and/or thiazide diuretics. The rationale for this strategy is based, in part, on their different effects on the renin-angiotensin system, which improves antihypertensive efficacy. Data from a large number of trials support the efficacy of ACEIs or ARBs in combination with CCBs and/or hydrochlorothiazide (HCTZ). Combining two different classes of antihypertensive drugs has an additive effect on lowering of blood pressure, and does not increase adverse events, with the ARBs showing a tolerability advantage over the ACEIs. Among the different ARBs, olmesartan medoxomil is available as a dual fixed-dose combination with either amlodipine or HCTZ, and the increased blood pressure-lowering efficacy of these two combinations is proven. Triple therapy is required in 15%–20% of treated uncontrolled hypertensive patients, with a renin-angiotensin system blocker, CCB, and thiazide diuretic considered to be a rational combination according to the European guidelines. Olmesartan, amlodipine, and HCTZ are available as a triple fixed-dose combination, and significant blood pressure reductions have been observed with this regimen compared with the possible dual combinations. The availability of these fixed-dose combinations should lead to improvement in blood pressure control and aid compliance with long-term therapy, optimizing the management of this chronic condition. PMID:22745561

  7. Otilonium: a potent blocker of neuronal nicotinic ACh receptors in bovine chromaffin cells.

    PubMed Central

    Gandía, L.; Villarroya, M.; Lara, B.; Olmos, V.; Gilabert, J. A.; López, M. G.; Martínez-Sierra, R.; Borges, R.; García, A. G.

    1996-01-01

    1. Otilonium, a clinically useful spasmolytic, behaves as a potent blocker of neuronal nicotinic acetylcholine receptors (AChR) as well as a mild wide-spectrum Ca2+ channel blocker in bovine adrenal chromaffin cells. 2. 45Ca2+ uptake into chromaffin cells stimulated with high K+ (70 mM, 1 min) was blocked by otilonium with an IC50 of 7.6 microM. The drug inhibited the 45Ca2+ uptake stimulated by the nicotinic AChR agonist, dimethylphenylpiperazinium (DMPP) with a 79 fold higher potency (IC50 = 0.096 microM). 3. Whole-cell Ba2+ currents (IBa) through Ca2+ channels of voltage-clamped chromaffin cells were blocked by otilonium with an IC50 of 6.4 microM, very close to that of K(+)-evoked 45Ca2+ uptake. Blockade developed in 10-20 s, almost as a single step and was rapidly and almost fully reversible. 4. Whole-cell nicotinic AChR-mediated currents (250 ms pulses of 100 microM DMPP) applied at 30 s intervals were blocked by otilonium in a concentration-dependent manner, showing an IC50 of 0.36 microM. Blockade was induced in a step-wise manner. Wash out of otilonium allowed a slow recovery of the current, also in discrete steps. 5. In experiments with recordings in the same cells of whole-cell IDMPP, Na+ currents (INa) and Ca2+ currents (ICa), 1 microM otilonium blocked 87% IDMPP, 7% INa and 13% ICa. 6. Otilonium inhibited the K(+)-evoked catecholamine secretory response of superfused bovine chromaffin cells with an IC50 of 10 microM, very close to the IC50 for blockade of K(+)-induced 45Ca2+ uptake and IBa. 7. Otilonium inhibited the secretory responses induced by 10 s pulses of 50 microM DMPP with an IC50 of 7.4 nM. Hexamethonium blocked the DMPP-evoked responses with an IC50 of 29.8 microM, 4,000 fold higher than that of otilonium. 8. In conclusion, otilonium is a potent blocker of nicotinic AChR-mediated responses. The drugs also blocked various subtypes of neuronal voltage-dependent Ca2+ channels at a considerably lower potency. Na+ channels were unaffected by

  8. Calcium Channel Blocker Enhances Beneficial Effects of an Angiotensin II AT1 Receptor Blocker against Cerebrovascular-Renal Injury in type 2 Diabetic Mice

    PubMed Central

    Rafiq, Kazi; Sherajee, Shamshad J.; Hitomi, Hirofumi; Nakano, Daisuke; Kobori, Hiroyuki; Ohmori, Koji; Mori, Hirohito; Kobara, Hideki; Masaki, Tsutomu; Kohno, Masakazu; Nishiyama, Akira

    2013-01-01

    Recent clinical trials have demonstrated that combination therapy with renin-angiotensin system inhibitors plus calcium channel blockers (CCBs) elicits beneficial effects on cardiovascular and renal events in hypertensive patients with high cardiovascular risks. In the present study, we hypothesized that CCB enhances the protective effects of an angiotensin II type 1 receptor blocker (ARB) against diabetic cerebrovascular-renal injury. Saline-drinking type 2 diabetic KK-Ay mice developed hypertension and exhibited impaired cognitive function, blood-brain barrier (BBB) disruption, albuminuria, glomerular sclerosis and podocyte injury. These brain and renal injuries were associated with increased gene expression of NADPH oxidase components, NADPH oxidase activity and oxidative stress in brain and kidney tissues as well as systemic oxidative stress. Treatment with the ARB, olmesartan (10 mg/kg/day) reduced blood pressure in saline-drinking KK-Ay mice and attenuated cognitive decline, BBB disruption, glomerular injury and albuminuria, which were associated with a reduction of NADPH oxidase activity and oxidative stress in brain and kidney tissues as well as systemic oxidative stress. Furthermore, a suppressive dose of azelnidipine (3 mg/kg/day) exaggerated these beneficial effects of olmesartan. These data support the hypothesis that a CCB enhances ARB-associated cerebrovascular-renal protective effects through suppression of NADPH oxidase-dependent oxidative stress in type 2 diabetes. PMID:24339994

  9. Renoprotective effect of calcium channel blockers in combination with an angiotensin receptor blocker in elderly patients with hypertension. A randomized crossover trial between benidipine and amlodipine.

    PubMed

    Miyagawa, Koichi; Dohi, Yasuaki; Nakazawa, Ai; Sugiura, Tomonori; Yamashita, Sumiyo; Sato, Koichi; Kimura, Genjiro

    2010-01-01

    Anti-hypertensive medication with an angiotensin II receptor blocker (ARB) is effective in slowing the progression of chronic kidney disease. The present study was designed to investigate whether calcium channel blockers (CCBs) in combination with an ARB differentially affect kidney function. Elderly hypertensive patients with chronic kidney disease (n = 17, 72 +/- 6 years old) were instructed to self-measure blood pressure. They were randomly assigned to receive either benidipine (4-8 mg/day) or amlodipine (5-10 mg/day) combined with olmesartan (10 mg/day). After 3 months, CCBs were switched in each patient and the same protocol was applied for another 3 months. At baseline, significant correlation was obtained between urine albumin (22.8 +/- 16.7 (median +/- median absolute deviation) mg/g creatinine) and self-measured blood pressure (170 +/- 23/87 +/- 10 (mean +/- SD) mmHg, r = 0.65, p < 0.01). Both regimens reduced blood pressure to a similar extent (139 +/- 22/75 +/- 11 mmHg and 133 +/- 17/72 +/- 10 mmHg, respectively; both p < 0.001), while urine albumin decreased only after combination therapy including benidipine (11.7 +/- 6.1 mg/g creatinine, p < 0.05). Benidipine, but not amlodipine, in combination with olmesartan, reduced urinary albumin excretion in elderly hypertensive patients with chronic kidney disease. The results suggest the importance of selecting medications used in combination with ARB in hypertensive patients with chronic kidney disease. PMID:20144066

  10. [Effects of ionotropic glutamate receptor channel blockers on the development of audiogenic seizures in Krushinski-Molodkina rats].

    PubMed

    Lukomskaia, N Ia; Vataev, S I; Zhabko, E P; Magazanik, L G

    2012-04-01

    The action of noncompetitive blockers of glutamate receptors has been investigated on Krushinski-Molodkina rats genetically-prone to audiogenic seizures. The selective blockers of NMDA receptor channels, memantine and IEM-1921, and their dicationic homologues, IEM-1925 and IEM-1754, capable of blocking in varying degrees both NMDA and Ca-permeable AMPA receptor channels, were studied. The drugs were injected intramuscularly to rats with the different time intervals (30 min, 1, 2 or 3 hours) before sound signal. The effects of the drugs on latent period of initial locomotor activity provoked by audio stimulation (8 kHz sine-wave tone, 90 dB volume), the appearance of clonic convulsions of different intensities, and, finally, tonic convulsions with limb and tail extension were evaluated. Within 30 min after injection IEM-1921 at a dose of 5 mg/kg, 33% of rats manifested a complete absence of convulsive reactions to sound, and in 59% of rats audiogenic seizures occured only in the form of motor excitation without a generalized clonic-tonic convulsions. Memantine at a dose of 5 mg/kg did not cause a complete blockade of seizures, but after 1 h of injection in 50% of the rats and after 2 h in 70% of rats a weakening of the audiogenic seizures to the level of motor excitation only was observed. After 3 hrs after administration of blockers its anticonvulsive action weakened significantly (p < 0.01). Dicationic blockers that block both NMDA and AMPA/kainate receptors, IEM-1925 (in doses of 0.001-20.0 mg/kg) and IEM-1754 (0.025-50.0 mg/kg), did not affect audiogenic clonic-tonic convulsive reactions. The involvement of activation of NMDA and calcium permeable AMPA/kainate receptors in the pathogenesis of audiogenic seizures is discussed.

  11. Regulation of rat cortical 5-hydroxytryptamine2A-receptor mediated electrophysiological responses by repeated daily treatment with electroconvulsive shock or imipramine

    PubMed Central

    Marek, Gerard J.

    2008-01-01

    Down-regulation of 5-hydroxytryptamine2A (5-HT2A) receptors has been a consistent effect induced by most antidepressant drugs. In contrast, electroconvulsive shock (ECS) up-regulates the number of 5-HT2A receptor binding sites. However, the effects of antidepressants on 5-HT2A receptor-mediated responses on identified cells of the cerebral cortex has not been examined. The purpose of the present study was to compare the effects of the tricyclic antidepressant imipramine and ECS on 5-HT2A receptor-mediated electrophysiological responses involving glutamatergic and GABAergic neurotransmission in the rat medial prefrontal cortex (mPFC) and piriform cortex, respectively. The electrophysiological effects of activating 5-HT2A receptors was consistent with 5-HT2A receptor binding regulation for imipramine and ECS except for the mPFC where chronic ECS decreased the potency of 5-HT at a 5-HT2A receptor-mediated response. These findings are consistent with the general hypothesis that chronic antidepressant treatments shift the balance of serotonergic neurotransmission towards inhibitory effects in the cortex. PMID:18294819

  12. Regulation of rat cortical 5-hydroxytryptamine2A receptor-mediated electrophysiological responses by repeated daily treatment with electroconvulsive shock or imipramine.

    PubMed

    Marek, Gerard J

    2008-07-01

    Down-regulation of 5-hydroxytryptamine(2A) (5-HT(2A)) receptors has been a consistent effect induced by most antidepressant drugs. In contrast, electroconvulsive shock (ECS) up-regulates the number of 5-HT(2A) receptor binding sites. However, the effects of antidepressants on 5-HT(2A) receptor-mediated responses on identified cells of the cerebral cortex have not been examined. The purpose of the present study was to compare the effects of the tricyclic antidepressant imipramine and ECS on 5-HT(2A) receptor-mediated electrophysiological responses involving glutamatergic and GABAergic neurotransmission in the rat medial prefrontal cortex (mPFC) and piriform cortex, respectively. The electrophysiological effects of activating 5-HT(2A) receptors were consistent with 5-HT(2A) receptor binding regulation for imipramine and ECS except for the mPFC where chronic ECS decreased the potency of 5-HT at a 5-HT(2A) receptor-mediated response. These findings are consistent with the general hypothesis that chronic antidepressant treatments shift the balance of serotonergic neurotransmission towards inhibitory effects in the cortex.

  13. Moderation of dietary sodium potentiates the renal and cardiovascular protective effects of angiotensin receptor blockers.

    PubMed

    Lambers Heerspink, Hiddo J; Holtkamp, Frank A; Parving, Hans-Henrik; Navis, Gerjan J; Lewis, Julia B; Ritz, Eberhard; de Graeff, Pieter A; de Zeeuw, Dick

    2012-08-01

    Dietary sodium restriction has been shown to enhance the short-term response of blood pressure and albuminuria to angiotensin receptor blockers (ARBs). Whether this also enhances the long-term renal and cardiovascular protective effects of ARBs is unknown. Here we conducted a post-hoc analysis of the RENAAL and IDNT trials to test this in patients with type 2 diabetic nephropathy randomized to ARB or non-renin-angiotensin-aldosterone system (non-RAASi)-based antihypertensive therapy. Treatment effects on renal and cardiovascular outcomes were compared in subgroups based on dietary sodium intake during treatment, measured as the 24-h urinary sodium/creatinine ratio of 1177 patients with available 24-h urinary sodium measurements. ARB compared to non-RAASi-based therapy produced the greatest long-term effects on renal and cardiovascular events in the lowest tertile of sodium intake. Compared to non-RAASi, the trend in risk for renal events was significantly reduced by 43%, not changed, or increased by 37% for each tertile of increased sodium intake, respectively. The trend for cardiovascular events was significantly reduced by 37%, increased by 2% and 25%, respectively. Thus, treatment effects of ARB compared with non-RAASi-based therapy on renal and cardiovascular outcomes were greater in patients with type 2 diabetic nephropathy with lower than higher dietary sodium intake. This underscores the avoidance of excessive sodium intake, particularly in type 2 diabetic patients receiving ARB therapy.

  14. Effects of Angiotensin II Receptor Blockers on Metabolism of Arachidonic Acid via CYP2C8.

    PubMed

    Senda, Asuna; Mukai, Yuji; Toda, Takaki; Hayakawa, Toru; Yamashita, Miki; Eliasson, Erik; Rane, Anders; Inotsume, Nobuo

    2015-01-01

    Arachidonic acid (AA) is metabolized to epoxyeicosatrienoic acids (EETs) via cytochrome enzymes such as CYP 2C9, 2C8 and 2J2. EETs play a role in cardioprotection and regulation of blood pressure. Recently, adverse reactions such as sudden heart attack and fatal myocardial infarction were reported among patients taking angiotensin II receptor blockers (ARBs). As some ARBs have affinity for these CYP enzymes, metabolic inhibition of AA by ARBs is a possible cause for the increase in cardiovascular events. In this study, we quantitatively investigated the inhibitory effects of ARBs on the formation of EETs and further metabolites, dihydroxyeicosatrienoic acids (DHETs), from AA via CYP2C8. In incubations with recombinant CYP2C8 in vitro, the inhibitory effects were compared by measuring EETs and DHETs by HPLC-MS/MS. Inhibition of AA metabolism by ARBs was detected in a concentration-dependent manner with IC50 values of losartan (42.7 µM), telmisartan (49.5 µM), irbesartan (55.6 µM), olmesartan (66.2 µM), candesartan (108 µM), and valsartan (279 µM). Losartan, telmisartan and irbesartan, which reportedly accumulate in the liver and kidneys, have stronger inhibitory effects than other ARBs. The lower concentration of EETs leads to less protective action on the cardiovascular system and a higher incidence of adverse effects such as sudden heart attack and myocardial infarction in patients taking ARBs. PMID:26632190

  15. Angiotensin II receptor blocker telmisartan attenuates aortic stiffening and remodelling in STZ-diabetic rats

    PubMed Central

    2014-01-01

    Background Prevention or attenuation of diabetic vascular complications includes anti-hypertensive treatment with renin-angiotensin system inhibitors on account of their protective effects beyond blood pressure reduction. The present study aimed to investigate the effects of telmisartan, an angiotensin II type 1 receptor blocker (ARB), on blood pressure, aortic stiffening, and aortic remodelling in experimental type 1 diabetes in rats. Methods Diabetes was induced by streptozotocin (STZ) (65 mg/kg) in male Wistar rats. One diabetic group was treated for 10 weeks with telmisartan (10 mg/kg/day p/o). Pressure-independent aortic pulse wave velocity (PWV) was measured under anaesthesia after intravenous infusion of phenylephrine and nitroglycerine. Aortic wall samples were collected for histomorphometrical analysis. Results Untreated diabetes imposed differential effects on aortic stiffening, as demonstrated by increased isobaric PWV over a range of high blood pressures, but not at lower blood pressures. This was associated with loss and disruption of elastin fibres and an increase in collagen fibres in the aortic media. Treatment with telmisartan decreased resting blood pressure, reduced aortic stiffness, and partially prevented the degradation of elastin network within the aortic wall. Conclusions Telmisartan improved the structural and functional indices of aortic stiffening induced by untreated STZ-diabetes, demonstrating the importance of ARBs in the therapeutic approach to diabetic vascular complications. PMID:24920962

  16. Severe Hyponatremia Associated with the Use of Angiotensin II Receptor Blocker/thiazide Combinations

    PubMed Central

    Kim, Da-Rae; Cho, Joo-Hee; Jang, Won-Seok; Kim, Jin-Sug; Jeong, Kyung-Hwan; Lee, Tae-Won

    2013-01-01

    There are several widely used combinations of angiotensin II receptor blocker (ARB)/thiazide. The complimentary mechanism of action for such anti-hypertensive therapies is that, while ARB inhibits the vasoconstricting and aldosterone-secreting effects of angiotensin II, hydrochlorothiazide affects the renal tubular mechanisms of electrolyte reabsorption and increases excretion of sodium and chloride in the distal tubule, consequently promoting water excretion. In addition, hypokalemia, which may be triggered by a hydrochlorothiazide-induced increase in urinary potassium loss, is resisted by the use of ARB. Hence, the ARB/thiazide combination is safe in terms of potassium imbalance. For these reasons, fixed-dose ARB/thiazide combination anti-hypertensive drugs have been widely used for the treatment of hypertension. However, there have not been many studies done regarding cases where patients under such regimens showed severe hyponatremia, even when the amount of thiazide included was low. Here we report two cases in which severe hyponatremia occurred following treatment with the ARB/thiazide combinations. Upon discontinuation of the regimen, both patients showed recovery from hyponatremia. PMID:24627706

  17. 5-Hydroxytryptamine2A serotonin receptors in the primate cerebral cortex: possible site of action of hallucinogenic and antipsychotic drugs in pyramidal cell apical dendrites.

    PubMed

    Jakab, R L; Goldman-Rakic, P S

    1998-01-20

    To identify the cortical sites where 5-hydroxytryptamine2A (5-HT2A) serotonin receptors respond to the action of hallucinogens and atypical antipsychotic drugs, we have examined the cellular and subcellular distribution of these receptors in the cerebral cortex of macaque monkeys (with a focus on prefrontal areas) by using light and electron microscopic immunocytochemical techniques. 5-HT2A receptor immunoreactivity was detected in all cortical layers, among which layers II and III and layers V and VI were intensely stained, and layer IV was weakly labeled. The majority of the receptor-labeled cells were pyramidal neurons and the most intense immunolabeling was consistently confined to their parallelly aligned proximal apical dendrites that formed two intensely stained bands above and below layer IV. In double-label experiments, 5-HT2A label was found in calbindin D28k-positive, nonphosphorylated-neurofilament-positive, and immuno-negative pyramidal cells, suggesting that probably all pyramidal cells express 5-HT2A receptors. 5-HT2A label was also found in large- and medium-size interneurons, some of which were immuno-positive for calbindin. 5-HT2A receptor label was also associated with axon terminals. These findings reconcile the data on the receptor's cortical physiology and localization by (i) establishing that 5-HT2A receptors are located postsynaptically and presynaptically, (ii) demonstrating that pyramidal neurons constitute the major 5-HT2A-receptor-expressing cells in the cortex, and (iii) supporting the view that the apical dendritic field proximal to the pyramidal cell soma is the "hot spot" for 5-HT2A-receptor-mediated physiological actions relevant to normal and "psychotic" functional states of the cerebral cortex.

  18. Differentiation in the effects of the angiotensin II receptor blocker class on autonomic function.

    PubMed

    Esler, Murray

    2002-06-01

    Measurement of regional sympathetic activity with nerve recording and noradrenaline spillover isotope dilution techniques demonstrates activation of the sympathetic nerves of the heart, kidneys and skeletal muscle vasculature in younger patients with essential hypertension. Sympathetic overactivity in the renal sympathetic outflow is a prominent pathophysiological feature in obesity-related hypertensives of any age. This increase in sympathetic activity is thought to both initiate and sustain the blood pressure elevation, and, in addition, contributes to adverse cardiovascular events. Sympathetic overactivity seems to particularly influence systolic pressure, by increasing the rate of left ventricular ejection, by reducing arterial compliance through increasing neural arterial tone, and via arteriolar vasoconstriction, by promoting rebound of the reflected arterial wave from the periphery. Inhibition of the renin-angiotensin system in certain circumstances appears to be able to reduce sympathetic nervous activity. Claims have been made for such an action at virtually every site in the sympathetic neuraxis. In reality, renin-angiotensin actions on the sympathetic nervous system are probably much more circumscribed than this, with the case perhaps being strongest for a presynaptic action of angiotensin on sympathetic nerves, to augment noradrenaline release. The ability of angiotensin receptor blockers to antagonize neural presynaptic angiotensin AT1 receptors appears to differ markedly between the individual agents in this drug class. In experimental models, such as the pithed rat, neural presynaptic actions are particularly evident with eprosartan. In a blinded study of crossover design, the effects of eprosartan and losartan on sympathetic nerve firing, measured by microneurography, and whole body noradrenaline spillover to plasma is currently being measured in patients with essential hypertension. A reduction in noradrenaline spillover disproportionate to any

  19. Regression of Glomerular and Tubulointerstitial Injuries by Dietary Salt Reduction with Combination Therapy of Angiotensin II Receptor Blocker and Calcium Channel Blocker in Dahl Salt-Sensitive Rats

    PubMed Central

    Rafiq, Kazi; Nishiyama, Akira; Konishi, Yoshio; Morikawa, Takashi; Kitabayashi, Chizuko; Kohno, Masakazu; Masaki, Tsutomu; Mori, Hirohito; Kobori, Hiroyuki; Imanishi, Masahito

    2014-01-01

    A growing body of evidence indicates that renal tissue injuries are reversible. We investigated whether dietary salt reduction with the combination therapy of angiotensin II type 1 receptor blocker (ARB) plus calcium channel blocker (CCB) reverses renal tissue injury in Dahl salt-sensitive (DSS) hypertensive rats. DSS rats were fed a high-salt diet (HS; 4% NaCl) for 4 weeks. Then, DSS rats were given one of the following for 10 weeks: HS diet; normal-salt diet (NS; 0.5% NaCl), NS + an ARB (olmesartan, 10 mg/kg/day), NS + a CCB (azelnidipine, 3 mg/kg/day), NS + olmesartan + azelnidipine or NS + hydralazine (50 mg/kg/day). Four weeks of treatment with HS diet induced hypertension, proteinuria, glomerular sclerosis and hypertrophy, glomerular podocyte injury, and tubulointerstitial fibrosis in DSS rats. A continued HS diet progressed hypertension, proteinuria and renal tissue injury, which was associated with inflammatory cell infiltration and increased proinflammatory cytokine mRNA levels, NADPH oxidase activity and NADPH oxidase-dependent superoxide production in the kidney. In contrast, switching to NS halted the progression of hypertension, renal glomerular and tubular injuries. Dietary salt reduction with ARB or with CCB treatment further reduced blood pressure and partially reversed renal tissues injury. Furthermore, dietary salt reduction with the combination of ARB plus CCB elicited a strong recovery from HS-induced renal tissue injury including the attenuation of inflammation and oxidative stress. These data support the hypothesis that dietary salt reduction with combination therapy of an ARB plus CCB restores glomerular and tubulointerstitial injury in DSS rats. PMID:25233358

  20. Assessment of viral interference using a chemical receptor blocker against avian influenza and establishment of protection levels in field outbreaks.

    PubMed

    Fernandez-Siurob, I; Retana, M A; Tellez, G; Arroyo-Navarro, L; Bañuelos-Hernandez, B; Castellanos-Huerta, I

    2014-03-01

    Avian influenza (AI) currently poses a serious problem for poultry farming worldwide. Its prevalence in Mexico, despite vaccination, has highlighted the need for new approaches to control AI and reduce the economic losses associated with its occurrence in susceptible birds. The different interactions between AI viruses (AIV) and cellular receptors have been described, along with the affinity of some viruses for certain types of species-specific receptors. This receptor-ligand specificity, combined with an understanding of viral interference processes and their relevance in different viral models, permits the assessment of new strategies for controlling AIV. The present study was designed to investigate the feasibility of using viral interference as a novel approach for AIV control, taking advantage of the high receptor-ligand specificity between AIV and animal cells. The results from field outbreak tests and cell culture analysis along with measurements of specific antibodies against AIV demonstrate that the mortality associated with AI infection can be reduced by using a receptor blocker against AIV. This receptor blocker approach also has the potential to be used on an industrial scale for the efficient control of AIV.

  1. Evidence to Consider Angiotensin II Receptor Blockers for the Treatment of Early Alzheimer's Disease.

    PubMed

    Saavedra, Juan M

    2016-03-01

    Alzheimer's disease is the most frequent type of dementia and diagnosed late in the progression of the illness when irreversible brain tissue loss has already occurred. For this reason, treatments have been ineffective. It is imperative to find novel therapies ameliorating modifiable risk factors (hypertension, stroke, diabetes, chronic kidney disease, and traumatic brain injury) and effective against early pathogenic mechanisms including alterations in cerebral blood flow leading to poor oxygenation and decreased access to nutrients, impaired glucose metabolism, chronic inflammation, and glutamate excitotoxicity. Angiotensin II receptor blockers (ARBs) fulfill these requirements. ARBs are directly neuroprotective against early injury factors in neuronal, astrocyte, microglia, and cerebrovascular endothelial cell cultures. ARBs protect cerebral blood flow and reduce injury to the blood brain barrier and neurological and cognitive loss in animal models of brain ischemia, traumatic brain injury, and Alzheimer's disease. These compounds are clinically effective against major risk factors for Alzheimer's disease: hypertension, stroke, chronic kidney disease, diabetes and metabolic syndrome, and ameliorate age-dependent cognitive loss. Controlled studies on hypertensive patients, open trials, case reports, and database meta-analysis indicate significant therapeutic effects of ARBs in Alzheimer's disease. ARBs are safe compounds, widely used to treat cardiovascular and metabolic disorders in humans, and although they reduce hypertension, they do not affect blood pressure in normotensive individuals. Overall, there is sufficient evidence to consider long-term controlled clinical studies with ARBs in patients suffering from established risk factors, in patients with early cognitive loss, or in normal individuals when reliable biomarkers of Alzheimer's disease risk are identified. PMID:26993513

  2. Hyperkalemia associated with use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers.

    PubMed

    Raebel, Marsha A

    2012-06-01

    The aims of this article are to review the current understanding of hyperkalemia associated with angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) therapy. This includes reviewing the pathophysiology of how these agents affect potassium handling within the kidney, risk factors for developing hyperkalemia, incidence, clinical signs and symptoms, and providing a practical approach to treatment of the patient who is either at risk of, or experiencing, hyperkalemia. ACEi and ARB are effective therapeutic agents used in a variety of clinical scenarios. However, related to their effects on the renin-angiotensin-aldosterone system, their use can be associated with hyperkalemia, particularly in patients who have chronic renal insufficiency. Published incidence estimates of hyperkalemia associated with ACEi or ARB vary, but up to 10% of patients may experience at least mild hyperkalemia. Important considerations when initiating ACEi or ARB therapy include obtaining an estimate of glomerular filtration rate and a baseline serum potassium concentration, as well as assessing whether the patient has excessive potassium intake from diet, supplements, or drugs that can also increase serum potassium. Serum potassium monitoring shortly after initiation of therapy can assist in preventing hyperkalemia. If hyperkalemia does develop, prompt recognition of cardiac dysrhythmias and effective treatment to antagonize the cardiac effects of potassium, redistribute potassium into cells, and remove excess potassium from the body is important.Understanding the mechanism of action of ACEi and ARB coupled with judicious drug use and clinical vigilance can minimize the risk to the patient of developing hyperkalemia. Should hyperkalemia occur, prompt recognition and management can optimize clinical outcome.

  3. ACE Inhibitor and Angiotensin Receptor Blocker Use and Mortality in Patients with Chronic Kidney Disease

    PubMed Central

    Molnar, Miklos Z; Kalantar-Zadeh, Kamyar; Lott, Evan H; Lu, Jun Ling; Malakauskas, Sandra M; Ma, Jennie Z; Quarles, Darryl L; Kovesdy, Csaba P

    2014-01-01

    Objective To assess the association between ACEI/ARB use and mortality in CKD patients. Background There is insufficient evidence about the association of angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARBs) with mortality in chronic kidney disease (CKD) patients. Methods A logistic regression analysis was used to calculate the propensity of ACEI/ARB initiation in 141,413 US veterans with non-dialysis CKD previously unexposed to ACEI/ARB treatment. We examined the association of ACEI/ARB administration with all-cause mortality in patients matched by propensity scores, using the Kaplan-Meier method and Cox models in “intention-to-treat” analyses, and in generalized linear models with binary outcomes and inverse probability treatment weighing (IPTW) in “as-treated” analyses. Results The mean±SD age of the patients at baseline was 75±10 years, 8% of patients were black, and 22% were diabetic. ACEI/ARB administration was associated with significantly lower risk of mortality both in the intention-to-treat analysis (HR=0.81; 95%CI: 0.78-0.84, p<0.001) and in the as-treated analysis with IPTW (OR=0.37; 95%CI: 0.34-0.41, p<0.001). The association of ACEI/ARB treatment with lower risk of mortality was present in all examined subgroups. Conclusions In this large contemporary cohort of non-dialysis dependent CKD patients, ACEI/ARB administration was associated with greater survival. PMID:24269363

  4. Does the use of ACE inhibitors or angiotensin receptor blockers affect bone loss in older men?

    PubMed Central

    Leung, J.; Zhang, Y. F.; Bauer, D.; Ensrud, K. E.; Barrett-Connor, E.; Leung, P. C.

    2013-01-01

    Summary In a prospective cohort study of 5,995 older American men (MrOS), users of angiotensin-converting enzyme (ACE) inhibitors had a small but significant increase in bone loss at the hip over 4 years after adjustment for confounders. Use of angiotensin II AT1 receptor blockers (ARB) was not significantly associated with bone loss. Introduction Experimental evidence suggests that angiotensin II promotes bone loss by its effects on osteoblasts. It is therefore plausible that ACE inhibitor and ARB may reduce rates of bone loss. The objective of this study is to examine the independent effects of ACE inhibitor and ARB on bone loss in older men. Methods Out of 5,995 American men (87.2%) aged ≥65 years, 5,229 were followed up for an average of 4.6 years in a prospective six-center cohort study—The Osteoporotic Fractures in Men Study (MrOS). Bone mineral densities (BMD) at total hip, femoral neck, and trochanter were measured by Hologic densitometer (QDR 4500) at baseline and year 4. Results Out of 3,494 eligible subjects with complete data, 1,166 and 433 subjects reported use of ACE inhibitors and ARBs, respectively. When compared with nonusers, continuous use of ACE inhibitors was associated with a small (0.004 g/cm2) but significant increase in the average rate of BMD loss at total hip and trochanter over 4 years after adjustment for confounders. Use of ARB was not significantly associated with bone loss. Conclusion Use of ACE inhibitors but not ARB may marginally increase bone loss in older men. PMID:22080379

  5. Angiotensin II type 1 receptor blockers as a first choice in patients with acute myocardial infarction

    PubMed Central

    Lee, Jang Hoon; Bae, Myung Hwan; Yang, Dong Heon; Park, Hun Sik; Cho, Yongkeun; Lee, Won Kee; Jeong, Myung Ho; Kim, Young Jo; Cho, Myeong Chan; Kim, Chong Jin; Chae, Shung Chull

    2016-01-01

    Background/Aims: Angiotensin II type 1 receptor blockers (ARBs) have not been adequately evaluated in patients without left ventricular (LV) dysfunction or heart failure after acute myocardial infarction (AMI). Methods: Between November 2005 and January 2008, 6,781 patients who were not receiving angiotensin-converting enzyme inhibitors (ACEIs) or ARBs were selected from the Korean AMI Registry. The primary endpoints were 12-month major adverse cardiac events (MACEs) including death and recurrent AMI. Results: Seventy percent of the patients were Killip class 1 and had a LV ejection fraction ≥ 40%. The prescription rate of ARBs was 12.2%. For each patient, a propensity score, indicating the likelihood of using ARBs during hospitalization or at discharge, was calculated using a non-parsimonious multivariable logistic regression model, and was used to match the patients 1:4, yielding 715 ARB users versus 2,860 ACEI users. The effect of ARBs on in-hospital mortality and 12-month MACE occurrence was assessed using matched logistic and Cox regression models. Compared with ACEIs, ARBs significantly reduced in-hospital mortality(1.3% vs. 3.3%; hazard ratio [HR], 0.379; 95% confidence interval [CI], 0.190 to0.756; p = 0.006) and 12-month MACE occurrence (4.6% vs. 6.9%; HR, 0.661; 95% CI, 0.457 to 0.956; p = 0.028). However, the benefit of ARBs on 12-month mortality compared with ACEIs was marginal (4.3% vs. 6.2%; HR, 0.684; 95% CI, 0.467 to 1.002; p = 0.051). Conclusions: Our results suggest that ARBs are not inferior to, and may actually be better than ACEIs in Korean patients with AMI. PMID:26701233

  6. A current evaluation of the safety of angiotensin receptor blockers and direct renin inhibitors

    PubMed Central

    Siragy, Helmy M

    2011-01-01

    The safety of angiotensin II receptor blockers (ARBs) for the treatment of hypertension and cardiovascular and renal diseases has been well documented in numerous randomized clinical trials involving thousands of patients. However, recent concerns have surfaced about possible links between ARBs and increased risks of myocardial infarction and cancer. Less is known about the safety of the direct renin inhibitor aliskiren, which was approved as an antihypertensive in 2007. This article provides a detailed review of the safety of ARBs and aliskiren, with an emphasis on the risks of cancer and myocardial infarction associated with ARBs. Safety data were identified by searching PubMed and Food and Drug Administration (FDA) Web sites through April 2011. ARBs are generally well tolerated, with no known class-specific adverse events. The possibility of an increased risk of myocardial infarction associated with ARBs was suggested predominantly because the Valsartan Antihypertensive Long-Term Use Evaluation (VALUE) trial reported a statistically significant increase in the incidence of myocardial infarction with valsartan compared with amlodipine. However, no large-scale, randomized clinical trials published after the VALUE study have shown a statistically significant increase in the incidence of myocardial infarction associated with ARBs compared with placebo or non-ARBs. Meta-analyses examining the risk of cancer associated with ARBs have produced conflicting results, most likely due to the inherent limitations of analyzing heterogeneous data and a lack of published cancer data. An ongoing safety investigation by the FDA has not concluded that ARBs increase the risk of cancer. Pooled safety results from clinical trials indicate that aliskiren is well tolerated, with a safety profile similar to that of placebo. ARBs and aliskiren are well tolerated in patients with hypertension and certain cardiovascular and renal conditions; their benefits outweigh possible safety concerns

  7. Olmesartan is an angiotensin II receptor blocker with an inhibitory effect on angiotensin-converting enzyme.

    PubMed

    Agata, Jun; Ura, Nobuyuki; Yoshida, Hideaki; Shinshi, Yasuyuki; Sasaki, Haruki; Hyakkoku, Masaya; Taniguchi, Shinya; Shimamoto, Kazuaki

    2006-11-01

    Angiotensin II receptor blockers (ARBs) are widely used for the treatment of hypertension. It is believed that treatment with an ARB increases the level of plasma angiotensin II (Ang II) because of a lack of negative feedback on renin activity. However, Ichikawa (Hypertens Res 2001; 24: 641-646) reported that long-term treatment of hypertensive patients with olmesartan resulted in a reduction in plasma Ang II level, though the mechanism was not determined. It has been reported that angiotensin 1-7 (Ang-(1-7)) potentiates the effect of bradykinin and acts as an angiotensin-converting enzyme (ACE) inhibitor. It is known that ACE2, which was discovered as a novel ACE-related carboxypeptidase in 2000, hydrolyzes Ang I to Ang-(1-9) and also Ang II to Ang-(1-7). It has recently been reported that olmesartan increases plasma Ang-(1-7) through an increase in ACE2 expression in rats with myocardial infarction. We hypothesized that over-expression of ACE2 may be related to a reduction in Ang II level and the cardioprotective effect of olmesartan. Administration of 0.5 mg/kg/day of olmesartan for 4 weeks to 12-week-old stroke-prone spontaneously hypertensive rats (SHRSP) significantly reduced blood pressure and left ventricular weight compared to those in SHRSP given a vehicle. Co-administration of olmesartan and (D-Ala7)-Ang-(1-7), a selective Ang-(1-7) antagonist, partially inhibited the effect of olmesartan on blood pressure and left ventricular weight. Interestingly, co-administration of (D-Ala7)-Ang-(1-7) with olmesartan significantly increased the plasma Ang II level (453.2+/-113.8 pg/ml) compared to olmesartan alone (144.9+/-27.0 pg/ml, p<0.05). Moreover, olmesartan significantly increased the cardiac ACE2 expression level compared to that in Wistar Kyoto rats and SHRSP treated with a vehicle. Olmesartan significantly improved cardiovascular remodeling and cardiac nitrite/ nitrate content, but co-administration of olmesartan and (D-Ala7)-Ang-(1-7) partially reversed

  8. Unambiguous observation of blocked states reveals altered, blocker-induced, cardiac ryanodine receptor gating

    PubMed Central

    Mukherjee, Saptarshi; Thomas, N. Lowri; Williams, Alan J.

    2016-01-01

    The flow of ions through membrane channels is precisely regulated by gates. The architecture and function of these elements have been studied extensively, shedding light on the mechanisms underlying gating. Recent investigations have focused on ion occupancy of the channel’s selectivity filter and its ability to alter gating, with most studies involving prokaryotic K+ channels. Some studies used large quaternary ammonium blocker molecules to examine the effects of altered ionic flux on gating. However, the absence of blocking events that are visibly distinct from closing events in K+ channels makes unambiguous interpretation of data from single channel recordings difficult. In this study, the large K+ conductance of the RyR2 channel permits direct observation of blocking events as distinct subconductance states and for the first time demonstrates the differential effects of blocker molecules on channel gating. This experimental platform provides valuable insights into mechanisms of blocker-induced modulation of ion channel gating. PMID:27703263

  9. Angiotensin-II receptor antagonist combined with calcium channel blocker or diuretic for essential hypertension.

    PubMed

    Ishimitsu, Toshihiko; Numabe, Atsushi; Masuda, Toshihide; Akabane, Tomoyuki; Okamura, Atsushi; Minami, Junichi; Matsuoka, Hiroaki

    2009-11-01

    To achieve the target blood pressure recommended by the latest guidelines, multiple antihypertensive drugs are needed in most patients. In this study, the efficacy of treatment using an angiotensin II receptor antagonist (ARB) combined with a calcium channel blocker (CCB) or a diuretic was compared from multiple perspectives in patients with hypertension. Twenty-nine patients with essential hypertension, who had failed to achieve their target blood pressure (<130/85 mm Hg for patients <65 years old and <140/90 mm Hg for those >/=65 years) when treated with the ARB olmesartan at 20 mg day(-1), were additionally given 8-16 mg day(-1) of the CCB azelnidipine or 1-2 mg day(-1) of trichlormethiazide (a thiazide diuretic) in a randomized crossover manner for 4 months each. At the end of each combination therapy period, blood and urine samples were collected and arterial stiffness was evaluated by measuring the cardio-ankle pulse wave velocity. Compared with monotherapy, the blood pressure was reduced similarly by adding azelnidipine (-12/-10 mm Hg) or trichlormethiazide (-14/-9 mm Hg). The heart rate was decreased with the CCB by 4 b.p.m. (P<0.05), whereas it was unchanged with the thiazide. Serum K, lipids and blood glucose were not significantly changed with either combination, whereas serum uric acid was increased with the thiazide (P<0.01) but was unchanged with azelnidipine. Plasma levels of renin, angiotensin II and aldosterone were also increased with the thiazide period, whereas high-sensitivity C-reactive protein and oxidized low-density lipoprotein were decreased with azelnidipine. In addition, the cardio-ankle vascular index, a parameter of arterial stiffness, was decreased with the azelnidipine period but was unchanged with the thiazide period (P<0.01). It is suggested that the combination of olmesartan and azelnidipine has advantages over the combination of olmesartan and a thiazide with respect to avoiding hyperuricemia, sympathetic activation, renin

  10. The Beta-1-Receptor Blocker Nebivolol Elicits Dilation of Cerebral Arteries by Reducing Smooth Muscle [Ca2+]i

    PubMed Central

    Cseplo, Peter; Vamos, Zoltan; Ivic, Ivan; Torok, Orsolya; Toth, Attila; Koller, Akos

    2016-01-01

    Rationale Nebivolol is known to have beta-1 blocker activity, but it was also suggested that it elicits relaxation of the peripheral arteries in part via release of nitric oxide (NO). However, the effect of nebivolol on the vasomotor tone of cerebral arteries is still unclear. Objective To assess the effects of nebivolol on the diameter of isolated rat basilar arteries (BA) in control, in the presence of inhibitors of vasomotor signaling pathways of know action and hemolysed blood. Methods and Results Vasomotor responses were measured by videomicroscopy and the intracellular Ca2+ by the Fura-2 AM ratiometric method. Under control conditions, nebivolol elicited a substantial dilation of the BA (from 216±22 to 394±20 μm; p<0.05) in a concentration-dependent manner (10−7 to 10−4 M). The dilatation was significantly reduced by endothelium denudation or by L-NAME (inhibitor of NO synthase) or by SQ22536 (adenylyl cyclase blocker). Dilatation of BA was also affected by beta-2 receptor blockade with butoxamine, but not by the guanylate cyclase blocker ODQ. Interestingly, beta-1 blockade by atenolol inhibited nebivolol-induced dilation. Also, the BKCa channel blocker iberiotoxin and KCa channel inhibitor TEA significantly reduced nebivolol-induced dilation. Nebivolol significantly reduced smooth muscle Ca2+ level, which correlated with the increases in diameters and moreover it reversed the hemolysed blood-induced constriction of BA. Conclusions Nebivolol seems to have an important dilator effect in cerebral arteries, which is mediated via several vasomotor mechanisms, converging on the reduction of smooth muscle Ca2+ levels. As such, nebivolol may be effective to improve cerebral circulation in various diseased conditions, such as hemorrhage. PMID:27716772

  11. The Impact of Type 2 Diabetes on the Efficacy of ADP Receptor Blockers in Patients with Acute ST Elevation Myocardial Infarction: A Pilot Prospective Study

    PubMed Central

    Fedor, Marián; Kovář, František; Galajda, Peter; Bolek, Tomáš; Stančiaková, Lucia; Fedorová, Jana; Staško, Ján; Kubisz, Peter; Mokáň, Marián

    2016-01-01

    Background. The aim of this study was to validate the impact of type 2 diabetes (T2D) on the platelet reactivity in patients with acute ST elevation myocardial infarction (STEMI) treated with adenosine diphosphate (ADP) receptor blockers. Methods. A pilot prospective study was performed. Totally 67 patients were enrolled. 21 patients had T2D. Among all study population, 33 patients received clopidogrel and 34 patients received prasugrel. The efficacy of ADP receptor blocker therapy had been tested in two time intervals using light transmission aggregometry with specific inducer and vasodilator-stimulated phosphoprotein phosphorylation (VASP-P) flow cytometry assay. Results. There were no significant differences in platelet aggregability among T2D and nondiabetic (ND) group. The platelet reactivity index of VASP-P did not differ significantly between T2D and ND group (59.4 ± 30.9% versus 60.0 ± 25.2% and 33.9 ± 25.3% versus 38.6 ± 29.3% in second testing). The number of ADP receptor blocker nonresponders did not differ significantly between T2D and ND patients. The time interval from ADP receptor blocker loading dosing to the blood sampling was similar in T2D and ND patients in both examinations. Conclusion. This prospective study did not confirm the higher platelet reactivity and higher prevalence of ADP receptor blocker nonresponders in T2D acute STEMI patients. PMID:27493970

  12. Directly acting drugs prostacyclin or nitroglycerine and endothelin receptor blocker bosentan improve cell engraftment in rat liver

    PubMed Central

    Bahde, Ralf; Kapoor, Sorabh; Bandi, Sriram; Bhargava, Kuldeep K.; Palestro, Christopher J.; Gupta, Sanjeev

    2012-01-01

    To optimize strategies for liver-directed cell therapy prevention of initial transplanted cell losses is particularly important for subsequent liver repopulation. After cell transplantation in hepatic sinusoids, perturbations in hepatic microcirculation along with changes in various liver cell types are among the earliest changes. Therefore, for advancing further concepts in cell engraftment, we studied vascular and related events in the liver after transplanting syngeneic hepatocytes into dipeptidyl peptidase IV-deficient rats. We treated rats with vascular drugs to define whether deleterious cell transplantation-induced events could be controlled followed by improvements in transplanted cell engraftment and proliferation. We found cell transplantation altered liver gene expression related to vessel tone, inflammation, cell adhesion, thrombosis, or tissue damage/remodeling. This was due to hepatic ischemia, endothelial injury and activation of neutrophils, Kupffer cells and hepatic stellate cells. Treatment of rats before cell transplantation with angiotensin converting enzyme blocker, lisinopril, or angiotensin II receptor blocker, losartan, did not improve cell engraftment. By contrast, direct-acting nitroglycerine or prostacyclin improved cell engraftment and also kinetics of liver repopulation. These drugs lowered hepatic ischemia and inflammation. Whereas pretreatment of rats with the dual endothelin-1 receptor blocker, bosentan, improved cell engraftment independently of hepatic ischemia or inflammation, without improving liver repopulation. However, incubation of hepatocytes with bosentan protected cells from cytokine toxicity in vitro and produced superior cell engraftment and proliferation in vivo. We concluded that cell transplantation-induced changes in hepatic microcirculation contributed to transplanted cell clearances from liver. Vascular drugs, such as nitroglycerine, prostacyclin and bosentan, offer opportunities for improving cell therapy results

  13. Serotonin 2a Receptor and Serotonin 1a Receptor Interact Within the Medial Prefrontal Cortex During Recognition Memory in Mice

    PubMed Central

    Morici, Juan F.; Ciccia, Lucia; Malleret, Gaël; Gingrich, Jay A.; Bekinschtein, Pedro; Weisstaub, Noelia V.

    2015-01-01

    Episodic memory, can be defined as the memory for unique events. The serotonergic system one of the main neuromodulatory systems in the brain appears to play a role in it. The serotonin 2a receptor (5-HT2aR) one of the principal post-synaptic receptors for 5-HT in the brain, is involved in neuropsychiatric and neurological disorders associated with memory deficits. Recognition memory can be defined as the ability to recognize if a particular event or item was previously encountered and is thus considered, under certain conditions, a form of episodic memory. As human data suggest that a constitutively decrease of 5-HT2A signaling might affect episodic memory performance we decided to compare the performance of mice with disrupted 5-HT2aR signaling (htr2a−/−) with wild type (htr2a+/+) littermates in different recognition memory and working memory tasks that differed in the level of proactive interference. We found that ablation of 5-HT2aR signaling throughout development produces a deficit in tasks that cannot be solved by single item strategy suggesting that 5-HT2aR signaling is involved in interference resolution. We also found that in the absence of 5-HT2aR signaling serotonin has a deleterious effect on recognition memory retrieval through the activation of 5-HT1aR in the medial prefrontal cortex. PMID:26779016

  14. Serotonin 2a Receptor and Serotonin 1a Receptor Interact Within the Medial Prefrontal Cortex During Recognition Memory in Mice.

    PubMed

    Morici, Juan F; Ciccia, Lucia; Malleret, Gaël; Gingrich, Jay A; Bekinschtein, Pedro; Weisstaub, Noelia V

    2015-01-01

    Episodic memory, can be defined as the memory for unique events. The serotonergic system one of the main neuromodulatory systems in the brain appears to play a role in it. The serotonin 2a receptor (5-HT2aR) one of the principal post-synaptic receptors for 5-HT in the brain, is involved in neuropsychiatric and neurological disorders associated with memory deficits. Recognition memory can be defined as the ability to recognize if a particular event or item was previously encountered and is thus considered, under certain conditions, a form of episodic memory. As human data suggest that a constitutively decrease of 5-HT2A signaling might affect episodic memory performance we decided to compare the performance of mice with disrupted 5-HT2aR signaling (htr2a (-/-)) with wild type (htr2a (+/+)) littermates in different recognition memory and working memory tasks that differed in the level of proactive interference. We found that ablation of 5-HT2aR signaling throughout development produces a deficit in tasks that cannot be solved by single item strategy suggesting that 5-HT2aR signaling is involved in interference resolution. We also found that in the absence of 5-HT2aR signaling serotonin has a deleterious effect on recognition memory retrieval through the activation of 5-HT1aR in the medial prefrontal cortex. PMID:26779016

  15. Molecular design and synthesis of 1,4-disubstituted piperazines as α(1)-adrenergic receptor blockers.

    PubMed

    Abou El-Ella, Dalal A; Hussein, Mohammed M; Serya, Rabah A T; Abdel Naby, Rana M; Al-Abd, Ahmed M; Saleh, Dalia O; El-Eraky, Wafaa I; Abouzid, Khaled A M

    2014-06-01

    A new series of 4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid amide and 3,5,6,8-tetrahydropyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-one derivatives were designed, synthesized, their binding and functional properties as α1-adrenoreceptors blockers were evaluated. A new validated α1-adrenoreceptor blocker pharmacophore model (hypothesis) was generated using Discovery Studio 2.5. The compare-fit study for the designed molecules with the generated hypothesis was fulfilled and several compounds showed significant high fit values. Compounds IVa-c, VIIa-d, VIIIa-c, Xa-c, XIa-d have shown blocking activity ranging from 46.73% up to 94.74% compared to 99.17% for prazosin.

  16. Induction of human adiponectin gene transcription by telmisartan, angiotensin receptor blocker, independently on PPAR-{gamma} activation

    SciTech Connect

    Moriuchi, Akie ||. E-mail: f1195@cc.nagasaki-u-ac.jp; Shimamura, Mika; Kita, Atsushi; Kuwahara, Hironaga; Satoh, Tsuyoshi; Satoh, Tsuyoshi; Fujishima, Keiichiro; Fukushima, Keiko |; Hayakawa, Takao; Mizuguchi, Hiroyuki; Nagayama, Yuji; Kawasaki, Eiji

    2007-05-18

    Adiponectin, an adipose tissue-specific plasma protein, has been shown to ameliorate insulin resistance and inhibit the process of atherosclerosis. Recently, several reports have stated that angiotensin type 1 receptor blockers (ARBs), increase adiponectin plasma level, and ameliorate insulin resistance. Telmisartan, a subclass of ARBs, has been shown to be a partial agonist of the peroxisome proliferator-activated receptor (PPAR)-{gamma}, and to increase the plasma adiponectin level. However, the transcriptional regulation of the human adiponectin gene by telmisartan has not been determined yet. To elucidate the effect of telmisartan on adiponectin, the stimulatory regulation of human adiponectin gene by telmisartan was investigated in 3T3-L1 adipocytes, utilizing adenovirus-mediated luciferase reporter gene-transferring technique. This study indicates that telmisartan may stimulate adiponectin transcription independent of PPAR-{gamma}.

  17. [Central effects of five beta-adrenergic receptor blockers in healthy volunteers: a quantitative EEG study].

    PubMed

    Sabot, C; Pechadre, J C; Beudin, P; Lauxerois, M; Trolese, J F; Kantelip, J P; Ducher, J L; Gibert, J

    1989-03-01

    The effects of five beta blockers on the central nervous system of healthy subjects was studied by computerized EEG analysis. All subjects underwent continuous recording with a Holter magnetic type recorder during the experimental period. For 10 consecutive days, five groups of subjects received alternately placebo and the beta blockers acebutolol 600 mg, carteolol 20 mg, metoprolol 200 mg, pindolol 30 mg and sotalol 320 mg. EEG recordings (C4/P4, P4/02 and C3/P3, P3/01) lasting 5 min were made between 8.30 and 9.30 a.m. Subjects were at rest with eyes closed and there was no vigilance control. The signal was recorded on a magnetic tape recorder and then processed by Nicolet MED 80 system. Comparisons of absolute and relative powers and of average frequencies were then made between the different sequences and groups. The possible correlations between the changes observed in the power spectrum and the clinical, pharmacological and pharmacokinetic specific properties of each beta blocker are discussed.

  18. Angiotensin II type 1 receptor blocker losartan prevents and rescues cerebrovascular, neuropathological and cognitive deficits in an Alzheimer's disease model.

    PubMed

    Ongali, Brice; Nicolakakis, Nektaria; Tong, Xin-Kang; Aboulkassim, Tahar; Papadopoulos, Panayiota; Rosa-Neto, Pedro; Lecrux, Clotilde; Imboden, Hans; Hamel, Edith

    2014-08-01

    Angiotensin II (AngII) receptor blockers that bind selectively AngII type 1 (AT1) receptors may protect from Alzheimer's disease (AD). We studied the ability of the AT1 receptor antagonist losartan to cure or prevent AD hallmarks in aged (~18months at endpoint, 3months treatment) or adult (~12months at endpoint, 10months treatment) human amyloid precursor protein (APP) transgenic mice. We tested learning and memory with the Morris water maze, and evaluated neurometabolic and neurovascular coupling using [(18)F]fluoro-2-deoxy-D-glucose-PET and laser Doppler flowmetry responses to whisker stimulation. Cerebrovascular reactivity was assessed with on-line videomicroscopy. We measured protein levels of oxidative stress enzymes (superoxide dismutases SOD1, SOD2 and NADPH oxidase subunit p67phox), and quantified soluble and deposited amyloid-β (Aβ) peptide, glial fibrillary acidic protein (GFAP), AngII receptors AT1 and AT2, angiotensin IV receptor AT4, and cortical cholinergic innervation. In aged APP mice, losartan did not improve learning but it consolidated memory acquisition and recall, and rescued neurovascular and neurometabolic coupling and cerebrovascular dilatory capacity. Losartan normalized cerebrovascular p67phox and SOD2 protein levels and up-regulated those of SOD1. Losartan attenuated astrogliosis, normalized AT1 and AT4 receptor levels, but failed to rescue the cholinergic deficit and the Aβ pathology. Given preventively, losartan protected cognitive function, cerebrovascular reactivity, and AT4 receptor levels. Like in aged APP mice, these benefits occurred without a decrease in soluble Aβ species or plaque load. We conclude that losartan exerts potent preventive and restorative effects on AD hallmarks, possibly by mitigating AT1-initiated oxidative stress and normalizing memory-related AT4 receptors.

  19. Angiotensin II type 1 receptor blocker telmisartan induces apoptosis and autophagy in adult T-cell leukemia cells.

    PubMed

    Kozako, Tomohiro; Soeda, Shuhei; Yoshimitsu, Makoto; Arima, Naomichi; Kuroki, Ayako; Hirata, Shinya; Tanaka, Hiroaki; Imakyure, Osamu; Tone, Nanako; Honda, Shin-Ichiro; Soeda, Shinji

    2016-05-01

    Adult T-cell leukemia/lymphoma (ATL), an aggressive T-cell malignancy that develops after long-term infection with human T-cell leukemia virus (HTLV-1), requires new treatments. Drug repositioning, reuse of a drug previously approved for the treatment of another condition to treat ATL, offers the possibility of reduced time and risk. Among clinically available angiotensin II receptor blockers, telmisartan is well known for its unique ability to activate peroxisome proliferator-activated receptor-γ, which plays various roles in lipid metabolism, cellular differentiation, and apoptosis. Here, telmisartan reduced cell viability and enhanced apoptotic cells via caspase activation in ex vivo peripheral blood monocytes from asymptomatic HTLV-1 carriers (ACs) or via caspase-independent cell death in acute-type ATL, which has a poor prognosis. Telmisartan also induced significant growth inhibition and apoptosis in leukemia cell lines via caspase activation, whereas other angiotensin II receptor blockers did not induce cell death. Interestingly, telmisartan increased the LC3-II-enriched protein fraction, indicating autophagosome accumulation and autophagy. Thus, telmisartan simultaneously caused caspase activation and autophagy. A hypertension medication with antiproliferation effects on primary and leukemia cells is intriguing. Patients with an early diagnosis of ATL are generally monitored until the disease progresses; thus, suppression of progression from AC and indolent ATL to acute ATL is important. Our results suggest that telmisartan is highly effective against primary cells and leukemia cell lines in caspase-dependent and -independent manners, and its clinical use may suppress acute transformation and improve prognosis of patients with this mortal disease. This is the first report demonstrating a cell growth-inhibitory effect of telmisartan in fresh peripheral blood mononuclear cells from leukemia patients. PMID:27419050

  20. The Comparative Efficacy and Safety of the Angiotensin Receptor Blockers in the Management of Hypertension and Other Cardiovascular Diseases

    PubMed Central

    Abraham, Hazel Mae A.; White, C. Michael; White, William B.

    2014-01-01

    All national guidelines for the management of hypertension recommend angiotensin receptor blockers (ARBs) as an initial or add-on antihypertensive therapy. The 8 available ARBs have variable clinical efficacy when used for control of hypertension. Additive blood pressure (BP) lowering effects have been demonstrated when ARBs are combined with thiazide diuretics or dihydropyridine calcium channel blockers, augmenting hypertension control. Furthermore, therapeutic use of ARBs goes beyond their antihypertensive effects with evidence-based benefits in heart failure and diabetic renal disease particularly among ACE inhibitor intolerant patients. On the other hand, combining renin-angiotensin system blocking agents, a formerly common practice among medical subspecialists focusing on the management of hypertension, have ceased to do so as there is not only evidence of cardiovascular benefit, but modest evidence of harm, particularly with regard to renal dysfunction. The ARBs are very well tolerated as monotherapy as well as in combination with other anti-hypertensive medications that improve adherence to therapy and have become a mainstay in the treatment of stage 1 and 2 hypertension. PMID:25416320

  1. Transcranial random noise stimulation-induced plasticity is NMDA-receptor independent but sodium-channel blocker and benzodiazepines sensitive

    PubMed Central

    Chaieb, Leila; Antal, Andrea; Paulus, Walter

    2015-01-01

    Background: Application of transcranial random noise stimulation (tRNS) between 0.1 and 640 Hz of the primary motor cortex (M1) for 10 min induces a persistent excitability increase lasting for at least 60 min. However, the mechanism of tRNS-induced cortical excitability alterations is not yet fully understood. Objective: The main aim of this study was to get first efficacy data with regard to the possible neuronal effect of tRNS. Methods: Single-pulse transcranial magnetic stimulation (TMS) was used to measure levels of cortical excitability before and after combined application of tRNS at an intensity of 1 mA for 10 min stimulation duration and a pharmacological agent (or sham) on eight healthy male participants. Results: The sodium channel blocker carbamazepine showed a tendency toward inhibiting MEPs 5–60 min poststimulation. The GABAA agonist lorazepam suppressed tRNS-induced cortical excitability increases at 0–20 and 60 min time points. The partial NMDA receptor agonist D-cycloserine, the NMDA receptor antagonist dextromethorphan and the D2/D3 receptor agonist ropinirole had no significant effects on the excitability increases seen with tRNS. Conclusions: In contrast to transcranial direct current stimulation (tDCS), aftereffects of tRNS are seem to be not NMDA receptor dependent and can be suppressed by benzodiazepines suggesting that tDCS and tRNS depend upon different mechanisms. PMID:25914617

  2. Renin-angiotensin-aldosterone system inhibition: overview of the therapeutic use of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, mineralocorticoid receptor antagonists, and direct renin inhibitors.

    PubMed

    Mercier, Kelly; Smith, Holly; Biederman, Jason

    2014-12-01

    Angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) therapy in hypertensive diabetic patients with macroalbuminuria, microalbuminuria, or normoalbuminuria has been repeatedly shown to improve cardiovascular mortality and reduce the decline in glomerular filtration rate. Renin-angiotensin-aldosterone system (RAAS) blockade in normotensive diabetic patients with normoalbuminuria or microalbuminuria cannot be advocated at present. Dual RAAS inhibition with ACE inhibitors plus ARBs or ACE inhibitors plus direct renin inhibitors has failed to improve cardiovascular or renal outcomes but has predisposed patients to serious adverse events.

  3. Renin-angiotensin-aldosterone system inhibition: overview of the therapeutic use of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, mineralocorticoid receptor antagonists, and direct renin inhibitors.

    PubMed

    Mercier, Kelly; Smith, Holly; Biederman, Jason

    2014-12-01

    Angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) therapy in hypertensive diabetic patients with macroalbuminuria, microalbuminuria, or normoalbuminuria has been repeatedly shown to improve cardiovascular mortality and reduce the decline in glomerular filtration rate. Renin-angiotensin-aldosterone system (RAAS) blockade in normotensive diabetic patients with normoalbuminuria or microalbuminuria cannot be advocated at present. Dual RAAS inhibition with ACE inhibitors plus ARBs or ACE inhibitors plus direct renin inhibitors has failed to improve cardiovascular or renal outcomes but has predisposed patients to serious adverse events. PMID:25439533

  4. [NEPHROPROTECTIVE PROPERTIES OF 5-HT3 RECEPTOR BLOCKER RU-63 IN EXPERIMENTAL ACUTE RENAL FAILURE UNDER HYPERGRAVITY CONDITIONS].

    PubMed

    Zaitseva, E N; Dubishchev, A V; Yakovlev, D S; Anisimova, V A

    2016-01-01

    The effective diuretic dose of 5-HT3 receptor blocker RU-63 (1 mg/kg) was found in experiments on white rats. It is established that the diuretic and saluretic effects of compound RU-63 increase on the background of impact of the gravitational factor. Compound RU-63 (1 mg/kg, subcutaneously) administered daily under hypergravity conditions (3 g in the direction of centrifugal force toward the kidneys) in animals with model ischemic acute renal failure increased excretory function of kidneys, glomerular filtration rate, and creatininuresis (on average by 180%; p < 0.05), and decreased serum creatinine, urinary excretion of protein, lactate dehydrogenase, and g-glutamyl transferase (on average by 49%; p < 0.05) as compared to the untreated control. Under similar conditions, the diuretic hydrochlorothiazide (in a dose of 20 mg/kg, intragastric) produced a more pronounced creatininuretic action than that of RU-63 (by 358%; p < 0.05). PMID:27455574

  5. Quantitative phosphoproteomics unravels biased phosphorylation of serotonin 2A receptor at Ser280 by hallucinogenic versus nonhallucinogenic agonists.

    PubMed

    Karaki, Samah; Becamel, Carine; Murat, Samy; Mannoury la Cour, Clotilde; Millan, Mark J; Prézeau, Laurent; Bockaert, Joël; Marin, Philippe; Vandermoere, Franck

    2014-05-01

    The serotonin 5-HT(2A) receptor is a primary target of psychedelic hallucinogens such as lysergic acid diethylamine, mescaline, and psilocybin, which reproduce some of the core symptoms of schizophrenia. An incompletely resolved paradox is that only some 5-HT(2A) receptor agonists exhibit hallucinogenic activity, whereas structurally related agonists with comparable affinity and activity lack such a psychoactive activity. Using a strategy combining stable isotope labeling by amino acids in cell culture with enrichment in phosphorylated peptides by means of hydrophilic interaction liquid chromatography followed by immobilized metal affinity chromatography, we compared the phosphoproteome in HEK-293 cells transiently expressing the 5-HT(2A) receptor and exposed to either vehicle or the synthetic hallucinogen 1-[2,5-dimethoxy-4-iodophenyl]-2-aminopropane (DOI) or the nonhallucinogenic 5-HT(2A) agonist lisuride. Among the 5995 identified phosphorylated peptides, 16 sites were differentially phosphorylated upon exposure of cells to DOI versus lisuride. These include a serine (Ser(280)) located in the third intracellular loop of the 5-HT(2A) receptor, a region important for its desensitization. The specific phosphorylation of Ser(280) by hallucinogens was further validated by quantitative mass spectrometry analysis of immunopurified receptor digests and by Western blotting using a phosphosite specific antibody. The administration of DOI, but not of lisuride, to mice, enhanced the phosphorylation of 5-HT(2A) receptors at Ser(280) in the prefrontal cortex. Moreover, hallucinogens induced a less pronounced desensitization of receptor-operated signaling in HEK-293 cells and neurons than did nonhallucinogenic agonists. The mutation of Ser(280) to aspartic acid (to mimic phosphorylation) reduced receptor desensitization by nonhallucinogenic agonists, whereas its mutation to alanine increased the ability of hallucinogens to desensitize the receptor. This study reveals a biased

  6. Quantitative Phosphoproteomics Unravels Biased Phosphorylation of Serotonin 2A Receptor at Ser280 by Hallucinogenic versus Nonhallucinogenic Agonists*

    PubMed Central

    Karaki, Samah; Becamel, Carine; Murat, Samy; Mannoury la Cour, Clotilde; Millan, Mark J.; Prézeau, Laurent; Bockaert, Joël; Marin, Philippe; Vandermoere, Franck

    2014-01-01

    The serotonin 5-HT2A receptor is a primary target of psychedelic hallucinogens such as lysergic acid diethylamine, mescaline, and psilocybin, which reproduce some of the core symptoms of schizophrenia. An incompletely resolved paradox is that only some 5-HT2A receptor agonists exhibit hallucinogenic activity, whereas structurally related agonists with comparable affinity and activity lack such a psychoactive activity. Using a strategy combining stable isotope labeling by amino acids in cell culture with enrichment in phosphorylated peptides by means of hydrophilic interaction liquid chromatography followed by immobilized metal affinity chromatography, we compared the phosphoproteome in HEK-293 cells transiently expressing the 5-HT2A receptor and exposed to either vehicle or the synthetic hallucinogen 1-[2,5-dimethoxy-4-iodophenyl]-2-aminopropane (DOI) or the nonhallucinogenic 5-HT2A agonist lisuride. Among the 5995 identified phosphorylated peptides, 16 sites were differentially phosphorylated upon exposure of cells to DOI versus lisuride. These include a serine (Ser280) located in the third intracellular loop of the 5-HT2A receptor, a region important for its desensitization. The specific phosphorylation of Ser280 by hallucinogens was further validated by quantitative mass spectrometry analysis of immunopurified receptor digests and by Western blotting using a phosphosite specific antibody. The administration of DOI, but not of lisuride, to mice, enhanced the phosphorylation of 5-HT2A receptors at Ser280 in the prefrontal cortex. Moreover, hallucinogens induced a less pronounced desensitization of receptor-operated signaling in HEK-293 cells and neurons than did nonhallucinogenic agonists. The mutation of Ser280 to aspartic acid (to mimic phosphorylation) reduced receptor desensitization by nonhallucinogenic agonists, whereas its mutation to alanine increased the ability of hallucinogens to desensitize the receptor. This study reveals a biased phosphorylation of

  7. Perioperative management of patients treated with angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers: a quality improvement audit.

    PubMed

    Vijay, A; Grover, A; Coulson, T G; Myles, P S

    2016-05-01

    Previous studies have shown that patients continuing angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers on the day of surgery are more likely to have significant intraoperative hypotension, higher rates of postoperative acute kidney injury, and lower incidences of postoperative atrial fibrillation. However, many of these studies were prone to bias and confounding, and questions remain over the validity of these outcomes. This observational, before-and-after quality improvement audit aimed to assess the effect of withholding these medications on the morning of surgery. We recruited 323 participants, with 83 (26%) having their preoperative angiotensin-converting enzyme inhibitor (ACEi) or angiotensin II receptor blocker (ARB) withheld on the day of surgery. There were only very small Spearman rank-order correlations between time since last dose of these medications (rho -0.12, P=0.057) and intraoperative and recovery room intravenous fluid administration (rho -0.11, P=0.042). There was no statistically significant difference between the continued or withheld groups in vasopressor (metaraminol use 3.5 [1.5-8.3] mg versus 3.5 [1.5-8.5] mg, P=0.67) or intravenous fluid administration (1000 ml [800-1500] ml versus 1000 [800-1500] ml, P=0.096), nor rates of postoperative acute kidney injury (13% vs 18%, P=0.25) or atrial fibrillation (15% versus 18%, P=0.71). This audit found no significant differences in measured outcomes between the continued or withheld ACEi/ARB groups. This finding should be interpreted with caution due to the possibility of confounding and an insufficient sample size. However, as the finding is in contrast to many previous studies, future prospective randomised clinical trials are required to answer this important question.

  8. Perioperative management of patients treated with angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers: a quality improvement audit.

    PubMed

    Vijay, A; Grover, A; Coulson, T G; Myles, P S

    2016-05-01

    Previous studies have shown that patients continuing angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers on the day of surgery are more likely to have significant intraoperative hypotension, higher rates of postoperative acute kidney injury, and lower incidences of postoperative atrial fibrillation. However, many of these studies were prone to bias and confounding, and questions remain over the validity of these outcomes. This observational, before-and-after quality improvement audit aimed to assess the effect of withholding these medications on the morning of surgery. We recruited 323 participants, with 83 (26%) having their preoperative angiotensin-converting enzyme inhibitor (ACEi) or angiotensin II receptor blocker (ARB) withheld on the day of surgery. There were only very small Spearman rank-order correlations between time since last dose of these medications (rho -0.12, P=0.057) and intraoperative and recovery room intravenous fluid administration (rho -0.11, P=0.042). There was no statistically significant difference between the continued or withheld groups in vasopressor (metaraminol use 3.5 [1.5-8.3] mg versus 3.5 [1.5-8.5] mg, P=0.67) or intravenous fluid administration (1000 ml [800-1500] ml versus 1000 [800-1500] ml, P=0.096), nor rates of postoperative acute kidney injury (13% vs 18%, P=0.25) or atrial fibrillation (15% versus 18%, P=0.71). This audit found no significant differences in measured outcomes between the continued or withheld ACEi/ARB groups. This finding should be interpreted with caution due to the possibility of confounding and an insufficient sample size. However, as the finding is in contrast to many previous studies, future prospective randomised clinical trials are required to answer this important question. PMID:27246933

  9. Lysergic acid diethylamide-induced Fos expression in rat brain: role of serotonin-2A receptors.

    PubMed

    Gresch, P J; Strickland, L V; Sanders-Bush, E

    2002-01-01

    Lysergic acid diethylamide (LSD) produces altered mood and hallucinations in humans and binds with high affinity to serotonin-2A (5-HT(2A)) receptors. Although LSD interacts with other receptors, the activation of 5-HT(2A) receptors is thought to mediate the hallucinogenic properties of LSD. The goal of this study was to identify the brain sites activated by LSD and to determine the influence of 5-HT(2A) receptors in this activation. Rats were pretreated with the 5-HT(2A) receptor antagonist MDL 100907 (0.3 mg/kg, i.p.) or vehicle 30 min prior to LSD (500 microg/kg, i.p.) administration and killed 3 h later. Brain tissue was examined for Fos protein expression by immunohistochemistry. LSD administration produced a five- to eight-fold increase in Fos-like immunoreactivity in medial prefrontal cortex, anterior cingulate cortex, and central nucleus of amygdala. However, in dorsal striatum and nucleus accumbens no increase in Fos-like immunoreactivity was observed. Pretreatment with MDL 100907 completely blocked LSD-induced Fos-like immunoreactivity in medial prefrontal cortex and anterior cingulate cortex, but only partially blocked LSD-induced Fos-like immunoreactivity in amygdala. Double-labeled immunohistochemistry revealed that LSD did not induce Fos-like immunoreactivity in cortical cells expressing 5-HT(2A) receptors, suggesting an indirect activation of cortical neurons. These results indicate that the LSD activation of medial prefrontal cortex and anterior cingulate cortex is mediated by 5-HT(2A) receptors, whereas in amygdala 5-HT(2A) receptor activation is a component of the response. These findings support the hypothesis that the medial prefrontal cortex, anterior cingulate cortex, and perhaps the amygdala, are important regions involved in the production of hallucinations.

  10. [The ability of NMDA glutamate receptor blockers to prevent a pentylenetetrazole kindling in mice and morphological changes in the hippocampus].

    PubMed

    Vasil'ev, D S; Tumanova, N L; Lavrent'eva, V V; Starshinova, L A; Zhabko, E P; Lukomskaia, N Ia; Zhuravin, I A; Magazanik, L G

    2013-09-01

    We investigated in mice the relationship between convulsions and morphological changes of hippocampal neurons that arise in the development of pentylentetrazol (PTZ)-induced kindling. The kindling was caused by of 35 mg/kg PTZ i.p. 3 times a week for a month. By the end of this period, 70% of the mice responded to the injections of PTZ with pronounced clonic or tonic-clonic seizures. The hippocampal slices (layer stratum pyramidale, CA1, Nissl's stain) obtained from mice exhibiting seizures revealed a large number of modified cells (24.7 +/- 2.1%). These hyperchromic neurons have been characterized by a decrease of the size cell body, there was a loss of turgor, the body cells shrink, and dendritic spines curl. Part of the cells took the shape of elongated neck. Such modified the dark type of neurons contained only 2.3 +/- 2.3% in the hippocampus of intact mice, and 30% of the mice resistant to the convulsive action ofPTZ during the period of observation. The expression of protein NeuN (Fox3) in hippocamal neuron including the hyperchromic once suggests that neurons on the whole did not die and were relatively viable. Preventive administration of NMDA receptor blockers (0.5 mg/kg, memantine 0.1 mg/kg or IEM-1958 1 mg/kg, s.c.) 30 minutes prior to PTZ reduced the proportion of mice which exhibited PTZ kindling from 70% to 40%. The modified neurons were observed in which the PTZ kindling due to the blocker presence did not develop, i.e., the same as in intact mice. Contrary, 24.0 +/- 5.6% of hyperchromic neurons were found in the hippocampal slices from mice manifested seizures, despite the co-administration of NMDA blockers. The data obtained indicate that modified neurons are the result of seizures suffered by the animals in the course of PTZ kindling, and that the blockade of NMDA glutamate receptors can suppress manifestations of seizures and the accompanying morphological changes of hippocampal neurons.

  11. A small difference in the molecular structure of angiotensin II receptor blockers induces AT1 receptor-dependent and -independent beneficial effects

    PubMed Central

    Fujino, Masahiro; Miura, Shin-ichiro; Kiya, Yoshihiro; Tominaga, Yukio; Matsuo, Yoshino; Karnik, Sadashiva S; Saku, Keijiro

    2013-01-01

    Angiotensin II (Ang II) type 1 (AT1) receptor blockers (ARBs) induce multiple pharmacological beneficial effects, but not all ARBs have the same effects and the molecular mechanisms underlying their actions are not certain. In this study, irbesartan and losartan were examined because of their different molecular structures (irbesartan has a cyclopentyl group whereas losartan has a chloride group). We analyzed the binding affinity and production of inositol phosphate (IP), monocyte chemoattractant protein-1 (MCP-1) and adiponectin. Compared with losartan, irbesartan showed a significantly higher binding affinity and slower dissociation rate from the AT1 receptor and a significantly higher degree of inverse agonism and insurmountability toward IP production. These effects of irbesartan were not seen with the AT1-Y113A mutant receptor. On the basis of the molecular modeling of the ARBs–AT1 receptor complex and a mutagenesis study, the phenyl group at Tyr113 in the AT1 receptor and the cyclopentyl group of irbesartan may form a hydrophobic interaction that is stronger than the losartan–AT1 receptor interaction. Interestingly, irbesartan inhibited MCP-1 production more strongly than losartan. This effect was mediated by the inhibition of nuclear factor-kappa B activation that was independent of the AT1 receptor in the human coronary endothelial cells. In addition, irbesartan, but not losartan, induced significant adiponectin production that was mediated by peroxisome proliferator-activated receptor-γ activation in 3T3-L1 adipocytes, and this effect was not mediated by the AT1 receptor. In conclusion, irbesartan induced greater beneficial effects than losartan due to small differences between their molecular structures, and these differential effects were both dependent on and independent of the AT1 receptor. PMID:20668453

  12. Telmisartan, an AT1 receptor blocker and a PPAR gamma activator, alleviates liver fibrosis induced experimentally by Schistosoma mansoni infection

    PubMed Central

    2013-01-01

    Background Hepatic schistosomiasis is considered to be one of the most prevalent forms of chronic liver disease in the world due to its complication of liver fibrosis. The demonstration of the pro-fibrogenic role of angiotensin (Ang) II in chronic liver disease brought up the idea that anti-Ang II agents may be effective in improving hepatic fibrosis by either blocking Ang II type 1 (AT1) receptors or inhibiting the angiotensin converting enzyme. Peroxisome proliferator-activated receptors gamma (PPARγ) activation has been also shown to inhibit hepatic stellate cell activation and progression of fibrosis. The present study has aimed at testing the anti-fibrogenic effects of telmisartan; an AT1 receptor blocker and a PPARγ partial agonist, alone or combined with praziquantel (PZQ) on Schistosoma mansoni-induced liver fibrosis in mice. Methods To achieve the aim of the study, two sets of experiments were performed in which telmisartan was initiated at the 5th (set 1) and the 10th (set 2) weeks post infection to assess drug efficacy in both acute and chronic stages of liver fibrosis, respectively. Schistosoma mansoni-infected mice were randomly divided into the following four groups: infected-control (I), telmisartan-treated (II), PZQ-treated (III), and telmisartan+PZQ-treated (IV). In addition, a normal non-infected group was used for comparison. Parasitological (hepatomesenteric worm load and oogram pattern), histopathological, morphometric, immunohistochemical (hepatic expressions of matrix metalloproteinase-2; MMP-2 and tissue inhibitor of metalloproteinase-2; TIMP-2), and biochemical (serum transforming growth factor beta 1; TGF-β1 and liver function tests) studies were performed. Results Telmisartan failed to improve the parasitological parameters, while it significantly (P<0.05) decreased the mean granuloma diameter, area of fibrosis, and serum TGF-β1. Additionally, telmisartan increased MMP-2 and decreased TIMP-2 hepatic expression. Combined treatment

  13. Inhibition of in vivo [(3)H]MK-801 binding by NMDA receptor open channel blockers and GluN2B antagonists in rats and mice.

    PubMed

    Fernandes, Alda; Wojcik, Trevor; Baireddy, Praveena; Pieschl, Rick; Newton, Amy; Tian, Yuan; Hong, Yang; Bristow, Linda; Li, Yu-Wen

    2015-11-01

    N-methyl-D-aspartate (NMDA) receptor antagonists, including open channel blockers and GluN2B receptor subtype selective antagonists, have been developed for the treatment of depression. The current study investigated effects of systemically administered NMDA channel blockers and GluN2B receptor antagonists on NMDA receptor activity in rodents using in vivo [(3)H]MK-801 binding. The receptor occupancy of GluN2B antagonists was measured using ex vivo [(3)H]Ro 25-6981 binding. Ketamine, a NMDA receptor channel blocker, produced a dose/exposure- and time-dependent inhibition of in vivo [(3)H]MK-801 binding that was maximal at ~100%. The complete inhibition of in vivo [(3)H]MK-801 binding was also observed with NMDA receptor channel blockers, AZD6765 (Lanicemine) and MK-801 (Dizocilpine). CP-101,606 (Traxoprodil), a GluN2B antagonist, produced a dose/exposure- and time-dependent inhibition of in vivo [(3)H]MK-801 binding that was maximal at ~60%. Partial inhibition was also observed with other GluN2B antagonists including MK-0657 (CERC-301), EVT-101, Ro 25-6981 and radiprodil. For all GluN2B antagonists tested, partial [(3)H]MK-801 binding inhibition was achieved at doses saturating GluN2B receptor occupancy. Combined treatment with ketamine (10mg/kg, i.p.) and Ro 25-6981(10mg/kg, i.p.) produced a level of inhibition of in vivo [(3)H]MK-801 binding that was similar to treatment with either agent alone. In conclusion, this in vivo [(3)H]MK-801 binding study shows that NMDA receptor activity in the rodent forebrain can be inhibited completely by channel blockers, but only partially (~60%) by GluN2B receptor antagonists. At doses effective in preclinical models of depression, ketamine may preferentially inhibit the same population of NMDA receptors as Ro 25-6981, namely those containing the GluN2B subunit. PMID:26325093

  14. Structure of the high-affinity binding site for noncompetitive blockers of the acetylcholine receptor: serine-262 of the delta subunit is labeled by [3H]chlorpromazine.

    PubMed Central

    Giraudat, J; Dennis, M; Heidmann, T; Chang, J Y; Changeux, J P

    1986-01-01

    The membrane-bound acetylcholine receptor from Torpedo marmorata was photolabeled by the noncompetitive channel blocker [3H]chlorpromazine under equilibrium conditions in the presence of agonist. Incorporation of radioactivity into all subunits occurred and was reduced by addition of phencyclidine, a specific ligand for the high-affinity site for noncompetitive blockers. The delta subunit was purified and digested with trypsin, and the resulting fragments were fractionated by reversed-phase HPLC. The labeled peptide could not be purified to homogeneity because of its marked hydrophobic character, but a combination of differential CNBr subcleavage and cosequencing of partially purified fragments enabled us to identify Ser-262 as being labeled by [3H]chlorpromazine. The labeling of this particular residue was prevented by phencyclidine and thus took place at the level of, or in proximity to, the high-affinity site for noncompetitive blockers. Ser-262 is located in a hydrophobic and potentially transmembrane segment termed MII. Images PMID:3085104

  15. Angiotensin receptor blockers for the reduction of proteinuria in diabetic patients with overt nephropathy: results from the AMADEO study

    PubMed Central

    Bichu, Prasad; Nistala, Ravi; Khan, Asma; Sowers, James R; Whaley-Connell, Adam

    2009-01-01

    Diabetic kidney disease is characterized by persistent albuminuria (>300 mg/dl or >200 μg/min) that is confirmed on at least 2 occasions 3 to 6 months apart, with a progressive decline in the glomerular filtration rate (GFR), elevated arterial blood pressure, and an increased risk for cardiovascular morbidity and mortality. Diabetic kidney disease is the leading cause of end stage renal disease (ESRD) prompting investigators to evaluate mechanisms by which to slow disease progression. One such mechanism is to block the activity of angiotensin II at the receptor site and agents that follow this mechanism are referred to as angiotensin receptor blockers (ARB). There is sufficient clinical evidence to support that ARB have protective effects on kidney function in patients with diabetes and hypertension. However, in the past decade there have been few investigations comparing individual ARBs on renal outcomes. Telmisartan, a lipophilic ARB with a long half-life, has been hypothesized to have a greater anti-proteinuric effect when compared to the shorter acting losartan. Therefore, the A comparison of telMisartan versus losArtan in hypertensive type 2 DiabEtic patients with Overt nephropathy (AMADEO) trial sought to investigate renal and cardiovascular endpoints. In this review, we discuss the pathophysiology of diabetic kidney disease and implications of the AMADEO trial in the context of current understanding from recent outcome trials. PMID:19436679

  16. Post-trial administration of H1 histamine receptor blocker improves appetitive reversal learning and memory in goldfish, Carassius auratus.

    PubMed

    Spieler, R E; Nelson, C A; Huston, J P; Mattioli, R

    1999-12-17

    Based on the hypothesis that neuronal histamine exerts an inhibitory influence on learning and reinforcement, goldfish were tested for post-trial effects of the H1 receptor blocker chlorpheniramine (CPA) on learning the location of a food source in one of two compartments, one black the other white, with a feeder located in each compartment. Testing was carried out over 6 days. On the training day a food pellet was placed into the feeder of one of the compartments. After consumption of the food the fish were injected i.p. with either vehicle or CPA either immediately after training or 3 h later. Twenty-four-hours later, food was placed in the same compartment and the time to begin feeding was recorded. On the next day the location of the food pellet was reversed, and testing was continued for 4 days. On the first test day the time to begin feeding was significantly longer for the vehicle injected fish as compared with those injected with CPA. The vehicle group also took longer to begin feeding than the CPA group on the first reversal test day. The results of the 3-h delay groups indicated no significant differences between vehicle and drug for any experimental session. These results suggest that post-trial blockade of the H1 histamine receptor can affect appetitive learning in goldfish either by improving long-term memory consolidation and/or by the additive reinforcing effects of CPA (known from previous studies) on behavior.

  17. 6-Methoxyflavanones as Bitter Taste Receptor Blockers for hTAS2R39

    PubMed Central

    Roland, Wibke S. U.; Gouka, Robin J.; Gruppen, Harry; Driesse, Marianne; van Buren, Leo; Smit, Gerrit; Vincken, Jean-Paul

    2014-01-01

    Many (dietary) bitter compounds, e.g. flavonoids, activate bitter receptor hTAS2R39 in cell-based assays. Several flavonoids, amongst which some flavanones, are known not to activate this receptor. As certain flavanones are known to mask bitter taste sensorially, flavanones might act as bitter receptor antagonists. Fourteen flavanones were investigated for their potential to reduce activation of hTAS2R39 by epicatechin gallate (ECG), one of the main bitter compounds occurring in green tea. Three flavanones showed inhibitory behavior towards the activation of hTAS2R39 by ECG: 4′-fluoro-6-methoxyflavanone, 6,3′-dimethoxyflavanone, and 6-methoxyflavanone (in order of decreasing potency). The 6-methoxyflavanones also inhibited activation of hTAS2R14 (another bitter receptor activated by ECG), though to a lesser extent. Dose-response curves of ECG at various concentrations of the full antagonist 4′-fluoro-6-methoxyflavanone and wash-out experiments indicated reversible insurmountable antagonism. The same effect was observed for the structurally different agonist denatonium benzoate. PMID:24722342

  18. Abilities of candesartan and other AT(1) receptor blockers to impair angiotensin II-induced AT(1) receptor activation after wash-out.

    PubMed

    Kiya, Yoshihiro; Miura, Shin-ichiro; Matsuo, Yoshino; Karnik, Sadashiva S; Saku, Keijiro

    2012-03-01

    Angiotensin II (Ang II) binds to Ang II type 1 (AT(1)) receptor and evokes cell signaling, and subsequently stimulates vasoconstriction and cell proliferation, which eventually lead to cardiovascular disease. Since most AT(1) receptor blockers (ARBs) have molecular (differential) effects, we evaluated the specific features of candesartan and compared the abilities of candesartan and other ARBs (olmesartan, telmisartan, valsartan, irbesartan and losartan) to bind to and activate AT(1) receptors using a cell-based wash-out assay. Each ARB blocked Ang II-induced extracellular signal-regulated kinase (ERK) activation and inositol phosphate production to different degrees after wash-out. In addition, a small difference in the molecular structure, i.e. a carboxyl group, between candesartan and candesartan-7H was associated with a difference in the degree of this blocking effect. In addition, interaction between Gln(257) in the AT(1) receptor and the carboxyl group of candesartan may be partially associated with the effect of candesartan after wash-out. Although our findings regarding the molecular effects of ARB are based on basic research, these findings may lead to an exciting new area in the clinical application of ARBs. PMID:21824992

  19. The antiarrhythmic properties of quifenadine, H1-histamine receptor blocker in children with premature beats: a randomized controlled pilot trial.

    PubMed

    Makarov, Leonid; Balykova, Larisa; Soldatova, Olga; Komolyatova, Vera; Serebruany, Victor

    2010-01-01

    Despite evolving success of mini-invasive techniques in treating cardiac arrhythmias in children, pharmaceuticals remain the cornerstone therapeutic option. Beyond conventional antiarrhythmic agents such as amiodarone, local anesthetics, tranquilizers, anticonvulsants, and neuroleptics exhibit antiarrhythmic properties. H(1)-histamine receptor blockers are widely used in treating allergies in children. Observational studies suggest efficacy of these agents for treating or preventing tachyarrhythmias, although prolongation of QT interval, and ventricular arrhythmias occur. We determined safety and efficacy of antihistamine, quifenadine, versus conventional amiodarone on cardiac rhythm in children with frequent premature beats (PB). One hundred and four patients (mean age 10.8 +/- 3.2 years) with ventricular (n = 65), supraventricular (n = 39) PB were randomized 1:1 to quifenadine (2 mg kg(-1) day(-1); n = 54), or amiodarone (9 mg kg(-1) day(-1), n = 50) arms. Both groups were treated for 2 weeks. All patients underwent 24-hour Holter monitoring 3 times: before at 14-28 days after randomization, and during the follow up at 2-3 months. The mean frequency of PB in quifenadine group was 562 +/- 61 per hour and 597 +/- 78 per hour in the amiodarone-treated children. Full antiarrhythmic efficacy (PB < 75% from baseline) has been achieved in 23/54 (43%) of quifenadine-treated patients, which was less than after amiodarone treatment (37/50, 74%, P = 0.02). Quifenadine was mostly beneficial in children with supraventricular PB and/or bradycardia than in those with ventricular PB; it was associated with a trend toward increased heart rate during day (88.5 +/- 8.4 beats/min) and night (67.3 +/- 6.2) compared with amiodarone (79.6 +/- 7.8 and 56.1 +/- 5.7 beats/min, respectively; P = 0.04). The incidence of side effects in quifenadine group (drowsiness and headache) was low (2%) in contrast to the alarming 40% risk associated with amiodarone therapy. Quifanidine exhibits

  20. Presynaptic serotonin 2A receptors modulate thalamocortical plasticity and associative learning

    PubMed Central

    Barre, Alexander; Berthoux, Coralie; De Bundel, Dimitri; Valjent, Emmanuel; Bockaert, Joël; Marin, Philippe; Bécamel, Carine

    2016-01-01

    Higher-level cognitive processes strongly depend on a complex interplay between mediodorsal thalamus nuclei and the prefrontal cortex (PFC). Alteration of thalamofrontal connectivity has been involved in cognitive deficits of schizophrenia. Prefrontal serotonin (5-HT)2A receptors play an essential role in cortical network activity, but the mechanism underlying their modulation of glutamatergic transmission and plasticity at thalamocortical synapses remains largely unexplored. Here, we show that 5-HT2A receptor activation enhances NMDA transmission and gates the induction of temporal-dependent plasticity mediated by NMDA receptors at thalamocortical synapses in acute PFC slices. Expressing 5-HT2A receptors in the mediodorsal thalamus (presynaptic site) of 5-HT2A receptor-deficient mice, but not in the PFC (postsynaptic site), using a viral gene-delivery approach, rescued the otherwise absent potentiation of NMDA transmission, induction of temporal plasticity, and deficit in associative memory. These results provide, to our knowledge, the first physiological evidence of a role of presynaptic 5-HT2A receptors located at thalamocortical synapses in the control of thalamofrontal connectivity and the associated cognitive functions. PMID:26903620

  1. Comparison of behavioral effects of the NMDA receptor channel blockers memantine and ketamine in rats.

    PubMed

    Kotermanski, Shawn E; Johnson, Jon W; Thiels, Edda

    2013-08-01

    Memantine and ketamine block N-methyl-D-aspartate (NMDA) receptors with similar affinity and kinetics, yet their behavioral consequences differ: e.g., memantine is used to alleviate symptoms of Alzheimer's disease, whereas ketamine reproduces symptoms of schizophrenia. The two drugs exhibit different pharmacokinetics, which may play a principal role in their differential behavioral effects. To gain insight into the drugs' behavioral consequences, we treated adult male rats acutely with varying doses (0-40 mg/kg i.p.) of memantine or ketamine and assessed exploratory behavior and spatial working memory. To examine the importance of pharmacokinetics, we assessed behavior either 15 or 45 min after drug administration. Both drugs decreased ambulation, fine movements, and rearing at the beginning of the exploratory activity test; however, at the end of the test, high doses of only memantine increased ambulation and fine movements. High doses of both drugs disrupted spontaneous alternation, a measure of working memory, but high doses of only memantine elicited perseverative behavior. Surprisingly, ketamine's effects were influenced by the delay between drug administration and testing no more frequently than were memantine's. Our findings show that, regardless of test delay, memantine and ketamine evoke similar behavioral effects at lower doses, consistent with NMDA receptors being both drugs' principal site of action, but can have divergent effects at higher doses. Our results suggest that the divergence of memantine's and ketamine's behavioral consequences is likely to result from differences in mechanisms of NMDA receptor antagonism or actions at other targets.

  2. New insights into the management of hypertension and cardiovascular risk with Angiotensin receptor blockers: observational studies help us?

    PubMed

    Goudev, Assen

    2014-01-01

    Post-marketing observational studies are valuable for establishing the real-world effectiveness of treatment regimens in routine clinical practice as they typically monitor a diverse population of patients over many months. This article reviews recent observational studies of angiotensin receptor blockers (ARBs) for the management of hypertension: the 6-month eprosartan POWER study (n~29,400), the 3-month valsartan translational research programme (n~19,500), the 9-month irbesartan Treat to Target study (n=14,200), the 6-month irbesartan DO-IT survey (n~3300) and the 12-week candesartan CHILI survey programme (n=4600). Reduction in blood pressure with ARBs reported across these studies appears to be comparable for the different agents, although direct comparisons between studies cannot be made owing to different treatment durations and baseline patient demographics. Of these studies, the eprosartan POWER study, 2 of the 7 studies in the valsartan translational research programme, and the candesartan CHILI Triple T study measured total cardiovascular risk, as recommended in the 2013 European Society of Cardiology-European Society of Hypertension guidelines. The POWER study confirmed the value of the Systemic Coronary Risk Evaluation (SCORE) to accurately assess total cardiovascular risk. With the advent of new healthcare practices, such as the use of electronic health records (EHRs), observational studies in larger patient populations will become possible. In the future, algorithms embedded in EHR systems could evolve as decision support tools to inform on patient care. PMID:24847388

  3. Cognitive enhancing effect of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on learning and memory

    PubMed Central

    Nade, V. S.; Kawale, L. A.; Valte, K. D.; Shendye, N. V.

    2015-01-01

    Objective: The present study was designed to investigate cognitive enhancing property of angiotensin-converting enzymes inhibitors (ACEI) and angiotensin receptor blockers (ARBs) in rats. Materials and Methods: The elevated plus maze (EPM), passive avoidance test (PAT), and water maze test (WMT) were used to assess cognitive enhancing activity in young and aged rats. Ramipril (10 mg/kg, p.o.), perindopril (10 mg/kg, i.p), losartan (20 mg/kg, i.p), and valsartan (20 mg/kg, p.o) were administered to assess their effect on learning and memory. Scopolamine (1 mg/kg, i.p) was used to impair cognitive function. Piracetam (200 mg/kg, i.p) was used as reference drug. Results: All the treatments significantly attenuated amnesia induced by aging and scopolamine. In EPM, aged and scopolamine-treated rats showed an increase in transfer latency (TL) whereas, ACEI and ARBs showed a significant decrease in TL. Treatment with ACEI and ARBs significantly increased step down latencies and decreased latency to reach the platform in target quadrant in young, aged and scopolamine-treated animals in PAT and WMT, respectively. The treatments inhibited acetylcholinesterase (AChE) enzyme in the brain. Similarly, all the treatments attenuated scopolamine-induced lipid peroxidation and normalize antioxidant enzymes. Conclusion: The results suggest that the cognitive enhancing effect of ACEI and ARBs may be due to inhibition of AChE or by regulation of antioxidant system or increase in formation of angiotensin IV. PMID:26069362

  4. Cardiovascular risk reduction in hypertension: angiotensin-converting enzyme inhibitors, angiotensin receptor blockers. Where are we up to?

    PubMed

    Sindone, A; Erlich, J; Lee, C; Newman, H; Suranyi, M; Roger, S D

    2016-03-01

    Previously, management of hypertension has concentrated on lowering elevated blood pressure. However, the target has shifted to reducing absolute cardiovascular (CV) risk. It is estimated that two in three Australian adults have three or more CV risk factors at the same time. Moderate reductions in several risk factors can, therefore, be more effective than major reductions in one. When managing hypertension, therapy should be focused on medications with the strongest evidence for CV event reduction, substituting alternatives only when a primary choice is not appropriate. Hypertension management guidelines categorise angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) interchangeably as first-line treatments in uncomplicated hypertension. These medications have different mechanisms of action and quite different evidence bases. They are not interchangeable and their prescription should be based on clinical evidence. Despite this, currently ARB prescriptions are increasing at a higher rate than those for ACEI and other antihypertensive classes. Evidence that ACEI therapy prevents CV events and death, in patients with coronary artery disease or multiple CV risk factors, emerged from the European trial on reduction of cardiac events with perindopril in stable coronary artery disease (EUROPA) and Heart Outcomes Prevention Evaluation (HOPE) trials respectively. The consistent benefit has been demonstrated in meta-analyses. The clinical trial data for ARB are less consistent, particularly regarding CV outcomes and mortality benefit. The evidence supports the use of ACEI (Class 1a) compared with ARB despite current prescribing trends. PMID:26968600

  5. Role of angiotensin converting enzyme inhibitors and angiotensin receptor blockers in hypertension of chronic kidney disease and renoprotection. Study results

    PubMed Central

    Baltatzi, M; Savopoulos, Ch; Hatzitolios, A

    2011-01-01

    Chronic kidney disease (CKD) is a global health problem associated with considerable morbidity and mortality and despite advances in the treatment of end stage renal disease (ESRD) mechanisms to prevent and delay its progression are still being sought. The renin-angiotensin-aldosterone system (RAAS) plays a pivotal role in many of the pathophysiologic changes that lead to progression of renal disease. Traditionally RAAS was considered as an endocrine system and its principal role was to maintain blood pressure (BP). In recent years local RAAS has been described to operate independently from systemic and local angiotensin II (AngII) in the kidney to contribute in hypertension and kidney damage. The benefits of strict BP control in slowing kidney disease progression have been demonstrated in several clinical trials and the question whether specific agents like angiotensin converting enzyme antagonists (ACEIs) and angiotensin receptor blockers (ARBs) provide renoprotective benefits beyond BP lowering is to be answered. Several studies support these agents reduce proteinuria and protect renal function, whereas the opposite is stated by others. According to guidelines, their use is recommended as first line agents in diabetic renal disease and non diabetic renal disease with albuminuria, whereas there is no data to support the same in non diabetic nonalbuminuric renal disease. Dual blockage of RAAS with the combination of ACEIs and ARBs could offer an alternative in strict RAAS blockade, but studies up to now can not prove its safety and the combination is not recommended until ongoing trials will provide new and unarguable results. PMID:21897755

  6. Clinical and Pharmacotherapeutic Relevance of the Double-Chain Domain of the Angiotensin II Type 1 Receptor Blocker Olmesartan

    PubMed Central

    Kiya, Yoshihiro; Miura, Shin-ichiro; Fujino, Masahiro; Imaizumi, Satoshi; Karnik, Sadashiva S.; Saku, Keijiro

    2014-01-01

    We previously reported that the angiotensin II type 1 (AT1) receptor blocker (ARB) olmesartan has two important interactions to evoke inverse agonism (IA). We refer to these interactions as the “double-chain domain (DCD).” Since the clinical pharmacotherapeutic relevance of olmesartan is still unclear, we examined these effects in rats and humans. We analyzed the effects at an advanced stage of renal insufficiency in Dahl salt-sensitive hypertensive rats (Study 1). Rats were fed a high-salt diet from age 9 weeks and arbitrarily assigned to three treatment regimens at age 16 to 21 weeks: olmesartan (2 mg/kg/day) with DCD, a compound related to olmesartan without DCD (6 mg/kg/day, R-239470) or placebo. We also compared the depressor effects of olmesartan to those of other ARBs in patients with essential hypertension (Study 2). Thirty essential hypertensive outpatients who had been receiving ARBs other than olmesartan were recruited for this study. Our protocol was approved by the hospital ethics committee and informed consent was obtained from all patients 12 weeks prior to switching from ARBs other than olmesartan to olmesartan. In Study 1, olmesartan induced a more prominent suppression of the ratio of urinary protein excretion to creatinine at age 21 weeks without lowering blood pressure among the three groups. In Study 2, the depressor effect of olmesartan was significantly stronger than those of other ARBs, which do not contain the DCD. These additive effects by olmesartan may be due to DCD. PMID:20374187

  7. On the role of 5-HT(1A) receptor gene in behavioral effect of brain-derived neurotrophic factor.

    PubMed

    Naumenko, Vladimir S; Kondaurova, Elena M; Bazovkina, Daria V; Tsybko, Anton S; Il'chibaeva, Tatyana V; Popova, Nina K

    2014-08-01

    Experiments were made on a congenic AKR.CBA-D13Mit76C (76C) mouse strain created by transferring a chromosome 13 fragment containing the 5-HT1A receptor gene from a CBA strain to an AKR background. It was shown that 76C mice differed from AKR mice by decreased 5-HT1A receptor and tryptophan hydroxylase-2 (tph-2) genes expression in the midbrain. Functional activity of 5-HT2A receptors and 5-HT(2A) receptor mRNA levels in the midbrain and hippocampus of 76C mice were decreased compared with AKR mice. Central brain-derived neurotrophic factor (BDNF) administration (300 ng i.c.v.) reduced 5-HT1A and 5-HT(2A) receptor mRNA levels in the frontal cortex and tph-2 mRNA level in the midbrain of AKR mice. However, BDNF failed to produce any effect on the expression of 5-HT(1A) , 5-HT(2A) , and tph-2 genes in 76C mice but decreased functional activity of 5-HT(2A) receptors in 76C mice and increased it in AKR mice. BDNF restored social deficiency in 76C mice but produced asocial behavior (aggressive attacks towards young mice) in AKR mice. The data indicate that a small genetic variation altered the response to BDNF and show an important role of 5-HT(1A) receptor gene in the 5-HT system response to BDNF treatment and in behavioral effects of BDNF.

  8. Behavioral evidence for interactions between a hallucinogenic drug and group II metabotropic glutamate receptors.

    PubMed

    Gewirtz, J C; Marek, G J

    2000-11-01

    Recent electrophysiological studies in our laboratory have demonstrated a physiological interaction between 5-HT(2A) and metabotropic glutamate2/3 (mGlu2/3) receptors in the medial prefrontal cortex. Several behavioral studies have found that phenethylamine hallucinogens with partial agonist activity at 5-HT(2A) receptors induce head shakes when directly administered into the medial prefrontal cortex. The purpose of the present experiments was to examine whether an interaction occurs between mGlu2/3 and 5-HT(2A) receptors on a behavioral level using head shakes induced by phenethylamine hallucinogens as a model of 5-HT(2A) receptor activation. Administration of the mGlu2/3 agonist LY354740 (0.3-10 mg/kg, ip) suppressed head shakes induced by the phenethylamine hallucinogen 1-(2, 5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI). Conversely, administration of the mGlu2/3 antagonist LY341495 (1 mg/kg, ip) enhanced the frequency of DOI-induced head shakes. Taken together, these results raise the possibility that the psychomimetic properties of hallucinogenic drugs may be mediated in part, via increased glutamate release following activation of 5-HT(2A) receptors.

  9. Arginine-Vasopressin Receptor Blocker Conivaptan Reduces Brain Edema and Blood-Brain Barrier Disruption after Experimental Stroke in Mice

    PubMed Central

    Zeynalov, Emil; Jones, Susan M.; Seo, Jeong-Woo; Snell, Lawrence D.; Elliott, J. Paul

    2015-01-01

    Background Stroke is a major cause of morbidity and mortality. Stroke is complicated by brain edema and blood-brain barrier (BBB) disruption, and is often accompanied by increased release of arginine-vasopressin (AVP). AVP acts through V1a and V2 receptors to trigger hyponatremia, vasospasm, and platelet aggregation which can exacerbate brain edema. The AVP receptor blockers conivaptan (V1a and V2) and tolvaptan (V2) are used to correct hyponatremia, but their effect on post-ischemic brain edema and BBB disruption remains to be elucidated. Therefore, we conducted this study to investigate if these drugs can prevent brain edema and BBB disruption in mice after stroke. Methods Experimental mice underwent the filament model of middle cerebral artery occlusion (MCAO) with reperfusion. Mice were treated with conivaptan, tolvaptan, or vehicle. Treatments were initiated immediately at reperfusion and administered IV (conivaptan) or orally (tolvaptan) for 48 hours. Physiological variables, neurological deficit scores (NDS), plasma and urine sodium and osmolality were recorded. Brain water content (BWC) and Evans Blue (EB) extravasation index were evaluated at the end point. Results Both conivaptan and tolvaptan produced aquaresis as indicated by changes in plasma and urine sodium levels. However plasma and urine osmolality was changed only by conivaptan. Unlike tolvaptan, conivaptan improved NDS and reduced BWC in the ipsilateral hemisphere: from 81.66 ± 0.43% (vehicle) to 78.28 ± 0.48% (conivaptan, 0.2 mg, p < 0.05 vs vehicle). Conivaptan also attenuated the EB extravasation from 1.22 ± 0.08 (vehicle) to 1.01 ± 0.02 (conivaptan, 0.2 mg, p < 0.05). Conclusion Continuous IV infusion with conivaptan for 48 hours after experimental stroke reduces brain edema, and BBB disruption. Conivaptan but not tolvaptan may potentially be used in patients to prevent brain edema after stroke. PMID:26275173

  10. Unmasking the functions of the chromaffin cell α7 nicotinic receptor by using short pulses of acetylcholine and selective blockers

    PubMed Central

    López, Manuela G.; Montiel, Carmen; Herrero, Carlos J.; García-Palomero, Esther; Mayorgas, Inés; Hernández-Guijo, Jesús M.; Villarroya, M.; Olivares, Román; Gandía, Luis; McIntosh, J. Michael; Olivera, Baldomero M.; García, Antonio G.

    1998-01-01

    Methyllycaconitine (MLA), α-conotoxin ImI, and α-bungarotoxin inhibited the release of catecholamines triggered by brief pulses of acetylcholine (ACh) (100 μM, 5 s) applied to fast-superfused bovine adrenal chromaffin cells, with IC50s of 100 nM for MLA and 300 nM for α-conotoxin ImI and α-bungarotoxin. MLA (100 nM), α-conotoxin ImI (1 μM), and α-bungarotoxin (1 μM) halved the entry of 45Ca2+ stimulated by 5-s pulses of 300 μM ACh applied to incubated cells. These supramaximal concentrations of α7 nicotinic receptor blockers depressed by 30% (MLA), 25% (α-bungarotoxin), and 50% (α-conotoxin ImI) the inward current generated by 1-s pulses of 100 μM ACh, applied to voltage-clamped chromaffin cells. In Xenopus oocytes expressing rat brain α7 neuronal nicotinic receptor for acetylcholine nAChR, the current generated by 1-s pulses of ACh was blocked by MLA, α-conotoxin ImI, and α-bungarotoxin with IC50s of 0.1 nM, 100 nM, and 1.6 nM, respectively; the current through α3β4 nAChR was unaffected by α-conotoxin ImI and α-bungarotoxin, and weakly blocked by MLA (IC50 = 1 μM). The functions of controlling the electrical activity, the entry of Ca2+, and the ensuing exocytotic response of chromaffin cells were until now exclusively attributed to α3β4 nAChR; the present results constitute the first evidence to support a prominent role of α7 nAChR in controlling such functions, specially under the more physiological conditions used here to stimulate chromaffin cells with brief pulses of ACh. PMID:9826675

  11. Activation of serotonin 2A receptors underlies the psilocybin-induced effects on α oscillations, N170 visual-evoked potentials, and visual hallucinations.

    PubMed

    Kometer, Michael; Schmidt, André; Jäncke, Lutz; Vollenweider, Franz X

    2013-06-19

    Visual illusions and hallucinations are hallmarks of serotonergic hallucinogen-induced altered states of consciousness. Although the serotonergic hallucinogen psilocybin activates multiple serotonin (5-HT) receptors, recent evidence suggests that activation of 5-HT2A receptors may lead to the formation of visual hallucinations by increasing cortical excitability and altering visual-evoked cortical responses. To address this hypothesis, we assessed the effects of psilocybin (215 μg/kg vs placebo) on both α oscillations that regulate cortical excitability and early visual-evoked P1 and N170 potentials in healthy human subjects. To further disentangle the specific contributions of 5-HT2A receptors, subjects were additionally pretreated with the preferential 5-HT2A receptor antagonist ketanserin (50 mg vs placebo). We found that psilocybin strongly decreased prestimulus parieto-occipital α power values, thus precluding a subsequent stimulus-induced α power decrease. Furthermore, psilocybin strongly decreased N170 potentials associated with the appearance of visual perceptual alterations, including visual hallucinations. All of these effects were blocked by pretreatment with the 5-HT2A antagonist ketanserin, indicating that activation of 5-HT2A receptors by psilocybin profoundly modulates the neurophysiological and phenomenological indices of visual processing. Specifically, activation of 5-HT2A receptors may induce a processing mode in which stimulus-driven cortical excitation is overwhelmed by spontaneous neuronal excitation through the modulation of α oscillations. Furthermore, the observed reduction of N170 visual-evoked potentials may be a key mechanism underlying 5-HT2A receptor-mediated visual hallucinations. This change in N170 potentials may be important not only for psilocybin-induced states but also for understanding acute hallucinatory states seen in psychiatric disorders, such as schizophrenia and Parkinson's disease. PMID:23785166

  12. Activation of serotonin 2A receptors underlies the psilocybin-induced effects on α oscillations, N170 visual-evoked potentials, and visual hallucinations.

    PubMed

    Kometer, Michael; Schmidt, André; Jäncke, Lutz; Vollenweider, Franz X

    2013-06-19

    Visual illusions and hallucinations are hallmarks of serotonergic hallucinogen-induced altered states of consciousness. Although the serotonergic hallucinogen psilocybin activates multiple serotonin (5-HT) receptors, recent evidence suggests that activation of 5-HT2A receptors may lead to the formation of visual hallucinations by increasing cortical excitability and altering visual-evoked cortical responses. To address this hypothesis, we assessed the effects of psilocybin (215 μg/kg vs placebo) on both α oscillations that regulate cortical excitability and early visual-evoked P1 and N170 potentials in healthy human subjects. To further disentangle the specific contributions of 5-HT2A receptors, subjects were additionally pretreated with the preferential 5-HT2A receptor antagonist ketanserin (50 mg vs placebo). We found that psilocybin strongly decreased prestimulus parieto-occipital α power values, thus precluding a subsequent stimulus-induced α power decrease. Furthermore, psilocybin strongly decreased N170 potentials associated with the appearance of visual perceptual alterations, including visual hallucinations. All of these effects were blocked by pretreatment with the 5-HT2A antagonist ketanserin, indicating that activation of 5-HT2A receptors by psilocybin profoundly modulates the neurophysiological and phenomenological indices of visual processing. Specifically, activation of 5-HT2A receptors may induce a processing mode in which stimulus-driven cortical excitation is overwhelmed by spontaneous neuronal excitation through the modulation of α oscillations. Furthermore, the observed reduction of N170 visual-evoked potentials may be a key mechanism underlying 5-HT2A receptor-mediated visual hallucinations. This change in N170 potentials may be important not only for psilocybin-induced states but also for understanding acute hallucinatory states seen in psychiatric disorders, such as schizophrenia and Parkinson's disease.

  13. Snooker Structure-Based Pharmacophore Model Explains Differences in Agonist and Blocker Binding to Bitter Receptor hTAS2R39

    PubMed Central

    Roland, Wibke S. U.; Sanders, Marijn P. A.; van Buren, Leo; Gouka, Robin J.; Gruppen, Harry; Vincken, Jean-Paul; Ritschel, Tina

    2015-01-01

    The human bitter taste receptor hTAS2R39 can be activated by many dietary (iso)flavonoids. Furthermore, hTAS2R39 activity can be blocked by 6-methoxyflavanones, 4’-fluoro-6-methoxyflavanone in particular. A structure-based pharmacophore model of the hTAS2R39 binding pocket was built using Snooker software, which has been used successfully before for drug design of GPCRs of the rhodopsin subfamily. For the validation of the model, two sets of compounds, both of which contained actives and inactives, were used: (i) an (iso)flavonoid-dedicated set, and (ii) a more generic, structurally diverse set. Agonists were characterized by their linear binding geometry and the fact that they bound deeply in the hTAS2R39 pocket, mapping the hydrogen donor feature based on T5.45 and N3.36, analogues of which have been proposed to play a key role in activation of GPCRs. Blockers lack hydrogen-bond donors enabling contact to the receptor. Furthermore, they had a crooked geometry, which could sterically hinder movement of the TM domains upon receptor activation. Our results reveal characteristics of hTAS2R39 agonist and bitter blocker binding, which might facilitate the development of blockers suitable to counter the bitterness of dietary hTAS2R39 agonists in food applications. PMID:25729848

  14. Patch clamp combined with voltage/concentration clamp to determine the kinetics and voltage dependency of N-methyl-D-aspartate (NMDA) receptor open channel blockers.

    PubMed

    Parsons, Chris G; Gilling, Kate E

    2014-01-01

    Electrophysiological techniques can be used to great effect to help determine the mechanism of action of a compound. However, many factors can compromise the resulting data and their analysis, such as the speed of solution exchange, expression of additional ion channel populations including other ligand-gated receptors and voltage-gated channels, compounds having multiple binding sites, and current desensitization and rundown. In this chapter, such problems and their solutions are discussed and illustrated using data from experiments involving the uncompetitive NMDA receptor antagonist memantine. Memantine differs from many other NMDA receptor channel blockers in that it is well tolerated and does not cause psychotomimetic effects at therapeutic doses. Various electrophysiological parameters of NMDA-induced current blockade by memantine have been proposed to be important in determining therapeutic tolerability; potency, onset and offset kinetics, and voltage dependency. These were all measured using whole cell patch clamp techniques using hippocampal neurons. Full results are shown here for memantine, and these are summarized and compared to those from similar experiments with other NMDA channel blockers. The interpretation of these results is discussed, as are theories concerning the tolerability of NMDA channel blockers, with the aim of illustrating how electrophysiological data can be used to form and support a physiological hypothesis.

  15. G-protein Receptor Kinase 5 Regulates the Cannabinoid Receptor 2-induced Up-regulation of Serotonin 2A Receptors*

    PubMed Central

    Franklin, Jade M.; Carrasco, Gonzalo A.

    2013-01-01

    We have recently reported that cannabinoid agonists can up-regulate and enhance the activity of serotonin 2A (5-HT2A) receptors in the prefrontal cortex (PFCx). Increased expression and activity of cortical 5-HT2A receptors has been associated with neuropsychiatric disorders, such as anxiety and schizophrenia. Here we report that repeated CP55940 exposure selectively up-regulates GRK5 proteins in rat PFCx and in a neuronal cell culture model. We sought to examine the mechanism underlying the regulation of GRK5 and to identify the role of GRK5 in the cannabinoid agonist-induced up-regulation and enhanced activity of 5-HT2A receptors. Interestingly, we found that cannabinoid agonist-induced up-regulation of GRK5 involves CB2 receptors, β-arrestin 2, and ERK1/2 signaling because treatment with CB2 shRNA lentiviral particles, β-arrestin 2 shRNA lentiviral particles, or ERK1/2 inhibitor prevented the cannabinoid agonist-induced up-regulation of GRK5. Most importantly, we found that GRK5 shRNA lentiviral particle treatment prevented the cannabinoid agonist-induced up-regulation and enhanced 5-HT2A receptor-mediated calcium release. Repeated cannabinoid exposure was also associated with enhanced phosphorylation of CB2 receptors and increased interaction between β-arrestin 2 and ERK1/2. These latter phenomena were also significantly inhibited by GRK5 shRNA lentiviral treatment. Our results suggest that sustained activation of CB2 receptors, which up-regulates 5-HT2A receptor signaling, enhances GRK5 expression; the phosphorylation of CB2 receptors; and the β-arrestin 2/ERK interactions. These data could provide a rationale for some of the adverse effects associated with repeated cannabinoid agonist exposure. PMID:23592773

  16. Debate: angiotensin-converting enzyme inhibitors versus angiotensin II receptor blockers--a gap in evidence-based medicine.

    PubMed

    Ball, Stephen G; White, William B

    2003-05-22

    In this article, 2 leading physicians debate the strength of outcome data on the efficacy of angiotensin-converting enzyme (ACE) inhibitors versus angiotensin II receptor blockers (ARBs) for reducing the incidence of cardiovascular, cerebrovascular, and renovascular events. Dr. Stephen G. Ball notes that the efficacy of ACE inhibitors for reducing the risk for myocardial infarction independent of their effects on blood pressure is controversial. In the Heart Outcomes Prevention Evaluation (HOPE) study, ramipril treatment in high-risk patients was associated with a 20% reduction in the risk for myocardial infarction; mean reduction in blood pressure was 3 mm Hg for systolic blood pressure and 1 mm Hg for diastolic blood pressure. The HOPE investigators propose that the 20% reduction was much greater than would be expected based on the observed blood pressure reduction. However, a meta-regression analysis of blood pressure reduction in >20 antihypertensive therapy outcome trials found that the reduction in myocardial infarction risk with ramipril observed in HOPE was consistent with the modest blood pressure reduction seen with that agent. Nevertheless, there are convincing data for prevention of myocardial infarction with ACE inhibitors in patients with heart failure, including those with heart failure after myocardial infarction, as well as supportive evidence from studies in patients with diabetes mellitus and concomitant hypertension. On the other hand, Dr. William B. White takes the position that ARBs are well-tolerated antihypertensive agents that specifically antagonize the angiotensin II type 1 (AT(1)) receptor and provide a more complete block of the pathologic effects of angiotensin II-which are mediated via the AT(1) receptor-than ACE inhibitors. The Evaluation of Losartan in the Elderly (ELITE) II study and the Valsartan Heart Failure Trial (ValHeFT) suggest that ARBs reduce the risk for mortality in patients with congestive heart failure. The Losartan

  17. Debate: angiotensin-converting enzyme inhibitors versus angiotensin II receptor blockers--a gap in evidence-based medicine.

    PubMed

    Ball, Stephen G; White, William B

    2003-05-22

    In this article, 2 leading physicians debate the strength of outcome data on the efficacy of angiotensin-converting enzyme (ACE) inhibitors versus angiotensin II receptor blockers (ARBs) for reducing the incidence of cardiovascular, cerebrovascular, and renovascular events. Dr. Stephen G. Ball notes that the efficacy of ACE inhibitors for reducing the risk for myocardial infarction independent of their effects on blood pressure is controversial. In the Heart Outcomes Prevention Evaluation (HOPE) study, ramipril treatment in high-risk patients was associated with a 20% reduction in the risk for myocardial infarction; mean reduction in blood pressure was 3 mm Hg for systolic blood pressure and 1 mm Hg for diastolic blood pressure. The HOPE investigators propose that the 20% reduction was much greater than would be expected based on the observed blood pressure reduction. However, a meta-regression analysis of blood pressure reduction in >20 antihypertensive therapy outcome trials found that the reduction in myocardial infarction risk with ramipril observed in HOPE was consistent with the modest blood pressure reduction seen with that agent. Nevertheless, there are convincing data for prevention of myocardial infarction with ACE inhibitors in patients with heart failure, including those with heart failure after myocardial infarction, as well as supportive evidence from studies in patients with diabetes mellitus and concomitant hypertension. On the other hand, Dr. William B. White takes the position that ARBs are well-tolerated antihypertensive agents that specifically antagonize the angiotensin II type 1 (AT(1)) receptor and provide a more complete block of the pathologic effects of angiotensin II-which are mediated via the AT(1) receptor-than ACE inhibitors. The Evaluation of Losartan in the Elderly (ELITE) II study and the Valsartan Heart Failure Trial (ValHeFT) suggest that ARBs reduce the risk for mortality in patients with congestive heart failure. The Losartan

  18. In vitro and in vivo human metabolism of degarelix, a gonadotropin-releasing hormone receptor blocker.

    PubMed

    Sonesson, Anders; Rasmussen, Birgitte Buur

    2013-07-01

    Degarelix is a decapeptide that shows high affinity/selectivity to human gonadotropin-releasing hormone receptors and has been approved for the treatment of advanced prostate cancer in the United States, European Union, and Japan. To investigate the metabolism of degarelix in humans, in vitro metabolism was addressed in liver tissue and in vivo metabolism was studied in plasma and excreta samples collected in clinical studies. In addition, drug transporter interaction potential of degarelix with selected efflux transporters and uptake transporters was studied using in vitro membrane vesicle-based assays and whole cell-based assays. In vitro degradation was observed in fresh hepatocytes; less than 25% of the initial concentration of degarelix remained after incubation at 37°C for 2 hours. One metabolite was detected, representing a truncated nonapeptide of degarelix. The same metabolite was also detected at low concentrations in plasma. The in vivo investigations also showed that degarelix is excreted unchanged via the urine but is undergoing extensive sequential peptidic degradation during its elimination via the hepato-biliary pathway. No unique human metabolites of degarelix were detected in the circulation or in the excreta. Degarelix did not show any interaction with selected efflux transporters and uptake transporters up to concentrations representing 200 times the clinical concentration. Because degarelix does not seem to interact with the cytochrome P450 enzyme system as substrate, inhibitor, or inducer and does not show any interaction with hepatic and renal uptake and efflux transporters, the risk for pharmacokinetic drug-drug interactions with this compound is highly unlikely.

  19. Structure-Function Basis of Attenuated Inverse Agonism of Angiotensin II Type 1 Receptor Blockers for Active-State Angiotensin II Type 1 Receptor

    PubMed Central

    Unal, Hamiyet; Karnik, Sadashiva S.; Node, Koichi

    2015-01-01

    Ligand-independent signaling by the angiotensin II type 1 receptor (AT1R) can be activated in clinical settings by mechanical stretch and autoantibodies as well as receptor mutations. Transition of the AT1R to the activated state is known to lower inverse agonistic efficacy of clinically used AT1R blockers (ARBs). The structure-function basis for reduced efficacy of inverse agonists is a fundamental aspect that has been understudied not only in relation to the AT1R but also regarding other homologous receptors. Here, we demonstrate that the active-state transition in the AT1R indeed attenuates an inverse agonistic effect of four biphenyl-tetrazole ARBs through changes in specific ligand-receptor interactions. In the ground state, tight interactions of four ARBs with a set of residues (Ser109TM3, Phe182ECL2, Gln257TM6, Tyr292TM7, and Asn295TM7) results in potent inverse agonism. In the activated state, the ARB-AT1R interactions shift to a different set of residues (Val108TM3, Ser109TM3, Ala163TM4, Phe182ECL2, Lys199TM5, Tyr292TM7, and Asn295TM7), resulting in attenuated inverse agonism. Interestingly, V108I, A163T, N295A, and F182A mutations in the activated state of the AT1R shift the functional response to the ARB binding toward agonism, but in the ground state the same mutations cause inverse agonism. Our data show that the second extracellular loop is an important regulator of the functional states of the AT1R. Our findings suggest that the quest for discovering novel ARBs, and improving current ARBs, fundamentally depends on the knowledge of the unique sets of residues that mediate inverse agonistic potency in the two states of the AT1R. PMID:26121982

  20. Beta-blocker, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, nitrate-hydralazine, diuretics, aldosterone antagonist, ivabradine, devices and digoxin (BANDAID(2) ): an evidence-based mnemonic for the treatment of systolic heart failure.

    PubMed

    Chia, N; Fulcher, J; Keech, A

    2016-06-01

    Heart failure causes significant morbidity and mortality, with recognised underutilisation rates of guideline-based therapies. Our aim was to review current evidence for heart failure treatments and derive a mnemonic summarising best practice, which might assist physicians in patient care. Treatments were identified for review from multinational society guidelines and recent randomised trials, with a primary aim of examining their effects in systolic heart failure patients on mortality, hospitalisation rates and symptoms. Secondary aims were to consider other clinical benefits. MEDLINE and EMBASE were searched using a structured keyword strategy and the retrieved articles were evaluated methodically to produce an optimised reference list for each treatment. We devised the mnemonic BANDAID (2) , standing for beta-blocker, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, nitrate-hydralazine (or potentially neprilysin inhibitor), diuretics, aldosterone antagonist, ivabradine, devices (automatic implantable cardioverter defibrillator, cardiac resynchronisation therapy or both) and digoxin as a representation of treatments with strong evidence for their use in systolic heart failure. Treatment with omega-3 fatty acids, statins or anti-thrombotic therapies has limited benefits in a general heart failure population. Adoption of this mnemonic for current evidence-based treatments for heart failure may help improve prescribing rates and patient outcomes in this debilitating, high mortality condition.

  1. 5-HT2 receptors mediate functional modulation of GABAa receptors and inhibitory synaptic transmissions in human iPS-derived neurons

    PubMed Central

    Wang, Haitao; Hu, Lingli; Liu, Chunhua; Su, Zhenghui; Wang, Lihui; Pan, Guangjin; Guo, Yiping; He, Jufang

    2016-01-01

    Neural progenitors differentiated from induced pluripotent stem cells (iPS) hold potentials for treating neurological diseases. Serotonin has potent effects on neuronal functions through multiple receptors, underlying a variety of neural disorders. Glutamate and GABA receptors have been proven functional in neurons differentiated from iPS, however, little is known about 5-HT receptor-mediated modulation in such neuronal networks. In the present study, human iPS were differentiated into cells possessing featured physiological properties of cortical neurons. Whole-cell patch-clamp recording was used to examine the involvement of 5-HT2 receptors in functional modulation of GABAergic synaptic transmission. We found that serotonin and DOI (a selective agonist of 5-HT2A/C receptor) reversibly reduced GABA-activated currents, and this 5-HT2A/C receptor mediated inhibition required G protein, PLC, PKC, and Ca2+ signaling. Serotonin increased the frequency of miniature inhibitory postsynaptic currents (mIPSCs), which could be mimicked by α-methylserotonin, a 5-HT2 receptor agonist. In contrast, DOI reduced both frequency and amplitude of mIPSCs. These findings suggested that in iPS-derived human neurons serotonin postsynaptically reduced GABAa receptor function through 5-HT2A/C receptors, but presynaptically other 5-HT2 receptors counteracted the action of 5-HT2A/C receptors. Functional expression of serotonin receptors in human iPS-derived neurons provides a pre-requisite for their normal behaviors after grafting. PMID:26837719

  2. Outcomes of 83 fetuses exposed to angiotensin receptor blockers during the second or third trimesters: a literature review.

    PubMed

    Shimada, Chisa; Akaishi, Rina; Cho, Kazutoshi; Morikawa, Mamoru; Kaneshi, Yosuke; Yamda, Takahiro; Minakami, Hisanori

    2015-05-01

    This literature review was conducted to provide better counsel to pregnant women who erroneously took angiotensin receptor blockers (ARBs) during the second and/or third trimesters regarding infant outcomes. Information was available on 83 fetuses in 34 literature reports, including one that we encountered recently. Fourteen pregnancies were terminated, and six were unknown regarding status of amniotic fluid volume (AFV). Fifty-eight and five fetuses did and did not show oligohydramnios, respectively, after being exposed to ARBs. Of the 58 fetuses that presented with oligohydramnios, 57 were exposed to ARBs at gestational week (GW) ⩾ 20, and 19 exhibited resolution of oligohydramnios 1-6 weeks after cessation of ARBs. The 24 mothers without oligohydramnios at delivery ceased taking ARBs earlier (GW of 26.8 ± 5.1 vs. 31.8 ± 4.0, respectively, P = 0.000) and had longer duration of gestation after cessation of ARBs (8.4 ± 5.2 vs. 0.7 ± 2.3 weeks, respectively, P = 0.000). The mothers without oligohydramnios also had better outcomes in terms of favorable infant outcomes (63% (15/24) vs. 15% (6/39), respectively, P = 0.000) and infant mortality rates (13% (3/24) vs. 56% (22/39), respectively, P = 0.001) than the 39 with oligohydramnios. Thus, a favorable outcome may be feasible if the fetuses are not indicated for prompt delivery at presentation and exhibit normal AFV or resolution of oligohydramnios after cessation of ARBs. Although the prevalence rate of oligohydramnios was high in this study, it may have been due to publication bias. A prospective study suggested a lower prevalence rate than that reported in the present study. PMID:25693853

  3. Renoprotective effects of angiotensin receptor blocker and stem cells in acute kidney injury: Involvement of inflammatory and apoptotic markers

    PubMed Central

    Al-Mutabagani, Laila A; Alnakhli, Anwar M; Sobh, Mohamed A; Mohammed, Hoda E

    2015-01-01

    Cisplatin, Cis-diamminedichloroplatinum (CDDP), is a platinum-based chemotherapy drug, and its chemotherapeutic use is restricted by nephrotoxicity. Inflammatory and apoptotic mechanisms play a central role in the pathogenesis of CDDP-induced acute kidney injury (AKI). The aim of this study was to compare the therapeutic potential of candesartan, angiotensin II receptor blocker, versus bone marrow-derived mesenchymal stem cells (BM-MSCs) in a rat model of CDDP-induced nephrotoxicity. Adult male Wistar rats (n = 40) were divided into four groups; Normal control: received saline injection, CDPP group: received CDDP injection (6 mg/kg single dose), Candesartan group: received candesartan (10 mg/kg/day) for 10 days + CDDP at day 3, and Stem cells group: received CDDP + BM-MSCs intravenously one day after CDDP injection. The rats were sacrificed seven days after CDDP injection. Significant elevation in serum creatinine and urea, renal levels of tumor necrosis factor (TNF)-α and monocyte chemoattractant protein (MCP)-1, renal expressions of nuclear factor kappa B (NF-κB), p38-mitogen-activated protein kinase (MAPK), caspase-3 and Bcl-2-associated x protein (Bax) were found in CDDP-injected rats when compared to normal rats. Both candesartan and BM-MSCs ameliorated renal function and reduced significantly the inflammatory markers (TNF-α , NF-κB, p38-MAPK and MCP-1) and apoptotic markers (caspase-3 and Bax) in renal tissue after CDDP injection. Candesartan as well as BM-MSCs have anti-inflammatory and anti-apoptotic actions and they can be used as nephroprotective agents against CDDP-induced nephrotoxicity. BM-MSCs is more effective than candesartan in amelioration of AKI induced by CDDP. PMID:25825359

  4. Effects of Angiotensin-II Receptor Blocker on Inhibition of Thrombogenicity in a Canine Atrial Fibrillation Model

    PubMed Central

    Jung, Jae Seung; Kim, Min Kyung; Sim, Jaemin; Kim, Jin Seok; Lim, Hong Euy; Park, Sang Weon; Kim, Young-Hoon

    2016-01-01

    Background and Objectives Angiotensin-II receptor blockers (ARBs) are known to reduce the development of atrial fibrillation (AF) through reverse-remodeling. However, the effect of ARBs on thrombogenicity in AF remains unknown. Materials and Methods Twelve dogs were assigned to control (n=4), ARB (candesartan cilexitil 10 mg/kg/day p.o., 12 weeks; n=4), or sham (n=4) groups. Sustained AF was induced by rapid atrial pacing. Both arterial and venous serum levels of tissue inhibitor of matrix metalloproteinase-1, von Willebrand factor, P-selectin, and vascular cell adhesion molecule-1 (VCAM-1) were measured at baseline and during AF (0, 4, and 12 weeks) with enzyme-linked immunosorbent assay. Biopsies from both atria including the appendages were performed to semi-quantitatively assess endocardial and myocardial fibrosis after 12 weeks. Results The serum levels of bio-markers were not significantly different at baseline or during AF between the control and the candesartan groups. The levels were not significantly different over time, but there was a trend toward a decrease in arterial VCAM-1 from 4 to 12 weeks in the candesartan group compared to the control group. The grades of endocardial fibrosis after 12 weeks but not those of myocardial fibrosis were slightly reduced in the candesartan group compared to the control group. Conclusion This study did not show that the ARB candesartan significantly reverses thrombogenicity or fibrosis during AF. Future studies using a larger number of subjects are warranted to determine the therapeutic effect of renin-angiotensin-aldosterone system blockade on prothrombogenic processes in AF. PMID:27275170

  5. Antihypertensive efficacy of the angiotensin receptor blocker azilsartan medoxomil compared with the angiotensin-converting enzyme inhibitor ramipril

    PubMed Central

    Bönner, G; Bakris, G L; Sica, D; Weber, M A; White, W B; Perez, A; Cao, C; Handley, A; Kupfer, S

    2013-01-01

    Drug therapy often fails to control hypertension. Azilsartan medoxomil (AZL-M) is a newly developed angiotensin II receptor blocker with high efficacy and good tolerability. This double-blind, controlled, randomised trial compared its antihypertensive efficacy and safety vs the angiotensin-converting enzyme inhibitor ramipril (RAM) in patients with clinic systolic blood pressure (SBP) 150–180 mm Hg. Patients were randomised (n=884) to 20 mg AZL-M or 2.5 mg RAM once daily for 2 weeks, then force-titrated to 40 or 80 mg AZL-M or 10 mg RAM for 22 weeks. The primary endpoint was change in trough, seated, clinic SBP. Mean patient age was 57±11 years, 52.4% were male, 99.5% were Caucasian. Mean baseline BP was 161.1±7.9/94.9±9.0 mm Hg. Clinic SBP decreased by 20.6±0.95 and 21.2±0.95 mm Hg with AZL-M 40 and 80 mg vs12.2±0.95 mm Hg with RAM (P<0.001 for both AZL-M doses). Adverse events leading to discontinuation were less frequent with AZL-M 40 and 80 mg (2.4% and 3.1%, respectively) than with RAM (4.8%). These data demonstrated that treatment of stage 1–2 hypertension with AZL-M was more effective than RAM and better tolerated. PMID:23514842

  6. Antihypertensive, insulin-sensitising and renoprotective effects of a novel, potent and long-acting angiotensin II type 1 receptor blocker, azilsartan medoxomil, in rat and dog models.

    PubMed

    Kusumoto, Keiji; Igata, Hideki; Ojima, Mami; Tsuboi, Ayako; Imanishi, Mitsuaki; Yamaguchi, Fuminari; Sakamoto, Hiroki; Kuroita, Takanobu; Kawaguchi, Naohiro; Nishigaki, Nobuhiro; Nagaya, Hideaki

    2011-11-01

    The pharmacological profile of a novel angiotensin II type 1 receptor blocker, azilsartan medoxomil, was compared with that of the potent angiotensin II receptor blocker olmesartan medoxomil. Azilsartan, the active metabolite of azilsartan medoxomil, inhibited the binding of [(125)I]-Sar(1)-I1e(8)-angiotensin II to angiotensin II type 1 receptors. Azilsartan medoxomil inhibited angiotensin II-induced pressor responses in rats, and its inhibitory effects lasted 24h after oral administration. The inhibitory effects of olmesartan medoxomil disappeared within 24h. ID(50) values were 0.12 and 0.55 mg/kg for azilsartan medoxomil and olmesartan medoxomil, respectively. In conscious spontaneously hypertensive rats (SHRs), oral administration of 0.1-1mg/kg azilsartan medoxomil significantly reduced blood pressure at all doses even 24h after dosing. Oral administration of 0.1-3mg/kg olmesartan medoxomil also reduced blood pressure; however, only the two highest doses significantly reduced blood pressure 24h after dosing. ED(25) values were 0.41 and 1.3mg/kg for azilsartan medoxomil and olmesartan medoxomil, respectively. In renal hypertensive dogs, oral administration of 0.1-1mg/kg azilsartan medoxomil reduced blood pressure more potently and persistently than that of 0.3-3mg/kg olmesartan medoxomil. In a 2-week study in SHRs, azilsartan medoxomil showed more stable antihypertensive effects than olmesartan medoxomil and improved the glucose infusion rate, an indicator of insulin sensitivity, more potently (≥ 10 times) than olmesartan medoxomil. Azilsartan medoxomil also exerted more potent antiproteinuric effects than olmesartan medoxomil in Wistar fatty rats. These results suggest that azilsartan medoxomil is a potent angiotensin II receptor blocker that has an attractive pharmacological profile as an antihypertensive agent.

  7. Differential interactions of indolealkylamines with 5-hydroxytryptamine receptor subtypes.

    PubMed

    McKenna, D J; Repke, D B; Lo, L; Peroutka, S J

    1990-03-01

    Affinities of drugs for 21 indolealkylamine derivatives, some with putative hallucinogenic activity, were determined at 5-HT1A, 5-HT2A and 5-HT2B recognition sites, using radioligand competition studies. Nearly all of the derivatives displayed greatest potency for the 5-HT2A receptor, labelled by [125I]R-(-)DOI in the cortex of the rat. Most derivatives displayed 2-10 times lower affinity at the HT2B receptor labelled by [3H]ketanserin in bovine cortex. Derivatives lacking ring substituents displayed lower affinities for all of the recognition sites, compared to derivatives substituted in the 4- or 5-position of the indole ring. The 4-hydroxylated derivatives displayed 25-380-fold selectivity for the 5-HT2A site, vs the 5-HT1A site, while the 5-substituted derivatives displayed approximately equal potency at the 5-HT1A and 5-HT2A sites. Affinity of all the compounds at the 5-HT2B site was greater than 300 nM. The 6-substituted derivatives displayed greater than micromolar affinities for all of the 5-HT recognition sites examined. The size of the N,N-dialkyl substituent was a secondary determinant of affinity, with groups larger than N,N-diisopropyl resulting in a marked reduction in affinity at both the 5-HT2A and 5-HT1A recognition sites. This study demonstrated that hallucinogenic 4-hydroxy-indolealkylamines, like psychotomimetic phenylisopropylamines, bind potently and selectively to the 5-HT2A recognition site, labelled by [125I]R-(-)DOI. This provides further evidence indicating that this recently described subtype of the 5-HT2 receptor may partially mediate the action of hallucinogenic agents.

  8. Serotonin 2A receptor agonist binding in the human brain with [11C]Cimbi-36

    PubMed Central

    Ettrup, Anders; da Cunha-Bang, Sophie; McMahon, Brenda; Lehel, Szabolcs; Dyssegaard, Agnete; Skibsted, Anine W; Jørgensen, Louise M; Hansen, Martin; Baandrup, Anders O; Bache, Søren; Svarer, Claus; Kristensen, Jesper L; Gillings, Nic; Madsen, Jacob; Knudsen, Gitte M

    2014-01-01

    [11C]Cimbi-36 was recently developed as a selective serotonin 2A (5-HT2A) receptor agonist radioligand for positron emission tomography (PET) brain imaging. Such an agonist PET radioligand may provide a novel, and more functional, measure of the serotonergic system and agonist binding is more likely than antagonist binding to reflect 5-HT levels in vivo. Here, we show data from a first-in-human clinical trial with [11C]Cimbi-36. In 29 healthy volunteers, we found high brain uptake and distribution according to 5-HT2A receptors with [11C]Cimbi-36 PET. The two-tissue compartment model using arterial input measurements provided the most optimal quantification of cerebral [11C]Cimbi-36 binding. Reference tissue modeling was feasible as it induced a negative but predictable bias in [11C]Cimbi-36 PET outcome measures. In five subjects, pretreatment with the 5-HT2A receptor antagonist ketanserin before a second PET scan significantly decreased [11C]Cimbi-36 binding in all cortical regions with no effects in cerebellum. These results confirm that [11C]Cimbi-36 binding is selective for 5-HT2A receptors in the cerebral cortex and that cerebellum is an appropriate reference tissue for quantification of 5-HT2A receptors in the human brain. Thus, we here describe [11C]Cimbi-36 as the first agonist PET radioligand to successfully image and quantify 5-HT2A receptors in the human brain. PMID:24780897

  9. Distinct properties of telmisartan on agonistic activities for peroxisome proliferator-activated receptor γ among clinically used angiotensin II receptor blockers: drug-target interaction analyses.

    PubMed

    Kakuta, Hirotoshi; Kurosaki, Eiji; Niimi, Tatsuya; Gato, Katsuhiko; Kawasaki, Yuko; Suwa, Akira; Honbou, Kazuya; Yamaguchi, Tomohiko; Okumura, Hiroyuki; Sanagi, Masanao; Tomura, Yuichi; Orita, Masaya; Yonemoto, Takako; Masuzaki, Hiroaki

    2014-04-01

    A proportion of angiotensin II type 1 receptor blockers (ARBs) improves glucose dyshomeostasis and insulin resistance in a clinical setting. Of these ARBs, telmisartan has the unique property of being a partial agonist for peroxisome proliferator-activated receptor γ (PPARγ). However, the detailed mechanism of how telmisartan acts on PPARγ and exerts its insulin-sensitizing effect is poorly understood. In this context, we investigated the agonistic activity of a variety of clinically available ARBs on PPARγ using isothermal titration calorimetry (ITC) and surface plasmon resonance (SPR) system. Based on physicochemical data, we then reevaluated the metabolically beneficial effects of telmisartan in cultured murine adipocytes. ITC and SPR assays demonstrated that telmisartan exhibited the highest affinity of the ARBs tested. Distribution coefficient and parallel artificial membrane permeability assays were used to assess lipophilicity and cell permeability, for which telmisartan exhibited the highest levels of both. We next examined the effect of each ARB on insulin-mediated glucose metabolism in 3T3-L1 preadipocytes. To investigate the impact on adipogenesis, 3T3-L1 preadipocytes were differentiated with each ARB in addition to standard inducers of differentiation for adipogenesis. Telmisartan dose-dependently facilitated adipogenesis and markedly augmented the mRNA expression of adipocyte fatty acid-binding protein (aP2), accompanied by an increase in the uptake of 2-deoxyglucose and protein expression of glucose transporter 4 (GLUT4). In contrast, other ARBs showed only marginal effects in these experiments. In accordance with its highest affinity of binding for PPARγ as well as the highest cell permeability, telmisartan superbly activates PPARγ among the ARBs tested, thereby providing a fresh avenue for treating hypertensive patients with metabolic derangement. PMID:24424487

  10. Moderate versus intensive treatment of hypertension with amlodipine/valsartan for patients uncontrolled on angiotensin receptor blocker monotherapy

    PubMed Central

    Oparil, Suzanne; Giles, Thomas; Ofili, Elizabeth O.; Pitt, Bertram; Seifu, Yodit; Hilkert, Robert; Samuel, Rita; Sowers, James R.

    2013-01-01

    Objectives Many angiotensin receptor blocker (ARB) monotherapy patients need at least two agents to control blood pressure (BP). We investigated whether initiating intensive treatment with combination amlodipine/valsartan was superior to moderate treatment with amlodipine/valsartan in patients previously uncontrolled on ARB monotherapy. Methods In this 12-week study, patients aged at least 18 years on ARB (other than valsartan) for at least 28 days (with treatment-naïve patients or those not controlled on agents other than an ARB treated with open-label olmesartan 20 or 40 mg, respectively, for 28 days) and with uncontrolled mean sitting systolic blood pressure (MSSBP; ≥150–<200 mmHg) were randomized to amlodipine/valsartan 5/320 mg (n = 369) or 5/160 mg (n = 359). At week 2, the dose was increased to 10/320 mg in the intensive arm. Hydrochlorothiazide 12.5 mg was added to both arms at week 4. Optional up-titration with hydrochlorothiazide 12.5 mg at week 8 was allowed if MSSBP was more than 140 mmHg. Results At baseline, mean office sitting BP was comparable in the intensive (163.9/95.5 mmHg) and moderate (163.3/95.0 mmHg) groups. Intensive treatment provided greater BP reductions versus moderate treatment (P<0.05) from week 4 (−23.0/−10.4 versus −19.2/−8.7 mmHg; primary endpoint) to week 12 (−29.0/−14.8 versus −25.3/−12.3 mmHg). Adverse events were reported by a similar percentage of patients in both groups (36.3% intensive, 37.6% moderate); peripheral edema was more common with intensive versus moderate treatment (8.7 versus 4.5%; P=0.025). Conclusions Initiating treatment with an intensive dose of amlodipine/valsartan provides significantly greater BP lowering versus moderate treatment in hypertensive patients unresponsive to ARB monotherapy. Both treatment regimens were generally well tolerated based on adverse event reports, but the lack of routine laboratory testing after screening limits conclusions on tolerability. PMID:21045734

  11. Phosphoinositide system-linked serotonin receptor subtypes and their pharmacological properties and clinical correlates.

    PubMed Central

    Pandey, S C; Davis, J M; Pandey, G N

    1995-01-01

    Serotonergic neurotransmission represents a complex mechanism involving pre- and post-synaptic events and distinct 5-HT receptor subtypes. Serotonin (5-HT) receptors have been classified into several categories, and they are termed as 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6 and 5-HT7 type receptors. 5-HT1 receptors have been further subdivided into 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E and 5-HT1F. 5-HT2 receptors have been divided into 5-HT2A, 5-HT2B and 5-HT2C receptors. All 5-HT2 receptor subtypes are linked to the multifunctional phosphoinositide (PI) signalling system. 5-HT3 receptors are considered ion-gated receptors and are also linked to the PI signalling system by an unknown mechanism. The 5-HT2A receptor subtype is the most widely studied of the 5-HT receptors in psychiatric disorders (for example, suicide, depression and schizophrenia) as well as in relation to the mechanism of action of antidepressant drugs. The roles of 5-HT2C and 5-HT3 receptors in psychiatric disorders are less clear. These 5-HT receptors also play an important role in alcoholism. It has been shown that 5-HT2A, 5-HT2C and 5-HT3 antagonists cause attenuation of alcohol intake in animals and humans. However, the exact mechanisms are unknown. The recent cloning of the cDNAs for 5-HT2A, 5-HT2C and 5-HT3 receptors provides the opportunity to explore the molecular mechanisms responsible for the alterations in these receptors during illness as well as pharmacotherapy. This review article will focus on the current research into the pharmacological properties, molecular biology, and clinical correlates of 5-HT2A, 5-HT2C and 5-HT3 receptors. PMID:7786883

  12. Effects of antihypertensive drugs on carotid intima-media thickness: Focus on angiotensin II receptor blockers. A review of randomized, controlled trials

    PubMed Central

    Cuspidi, Cesare; Negri, Francesca; Giudici, Valentina; Capra, Anna; Sala, Carla

    2009-01-01

    Carotid intima-media thickness (IMT) and plaques have been shown to have a strong continuous relationship with cardiovascular (CV) morbidity and mortality; therefore, carotid atherosclerosis, as assessed by ultrasonography, can be regarded as a reliable surrogate end-point for therapeutic interventions. In this survey, we report the results of 16 double blind, randomized, controlled studies comparing: 1) antihypertensive drugs versus placebo/no treatment (five trials including 3,215 patients); 2) different active antihypertensive drug regimens (five trials including 4,662 patients); 3) angiotensin-II receptor blockers (ARBs) versus other antihypertensive agents (six trials including 841 patients). Our main findings can be summarized as follows: I) Long-term antihypertensive treatment has a blunting effect on carotid IMT progression, regardless of types of drugs. II) Calcium-channel blockers (CCBs) are more effective than other antihypertensive drugs including diuretics, beta-blockers, and angiotensin converting-enzyme (ACE)-inhibitors in this blunting effect; III) the effect of ARBs compared to other antihypertensive regimens (mostly based on atenolol) on carotid atherosclerosis progression needs to be further elucidated, as a protective effect was demonstrated by some, but not all studies examined. Thus, further studies are needed to clarify the role of ARBs in this therapeutic area. PMID:21949612

  13. Antidepressant, Antipsychotic, and Hallucinogen Drugs for the Treatment of Psychiatric Disorders: A Convergence at the Serotonin-2A Receptor.

    PubMed

    Howland, Robert H

    2016-07-01

    Antidepressant, atypical antipsychotic, and hallucinogen drugs mediate their actions in part by interactions with the serotonin-2A (5HT2A) receptor. Serotonergic hallucinogen drugs, such as psilocybin, bind most potently as agonists at the 5HT2A receptor, producing profound changes in perception, mood, and cognition. Some of these drugs have been or are currently being investigated in small Phase 2 studies for depression, alcoholism, smoking cessation, anxiety, and posttraumatic stress disorder. However, unlike the synergistic effects of combining antidepressant and atypical antipsychotic drugs, the potential therapeutic effects of hallucinogen drugs may be attenuated by the concurrent use of these medications because antidepressant and atypical antipsychotic drugs desensitize and/or down-regulate 5HT2A receptors. This finding has important implications for optimizing the potential therapeutic use of hallucinogen drugs in psychiatry. [Journal of Psychosocial Nursing and Mental Health Services, 54(7), 21-24.]. PMID:27362381

  14. Structure and function of the third intracellular loop of the 5-hydroxytryptamine2A receptor: the third intracellular loop is alpha-helical and binds purified arrestins.

    PubMed

    Gelber, E I; Kroeze, W K; Willins, D L; Gray, J A; Sinar, C A; Hyde, E G; Gurevich, V; Benovic, J; Roth, B L

    1999-05-01

    Understanding the precise structure and function of the intracellular domains of G protein-coupled receptors is essential for understanding how receptors are regulated, and how they transduce their signals from the extracellular milieu to intracellular sites. To understand better the structure and function of the intracellular domain of the 5-hydroxytryptamine2A (5-HT2A) receptor, a model G(alpha)q-coupled receptor, we overexpressed and purified to homogeneity the entire third intracellular loop (i3) of the 5-HT2A receptor, a region previously implicated in G-protein coupling. Circular dichroism spectroscopy of the purified i3 protein was consistent with alpha-helical and beta-loop, -turn, and -sheet structure. Using random peptide phage libraries, we identified several arrestin-like sequences as i3-interacting peptides. We subsequently found that all three known arrestins (beta-arrestin, arrestin-3, and visual arrestin) bound specifically to fusion proteins encoding the i3 loop of the 5-HT(2A) receptor. Competition binding studies with synthetic and recombinant peptides showed that the middle portion of the i3 loop, and not the extreme N and C termini, was likely to be involved in i3-arrestin interactions. Dual-label immunofluorescence confocal microscopic studies of rat cortex indicated that many cortical pyramidal neurons coexpressed arrestins (beta-arrestin or arrestin-3) and 5-HT2A receptors, particularly in intracellular vesicles. Our results demonstrate (a) that the i3 loop of the 5-HT2A receptor represents a structurally ordered domain composed of alpha-helical and beta-loop, -turn, and -sheet regions, (b) that this loop interacts with arrestins in vitro, and is hence active, and (c) that arrestins are colocalized with 5-HT2A receptors in vivo.

  15. Beta Blockers

    PubMed Central

    Admani, Shehla; Feldstein, Stephanie; Gonzalez, Ernesto M.

    2014-01-01

    Infantile hemangiomas are benign vascular tumors seen in 4.5 percent of neonates and infants. While most infantile hemangiomas can be managed with active nonintervention, a subset of patients will require more aggressive management. Here the authors review the use of beta-blockers in the treatment of infantile hemangiomas, including oral, topical, and multimodal treatment options. They discuss the latest data on propranolol, including criteria for patient selection, dosing recommendations, and appropriate monitoring for side effects and efficacy. Lastly, they review indications for topical timolol treatment and the potential benefits of concomitant laser therapy. PMID:25053982

  16. Interaction of psychoactive tryptamines with biogenic amine transporters and serotonin receptor subtypes

    PubMed Central

    Blough, Bruce E.; Landavazo, Antonio; Decker, Ann M.; Partilla, John S.; Baumann, Michael H.; Rothman, Richard B.

    2014-01-01

    Rationale Synthetic hallucinogenic tryptamines, especially those originally described by Alexander Shulgin, continue to be abused in the United States. The range of subjective experiences produced by different tryptamines suggests that multiple neurochemical mechanisms are involved in their actions, in addition to the established role of agonist activity at serotonin-2A (5-HT2A) receptors. Objectives This study evaluated the interaction of a series of synthetic tryptamines with biogenic amine neurotransmitter transporters and with serotonin (5-HT) receptor subtypes implicated in psychedelic effects. Methods Neurotransmitter transporter activity was determined in rat brain synaptosomes. Receptor activity was determined using calcium mobilization and DiscoveRx PathHunter® assays in HEK293, Gα16-CHO, and CHOk1 cells transfected with human receptors. Results Twenty-one tryptamines were analyzed in transporter uptake and release assays, and 5-HT2A, serotonin 1A (5-HT1A), and 5-HT2A β-arrestin functional assays. Eight of the compounds were found to have 5-HT-releasing activity. Thirteen compounds were found to be 5-HT uptake inhibitors or were inactive. All tryptamines were 5-HT2A agonists with a range of potencies and efficacies, but only a few compounds were 5-HT1A agonists. Most tryptamines recruited β-arrestin through 5-HT2A activation. Conclusions All psychoactive tryptamines are 5-HT2A agonists, but 5-HT transporter (SERT) activity may contribute significantly to the pharmacology of certain compounds. The in vitro transporter data confirm structure-activity trends for releasers and uptake inhibitors whereby releasers tend to be structurally smaller compounds. Interestingly, two tertiary amines were found to be selective substrates at SERT, which dispels the notion that 5-HT-releasing activity is limited only to primary or secondary amines. PMID:24800892

  17. Interaction between μ-opioid and 5-HT1A receptors in the regulation of panic-related defensive responses in the rat dorsal periaqueductal grey.

    PubMed

    Rangel, Marcel P; Zangrossi, Hélio; Roncon, Camila M; Graeff, Frederico G; Audi, Elisabeth A

    2014-12-01

    A wealth of evidence indicates that the activation of 5-HT1A and 5-HT2A receptors in the dorsal periaqueductal grey matter (dPAG) inhibits escape, a panic-related defensive behaviour. Results that were previously obtained with the elevated T-maze test of anxiety/panic suggest that 5-HT1A and μ-opioid receptors in this midbrain area work together to regulate this response. To investigate the generality of this finding, we assessed whether the same cooperative mechanism is engaged when escape is evoked by a different aversive stimulus electrical stimulation of the dPAG. Administration of the μ-receptor blocker CTOP into the dPAG did not change the escape threshold, but microinjection of the μ-receptor agonist DAMGO (0.3 and 0.5 nmol) or the 5-HT1A receptor agonist 8-OHDPAT (1.6 nmol) increased this index, indicating a panicolytic-like effect. Pretreatment with CTOP antagonised the anti-escape effect of 8-OHDPAT. Additionally, combined administration of subeffective doses of DAMGO and 8-OHDPAT increased the escape threshold, indicating drug synergism. Therefore, regardless of the aversive nature of the stimulus, μ-opioid and 5-HT1A receptors cooperatively act to regulate escape behaviour. A better comprehension of this mechanism might allow for new therapeutic strategies for panic disorder.

  18. The appropriate dose of angiotensin‐converting‐enzyme inhibitors or angiotensin receptor blockers in patients with dilated cardiomyopathy. The higher, the better?

    PubMed Central

    Konishi, Masaaki; von Haehling, Stephan

    2015-01-01

    Abstract Heart failure is a major public issue, and dilated cardiomyopathy (DCM) is one of the common etiologies of heart failure. DCM is generally progressive, and some patients with DCM need heart transplant despite optimal medical and mechanical therapy. Current guidelines recommend inhibitors of renin–angiotensin–aldosterone system, namely angiotensin‐converting‐enzyme (ACE) inhibitor, angiotensin receptor blocker (ARB), and mineralocorticoid receptor antagonist as well as beta‐blockers for the medical treatment of heart failure with reduced ejection fraction, including DCM. Furthermore, because they have beneficial effects on the outcome of heart failure in a dose‐related fashion, they should be titrated to the target dose. In clinical practice, the underuse and under‐dose of these agents matter; however, the efficacy and safety of supramaximal dose of ACE inhibitor or ARB have never been investigated in the patients with DCM. In this issue of ESC Heart Failure, it is demonstrated that benazepril or valsartan at supramaximal dose improved left ventricular function and reduced cardiovascular events compared with each drug at low dose, respectively. In this editorial, the current evidence concerning the use of ACE inhibitor or ARB in patients with HF and future prospective will be discussed.

  19. Atrial fibrillation after radiofrequency ablation of atrial flutter: preventive effect of angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, and diuretics

    PubMed Central

    Anné, W; Willems, R; Van der Merwe, N; Van de Werf, F; Ector, H; Heidbüchel, H

    2004-01-01

    Objectives: To determine risk factors for the development of atrial fibrillation (AF) after atrial flutter (AFL) ablation; and to study the relation between AF development and periprocedural drug use. Methods: AFL ablation was performed in 196 patients. The relation between AF occurrence and clinical, echocardiographic, and procedural factors and periprocedural drug use was analysed retrospectively by a Cox proportional hazard method. Results: After a median follow up of 2.2 years, 114 patients (58%) developed at least one AF episode. Factors associated with AF development were the presence of preprocedural AF, a history of cardioversion, and the number of antiarrhythmic drugs used before the procedure. Use of angiotensin converting enzyme (ACE) inhibitors/angiotensin II receptor blockers and diuretics was significantly associated by univariate and multivariate analyses with less development of AF. Conclusions: A high proportion of patients develop AF after AFL ablation. The incidence of AF is related to pre-ablation AF and its persistence. ACE inhibitors/angiotensin II receptor blockers and diuretics seem to protect against AF. PMID:15310691

  20. Genetic dysfunction of serotonin 2A receptor hampers response to antidepressant drugs: A translational approach.

    PubMed

    Qesseveur, Gaël; Petit, Anne Cécile; Nguyen, Hai Thanh; Dahan, Lionel; Colle, Romain; Rotenberg, Samuel; Seif, Isabelle; Robert, Pauline; David, Denis; Guilloux, Jean-Philippe; Gardier, Alain M; Verstuyft, Céline; Becquemont, Laurent; Corruble, Emmanuelle; Guiard, Bruno P

    2016-06-01

    Pharmacological studies have yielded valuable insights into the role of the serotonin 2A (5-HT2A) receptor in major depressive disorder (MDD) and antidepressant drugs (ADs) response. However, it is still unknown whether genetic variants in the HTR2A gene affect the therapeutic outcome of ADs and the mechanism underlying the regulation of such response remains poorly described. In this context, a translational human-mouse study offers a unique opportunity to address the possibility that variations in the HTR2A gene may represent a relevant marker to predict the efficacy of ADs. In a first part of this study, we investigated in depressed patients the effect of three HTR2A single nucleotide polymorphisms (SNPs), selected for their potential functional consequences on 5-HT2A receptor (rs6313, rs6314 and rs7333412), on response and remission rates after 3 months of antidepressant treatments. We also explored the consequences of the constitutive genetic inactivation of the 5-HT2A receptor (i.e. in 5-HT2A(-/-) mice) on the activity of acute and prolonged administration of SSRIs. Our clinical data indicate that GG patients for the rs7333412 SNP were less prone to respond to ADs than AA/AG patients. In the preclinical study, we demonstrated that the 5-HT2A receptor exerts an inhibitory influence on the neuronal activity of the serotonergic system after acute administration of SSRIs. However, while the chronic administration of the SSRIs escitalopram or fluoxetine elicited a progressive increased in the firing rate of 5-HT neurons in 5-HT2A(+/+) mice, it failed to do so in 5-HT2A(-/-) mutants. These electrophysiological impairments were associated with a decreased ability of the chronic administration of fluoxetine to stimulate hippocampal plasticity and to produce antidepressant-like activities. Genetic loss of the 5-HT2A receptor compromised the activity of chronic treatment with SSRIs, making this receptor a putative marker to predict ADs response. PMID:26764241

  1. Receptor interaction profiles of novel psychoactive tryptamines compared with classic hallucinogens.

    PubMed

    Rickli, Anna; Moning, Olivier D; Hoener, Marius C; Liechti, Matthias E

    2016-08-01

    The present study investigated interactions between the novel psychoactive tryptamines DiPT, 4-OH-DiPT, 4-OH-MET, 5-MeO-AMT, and 5-MeO-MiPT at monoamine receptors and transporters compared with the classic hallucinogens lysergic acid diethylamide (LSD), psilocin, N,N-dimethyltryptamine (DMT), and mescaline. We investigated binding affinities at human monoamine receptors and determined functional serotonin (5-hydroxytryptamine [5-HT]) 5-HT2A and 5-HT2B receptor activation. Binding at and the inhibition of human monoamine uptake transporters and transporter-mediated monoamine release were also determined. All of the novel tryptamines interacted with 5-HT2A receptors and were partial or full 5-HT2A agonists. Binding affinity to the 5-HT2A receptor was lower for all of the tryptamines, including psilocin and DMT, compared with LSD and correlated with the reported psychoactive doses in humans. Several tryptamines, including psilocin, DMT, DiPT, 4-OH-DiPT, and 4-OH-MET, interacted with the serotonin transporter and partially the norepinephrine transporter, similar to 3,4-methylenedioxymethamphetamine but in contrast to LSD and mescaline. LSD but not the tryptamines interacted with adrenergic and dopaminergic receptors. In conclusion, the receptor interaction profiles of the tryptamines predict hallucinogenic effects that are similar to classic serotonergic hallucinogens but also MDMA-like psychoactive properties.

  2. Receptor interaction profiles of novel psychoactive tryptamines compared with classic hallucinogens.

    PubMed

    Rickli, Anna; Moning, Olivier D; Hoener, Marius C; Liechti, Matthias E

    2016-08-01

    The present study investigated interactions between the novel psychoactive tryptamines DiPT, 4-OH-DiPT, 4-OH-MET, 5-MeO-AMT, and 5-MeO-MiPT at monoamine receptors and transporters compared with the classic hallucinogens lysergic acid diethylamide (LSD), psilocin, N,N-dimethyltryptamine (DMT), and mescaline. We investigated binding affinities at human monoamine receptors and determined functional serotonin (5-hydroxytryptamine [5-HT]) 5-HT2A and 5-HT2B receptor activation. Binding at and the inhibition of human monoamine uptake transporters and transporter-mediated monoamine release were also determined. All of the novel tryptamines interacted with 5-HT2A receptors and were partial or full 5-HT2A agonists. Binding affinity to the 5-HT2A receptor was lower for all of the tryptamines, including psilocin and DMT, compared with LSD and correlated with the reported psychoactive doses in humans. Several tryptamines, including psilocin, DMT, DiPT, 4-OH-DiPT, and 4-OH-MET, interacted with the serotonin transporter and partially the norepinephrine transporter, similar to 3,4-methylenedioxymethamphetamine but in contrast to LSD and mescaline. LSD but not the tryptamines interacted with adrenergic and dopaminergic receptors. In conclusion, the receptor interaction profiles of the tryptamines predict hallucinogenic effects that are similar to classic serotonergic hallucinogens but also MDMA-like psychoactive properties. PMID:27216487

  3. Modulation of GABA release from the thalamic reticular nucleus by cocaine and caffeine: role of serotonin receptors.

    PubMed

    Goitia, Belén; Rivero-Echeto, María Celeste; Weisstaub, Noelia V; Gingrich, Jay A; Garcia-Rill, Edgar; Bisagno, Verónica; Urbano, Francisco J

    2016-02-01

    Serotonin receptors are targets of drug therapies for a variety of neuropsychiatric and neurodegenerative disorders. Cocaine inhibits the re-uptake of serotonin (5-HT), dopamine, and noradrenaline, whereas caffeine blocks adenosine receptors and opens ryanodine receptors in the endoplasmic reticulum. We studied how 5-HT and adenosine affected spontaneous GABAergic transmission from thalamic reticular nucleus. We combined whole-cell patch clamp recordings of miniature inhibitory post-synaptic currents (mIPSCs) in ventrobasal thalamic neurons during local (puff) application of 5-HT in wild type (WT) or knockout mice lacking 5-HT2A receptors (5-HT2A -/-). Inhibition of mIPSCs frequency by low (10 μM) and high (100 μM) 5-HT concentrations was observed in ventrobasal neurons from 5-HT2A -/- mice. In WT mice, only 100 μM 5-HT significantly reduced mIPSCs frequency. In 5-HT2A -/- mice, NAN-190, a specific 5-HT1A antagonist, prevented the 100 μM 5-HT inhibition while blocking H-currents that prolonged inhibition during post-puff periods. The inhibitory effects of 100 μM 5-HT were enhanced in cocaine binge-treated 5-HT2A -/- mice. Caffeine binge treatment did not affect 5-HT-mediated inhibition. Our findings suggest that both 5-HT1A and 5-HT2A receptors are present in pre-synaptic thalamic reticular nucleus terminals. Serotonergic-mediated inhibition of GABA release could underlie aberrant thalamocortical physiology described after repetitive consumption of cocaine. Our findings suggest that both 5-HT1A , 5-HT2A and A1 receptors are present in pre-synaptic TRN terminals. 5-HT1A and A1 receptors would down-regulate adenylate cyclase, whereas 5-HT1A would also increase the probability of the opening of G-protein-activated inwardly rectifying K(+) channels (GIRK). Sustained opening of GIRK channels would hyperpolarize pre-synaptic terminals activating H-currents, resulting in less GABA release. 5-HT2A -would activate PLC and IP3 , increasing intracellular [Ca(2+) ] and

  4. H2 blockers

    MedlinePlus

    Peptic ulcer disease - H2 blockers; PUD - H2 blockers; Gastroesophageal reflux - H2 blockers ... used to: Relieve symptoms of acid reflux, or gastroesophageal reflux disease (GERD). This is a condition where food ...

  5. The serotonin 2C receptor potently modulates the head-twitch response in mice induced by a phenethylamine hallucinogen

    PubMed Central

    Canal, Clinton E.; Olaghere da Silva, Uade B.; Gresch, Paul J.; Watt, Erin E.; Sanders-Bush, Elaine

    2010-01-01

    Rationale Hallucinogenic serotonin 2A (5-HT2A) receptor partial agonists, such as (±)-1-(2,5-dimethoxy-4-iodo-phenyl)-2-aminopropane hydrochloride (DOI), induce a frontal cortex-dependent head-twitch response (HTR) in rodents, a behavioral proxy of a hallucinogenic response that is blocked by 5-HT2A receptor antagonists. In addition to 5-HT2A receptors, DOI and most other serotonin-like hallucinogens have high affinity and potency as partial agonists at 5-HT2C receptors. Objectives We tested for involvement of 5-HT2C receptors in the HTR induced by DOI. Results Comparison of 5-HT2C receptor knockout and wild-type littermates revealed an approximately 50% reduction in DOI-induced HTR in knockout mice. Also, pretreatment with either the 5-HT2C receptor antagonist SB206553 or SB242084 eradicated a twofold difference in DOI-induced HTR between the standard inbred mouse strains C57BL/6J and DBA/2J, and decreased the DOI-induced HTR by at least 50% in both strains. None of several measures of 5-HT2A receptors in frontal cortex explained the strain difference, including 5-HT2A receptor density, Gαq or Gαi/o protein levels, phospholipase C activity, or DOI-induced expression of Egr1 and Egr2. 5-HT2C receptor density in the brains of C57BL/6J and DBA/2J was also equivalent, suggesting that 5-HT2C receptor-mediated intracellular signaling or other physiological modulators of the HTR may explain the strain difference in response to DOI. Conclusions We conclude that the HTR to DOI in mice is strongly modulated by 5-HT2C receptor activity. This novel finding invites reassessment of hallucinogenic mechanisms involving 5-HT2 receptors. PMID:20165943

  6. Spinal 5-HT-receptors and tonic modulation of transmission through a withdrawal reflex pathway in the decerebrated rabbit.

    PubMed Central

    Clarke, R. W.; Harris, J.; Houghton, A. K.

    1996-01-01

    1. In decerebrated, non-spinalized rabbits, intrathecal administration of either of the selective 5-HT1A-receptor antagonists (S)WAY-100135 or WAY-100635 resulted in dose-dependent enhancement of the reflex responses of gastrocnemius motoneurones evoked by electrical stimulation of all myelinated afferents of the sural nerve. The approximate ED50 for WAY-100635 was 0.9 nmol and that for (S)WAY-100135 13 nmol. Intrathecal doses of the antagonists which caused maximal facilitation of reflexes in non-spinalized rabbits had no effect in spinalized preparations. 2. In non-spinalized animals, intravenous administration of (S)WAY-100135 was significantly less effective in enhancing reflexes than when it was given by the intrathecal route. 3. When given intrathecally, the selective 5-HT 2A/2C-receptor antagonist, ICI 170,809, produced a bellshaped dose-effect curve, augmenting reflexes at low doses (< or = 44 nmol), but reducing them at higher doses (982 nmol). Idazoxan, the selective alpha 2-adrenoceptor antagonist, was less effective in enhancing reflex responses when given intrathecally after ICI 170,809 compared to when it was given alone. Intravenous ICI 170,809 resulted only in enhancement of reflexes and the facilitatory effects of subsequent intrathecal administration of idazoxan were not compromised. 4. The selective 5-HT3-receptor blocker ondansetron faciliated gastrocnemius medialis reflex responses in a dose-related manner when given by either intrathecal or intravenous routes. This drug was slightly more potent when given i.v. and it did not alter the efficacy of subsequent intrathecal administration of idazoxan. 5. None of the antagonists had any consistent effects on arterial blood pressure or heart rate. 6. These data are consistent with the idea that, in the decrebrated rabbit, 5-HT released from descending axons has multiple roles in controlling transmission through the sural-gastrocnemius medialis reflex pathway. Thus, it appears 5-HT tonically inhibits

  7. In vivo imaging of oxidative stress in the kidney of diabetic mice and its normalization by angiotensin II type 1 receptor blocker

    SciTech Connect

    Sonta, Toshiyo; Inoguchi, Toyoshi . E-mail: toyoshi@intmed3.med.kyushu-u.ac.jp; Matsumoto, Shingo; Yasukawa, Keiji; Inuo, Mieko; Tsubouchi, Hirotaka; Sonoda, Noriyuki; Kobayashi, Kunihisa; Utsumi, Hideo; Nawata, Hajime

    2005-05-06

    This study was undertaken to evaluate oxidative stress in the kidney of diabetic mice by electron spin resonance (ESR) imaging technique. Oxidative stress in the kidney was evaluated as organ-specific reducing activity with the signal decay rates of carbamoyl-PROXYL probe using ESR imaging. The signal decay rates were significantly faster in corresponding image pixels of the kidneys of streptozotocin-induced diabetic mice than in those of controls. This technique further demonstrated that administration of angiotensin II type 1 receptor blocker (ARB), olmesartan (5 mg/kg), completely restored the signal decay rates in the diabetic kidneys to control values. In conclusion, this study provided for the first time the in vivo evidence for increased oxidative stress in the kidneys of diabetic mice and its normalization by ARB as evaluated by ESR imaging. This technique would be useful as a means of further elucidating the role of oxidative stress in diabetic nephropathy.

  8. The combination of amlodipine and angiotensin receptor blocker or diuretics in high-risk hypertensive patients: rationale, design and baseline characteristics

    PubMed Central

    Wang, W; Ma, L; Zhang, Y; Deng, Q; Liu, M; Liu, L

    2011-01-01

    The Chinese Hypertension Intervention Efficacy Study (CHIEF) is a multi-centre randomized controlled clinical trial comparing the effects of amlodipine+angiotensin II receptor blocker and amlodipine+diuretics on the incidence of cardiovascular events, represented as a composite of non-fatal stroke, non-fatal myocardial infarction and cardiovascular death events in high-risk Chinese hypertensive patients. The study also evaluates the long-term effects of lipid-lowering treatment and lifestyle modification. From October 2007 to October 2008, 13 542 patients were enrolled into the study in 180 centres in China. Patients will be followed up for 4 years. There was no difference in baseline characteristics between the two blood pressure arms. PMID:20445570

  9. Serotonin 2A and 2B receptor-induced phrenic motor facilitation: differential requirement for spinal NADPH oxidase activity

    PubMed Central

    MacFarlane, P.M.; Vinit, S.; Mitchell, G.S.

    2011-01-01

    Acute intermittent hypoxia (AIH) facilitates phrenic motor output by a mechanism that requires spinal serotonin (type 2) receptor activation, NADPH oxidase activity and formation of reactive oxygen species (ROS). Episodic spinal serotonin (5-HT) receptor activation alone, without changes in oxygenation, is sufficient to elicit NADPH oxidase-dependent phrenic motor facilitation (pMF). Here we investigated: 1) whether serotonin 2A and/or 2B (5-HT2a/b) receptors are expressed in identified phrenic motor neurons, and 2) which receptor subtype is capable of eliciting NADPH-oxidase-dependent pMF. In anesthetized, artificially ventilated adult rats, episodic C4 intrathecal injections (3 × 6µl injections, 5 min intervals) of a 5-HT2a (DOI) or 5-HT2b (BW723C86) receptor agonist elicited progressive and sustained increases in integrated phrenic nerve burst amplitude (i.e. pMF), an effect lasting at least 90 minutes post-injection for both receptor subtypes. 5-HT2a and 5-HT2b receptor agonist-induced pMF were both blocked by selective antagonists (ketanserin and SB206553, respectively), but not by antagonists to the other receptor subtype. Single injections of either agonist failed to elicit pMF, demonstrating a need for episodic receptor activation. Phrenic motor neurons retrogradely labeled with cholera toxin B fragment expressed both 5-HT2a and 5-HT2b receptors. Pre-treatment with NADPH oxidase inhibitors (apocynin and DPI) blocked 5-HT2b, but not 5-HT2a-induced pMF. Thus, multiple spinal type 2 serotonin receptors elicit pMF, but they act via distinct mechanisms that differ in their requirement for NADPH oxidase activity. PMID:21223996

  10. Platelet function and fibrinolytic activity in hypertension: differential effects of calcium antagonists and beta-adrenergic receptor blockers.

    PubMed

    Winther, K; Gleerup, G; Hedner, T

    1991-01-01

    Platelet function was investigated in healthy volunteers and patients with essential hypertension by measurement of thresholds for ADP and adrenaline-induced aggregation and plasma concentrations of platelet factor 4 (PF-4) and beta-thromboglobulin (beta-TG) after administration of antihypertensive drugs. Fibrinolytic activity was investigated by the euglobulin clot lysis time (ECLT) and tissue plasminogen activator (t-PA) activity. Compared to normotensive controls, patients with essential hypertension showed increased aggregation as evidenced by a decrease in ADP thresholds for ex vivo platelet aggregation. ECLT was significantly prolonged and t-PA significantly lowered, indicating impaired fibrinolytic activity in mild hypertension. In different studies, we have shown that various antihypertensive drug regimens differ in their effects on platelet function and fibrinolytic activity when given to healthy volunteers or patients with mild-to-moderate essential hypertension. In normal volunteers, treatment with the calcium antagonists verapamil, nifedipine, and felodipine lowered plasma concentrations of PF-4 and beta-TG, indicating a reduced platelet activity in vivo. Fibrinolytic activity was not influenced by calcium antagonist treatment in the normal volunteers. Interestingly, however, t-PA increased significantly in the hypertensive group. When compared to placebo or beta 1-selective blockers, propranolol, a non-selective beta-adrenergic blocker without partial agonist activity, reduced ADP and adrenaline threshold values for ex vivo platelet aggregation in hypertensive subjects and impaired fibrinolytic activity in the normal volunteers as well as in the hypertensive groups by increasing ECLT and reducing t-PA. Hypothetically, the effects of antihypertensive drugs on platelet function and fibrinolytic activity could be of importance for their proposed actions on cardiovascular morbidity and mortality.

  11. Control of sensory neuron excitability by serotonin involves 5HT2C receptors and Ca(2+)-activated chloride channels.

    PubMed

    Salzer, Isabella; Gantumur, Enkhbileg; Yousuf, Arsalan; Boehm, Stefan

    2016-11-01

    Serotonin (5HT) is a constituent of the so-called "inflammatory soup" that sensitizes nociceptors during inflammation. Nevertheless, receptors and signaling mechanisms that mediate an excitation of dorsal root ganglion (DRG) neurons by 5HT remained controversial. Therefore, capsaicin-sensitive nociceptive neurons dissociated from rat DRGs were used to investigate effects of 5HT on membrane excitability and currents through ligand- as well as voltage-gated ion channels. In 58% of the neurons tested, 5HT increased action potential firing, an effect that was abolished by the 5HT2 receptor antagonist ritanserin, but not by the 5HT3 antagonist tropisetron. Unlike other algogenic mediators, such as PGE2 and bradykinin, 5HT did not affect currents through TTX-resistant Na(+) channels or Kv7 K(+) channels. In all neurons investigated, 5HT potentiated capsaicin-evoked currents through TRPV1 channels, an effect that was attenuated by antagonists at 5HT2A (4 F 4 PP), 5HT2B (SB 204741), as well as 5HT2C (RS 102221) receptors. 5HT triggered slowly arising inward Cl(-) currents in 53% of the neurons. This effect was antagonized by the 5HT2C receptor blocker only, and the current was prevented by an inhibitor of Ca(2+)-activated chloride channels (CaCC). The 5HT-induced increase in action potential firing was also abolished by this CaCC blocker and by the TRPV1 inhibitor capsazepine. Amongst the subtype selective 5HT2 antagonists, only RS 102221 (5HT2C-selectively) counteracted the rise in action potential firing elicited by 5HT. These results show that 5HT excites DRG neurons mainly via 5HT2C receptors which concomitantly mediate a sensitization of TRPV1 channels and an opening of CaCCs.

  12. What is a preferred angiotensin II receptor blocker-based combination therapy for blood pressure control in hypertensive patients with diabetic and non-diabetic renal impairment?

    PubMed Central

    2012-01-01

    Hypertension has a major associated risk for organ damage and mortality, which is further heightened in patients with prior cardiovascular (CV) events, comorbid diabetes mellitus, microalbuminuria and renal impairment. Given that most patients with hypertension require at least two antihypertensives to achieve blood pressure (BP) goals, identifying the most appropriate combination regimen based on individual risk factors and comorbidities is important for risk management. Single-pill combinations (SPCs) containing two or more antihypertensive agents with complementary mechanisms of action offer potential advantages over free-drug combinations, including simplification of treatment regimens, convenience and reduced costs. The improved adherence and convenience resulting from SPC use is recognised in updated hypertension guidelines. Despite a wide choice of SPCs for hypertension treatment, clinical evidence from direct head-to-head comparisons to guide selection for individual patients is lacking. However, in patients with evidence of renal disease or at greater risk of developing renal disease, such as those with diabetes mellitus, microalbuminura and high-normal BP or overt hypertension, guidelines recommend renin-angiotensin system (RAS) blocker-based combination therapy due to superior renoprotective effects compared with other antihypertensive classes. Furthermore, RAS inhibitors attenuate the oedema and renal hyperfiltration associated with calcium channel blocker (CCB) monotherapy, making them a good choice for combination therapy. The occurrence of angiotensin-converting enzyme (ACE) inhibitor-induced cough supports the use of angiotensin II receptor blockers (ARBs) for RAS blockade rather than ACE inhibitors. In this regard, ARB-based SPCs are available in combination with the diuretic, hydrochlorothiazide (HCTZ) or the calcium CCB, amlodipine. Telmisartan, a long-acting ARB with preferential pharmacodynamic profile compared with several other ARBs, and the

  13. Interaction of SR 33557 with skeletal muscle calcium channel blocker receptors in the baboon: characterization of its binding sites

    SciTech Connect

    Sol-Rolland, J.; Joseph, M.; Rinaldi-Carmona, M. )

    1991-05-01

    A procedure for the isolation of primate skeletal microsomal membranes was initiated. Membranes exhibited specific enzymatic markers such as 5'-nucleotidase, Ca{sup 2}{sup +},Mg({sup 2}{sup +})-adenosine triphosphatase and an ATP-dependent calcium uptake. Baboon skeletal microsomes bound specifically with high-affinity potent Ca{sup 2}{sup +} channel blockers such as dihydropyridine, phenylalkylamine and benzothiazepine derivatives. Scatchard analysis of equilibrium binding assays with ({sup 3}H)(+)-PN 200-110, ({sup 3}H)(-)-desmethoxyverapamil (( {sup 3}H)(-)-D888) and ({sup 3}H)-d-cis-dilitiazem were consistent with a single class of binding sites for the three radioligands. The pharmacological profile of SR 33557, an original compound with calcium antagonist properties, was investigated using radioligand binding studies. SR 33557 totally inhibited the specific binding of the three main classes of Ca{sup 2}{sup +} channel effectors and interacted allosterically with them. In addition, SR 33557 bound with high affinity to a homogeneous population of binding sites in baboon skeletal muscle.

  14. Molecular dynamics simulations reveal fundamental role of water as factor determining affinity of binding of beta-blocker nebivolol to beta(2)-adrenergic receptor.

    PubMed

    Kaszuba, Karol; Róg, Tomasz; Bryl, Krzysztof; Vattulainen, Ilpo; Karttunen, Mikko

    2010-07-01

    The beta-adrenergic antagonists (beta-blockers) constitute a class of drugs that have well-established roles in treatments of various cardiovascular diseases. Despite a 50 year history, there are two clinically important subtypes of beta-adrenergic receptors (betaARs) called beta(1)AR and beta(2)AR that still are promising drug targets. Our study maps the interactions between nebivolol-one of the most efficient beta-blocking agents-and the beta(2)-adrenergic receptor by simulating two optical isomers of nebivolol: ssss-nebivolol and srrr-nebivolol. The srrr-configuration binds preferentially to beta(1)AR and beta(2)AR. The ssss-form has much lower binding affinity to both of them. Our work indicates that water is a very important component of the binding site of the beta(2)AR receptor. We found that the higher stereoselectivity of the srrr-configuration is due to interactions with water molecules, which extensively hydrate the binding site of beta(2)AR. By lowering the energy of binding, water enhanced the affinity of the srrr-form to beta(2)AR. We also address the problem of beta(1)AR/beta(2)AR selectivity. At higher concentrations, all beta-blocking agents lose their specificity and bind nonselectively, causing many adverse effects. Our simulations indicate that PHE194, TYR308, and ILE309 of the beta(2)AR and the corresponding residues of the beta(1)AR receptor may be important determinants of beta(1)AR versus beta(2)AR selectivity.

  15. The angiotensin receptor blocker, azilsartan medoxomil (TAK-491), suppresses vascular wall expression of plasminogen activator inhibitor type-I protein potentially facilitating the stabilization of atherosclerotic plaques.

    PubMed

    French, Christopher J; Zaman, A K M Tarikuz; Sobel, Burton E

    2011-08-01

    Increased expression of plasminogen activator inhibitor type-I (PAI-1) in vessel walls seems to accelerate atherosclerosis. Angiotensin II can increase the synthesis of PAI-1. Inhibition of this process may facilitate migration of vascular smooth muscle cells (VSMCs) stabilizing atherosclerotic plaques. To determine whether the inhibition of the angiotensin II type 1 receptor can blunt the expression of PAI-1 protein in the aortic wall, we administered azilsartan medoxomil (AZL-M), a prodrug of an angiotensin II type 1 receptor blocker developed by the Takeda Pharmaceutical Company Limited, for 16 weeks to ApoE knockout mice on a high fat diet rendered overexpressors of PAI-1 in VSMCs. Homogenates of the pooled aortas from each group were assayed for PAI-1 by enzyme-linked immunosorbent assay. Cellularity of atherosclerotic lesions was assessed by 4',6-diamidino-2-phenylindole staining in sections of aortic lesions, and collagen content in the lesions was quantified by immunohistochemistry. Aortic wall PAI-1 was decreased by each of the 3 dosage regimens of AZL-M (0.1-10 mg/kg). Cellularity and collagen were increased in lesions from mice given AZL-M, consistent with the development of more stable plaques. Accordingly, the suppression of PAI-1 expression by AZL-M may attenuate the evolution of atherosclerotic plaques vulnerable to rupture.

  16. A case of lithium intoxication induced by an antihypertensive angiotensin 1 subtype-specific angiotensin II receptor blocker in an elderly patient with bipolar disorder and hypertension.

    PubMed

    Hayashi, Yuichi; Nishida, Shohei; Takekoshi, Akira; Murakami, Muneharu; Yamada, Megumi; Kimura, Akio; Suzuki, Akio; Inuzuka, Takashi

    2016-01-01

    Lithium carbonate is considered to be a first-line treatment for bipolar disorder; however, this drug has a narrow therapeutic window, and lithium intoxication is commonly induced by various drugs interaction and situations. We herein report a case of lithium intoxication induced by the administration of an antihypertensive agent targeting the angiotensin 1 (AT1) subtype of the angiotensin II receptor in a 65-year-old woman with a 40-year history of bipolar disorder type 1, and 1-year history of essential hypertension. Her bipolar disorder had been well-controlled with 600 mg/day of lithium carbonate for more than 10 years. She was later diagnosed with hypertension and the AT1 receptor blocker, azilsartan was thereafter administrated on a daily basis. After 3 weeks of azilsartan administration, she presented with progressive action tremor and showed a gradual deterioration of her physical state. Four months after the start of azilsartan administration, she presented with alternating episodes of diarrhea and constipation. Two weeks before admission to our hospital, she presented with mild consciousness disturbances, myoclonus, truncal ataxia, and appetite loss. She was diagnosed to have lithium intoxication based on an elevated serum lithium concentration of 3.28 mEq/l.It is therefore important to evaluate the serum lithium concentration after the administration of antihypertensive agents, and consider lithium-antihypertensive agent interactions when selecting antihypertensive agents in elderly patients receiving long-term lithium carbonate treatment. PMID:27535187

  17. Continuous IV Infusion is the Choice Treatment Route for Arginine-vasopressin Receptor Blocker Conivaptan in Mice to Study Stroke-evoked Brain Edema.

    PubMed

    Zeynalov, Emil; Jones, Susan M; Elliott, J Paul

    2016-01-01

    Stroke is one of the major causes of morbidity and mortality in the world. Stroke is complicated by brain edema and other pathophysiological events. Among the most important players in the development and evolution of stroke-evoked brain edema is the hormone arginine-vasopressin and its receptors, V1a and V2. Recently, the V1a and V2 receptor blocker conivaptan has been attracting attention as a potential drug to reduce brain edema after stroke. However, animal models which involve conivaptan applications in stroke research need to be modified based on feasible routes of administration. Here the outcomes of 48 hr continuous intravenous (IV) are compared with intraperitoneal (IP) conivaptan treatments after experimental stroke in mice. We developed a protocol in which middle cerebral artery occlusion was combined with catheter installation into the jugular vein for IV treatment of conivaptan (0.2 mg) or vehicle. Different cohorts of animals were treated with 0.2 mg bolus of conivaptan or vehicle IP daily. Experimental stroke-evoked brain edema was evaluated in mice after continuous IV and IP treatments. Comparison of the results revealed that the continuous IV administration of conivaptan alleviates post-ischemic brain edema in mice, unlike the IP administration of conivaptan. We conclude that our model can be used for future studies of conivaptan applications in the context of stroke and brain edema. PMID:27684044

  18. Dorsal prefrontal cortical serotonin 2A receptor binding indices are differentially related to individual scores on harm avoidance.

    PubMed

    Baeken, Chris; Bossuyt, Axel; De Raedt, Rudi

    2014-02-28

    Although the serotonergic system has been implicated in healthy as well as in pathological emotional states, knowledge about its involvement in personality is limited. Earlier research on this topic suggests that post-synaptic 5-HT2A receptors could be involved in particular in frontal cortical areas. In drug-naïve healthy individuals, we examined the relationship between these 5-HT2A receptors and the temperament dimension harm avoidance (HA) using 123I-5-I-R91150 single photon emission computed tomography (SPECT). HA is a personality feature closely related to stress, anxiety and depression proneness, and it is thought to be mediated by the serotonergic system. We focused on the prefrontal cortices as these regions are frequently implicated in cognitive processes related to a variety of affective disorders. We found a positive relationship between dorsal prefrontal cortical (DPFC) 5-HT2A receptor binding indices (BI) and individual HA scores. Further, our results suggest that those individuals with a tendency to worry or to ruminate are particularly prone to display significantly higher 5-HT2A receptor BI in the left DPFC. Although we only examined psychologically healthy individuals, this relationship suggests a possible vulnerability for affective disorders. PMID:24412555

  19. Candesartan, an angiotensin II AT₁-receptor blocker and PPAR-γ agonist, reduces lesion volume and improves motor and memory function after traumatic brain injury in mice.

    PubMed

    Villapol, Sonia; Yaszemski, Alexandra K; Logan, Trevor T; Sánchez-Lemus, Enrique; Saavedra, Juan M; Symes, Aviva J

    2012-12-01

    Traumatic brain injury (TBI) results in complex pathological reactions, the initial lesion worsened by secondary inflammation and edema. Angiotensin II (Ang II) is produced in the brain and Ang II receptor type 1 (AT₁R) overstimulation produces vasoconstriction and inflammation. Ang II receptor blockers (ARBs) are neuroprotective in models of stroke but little is known of their effect when administered in TBI models. We therefore performed controlled cortical impact (CCI) injury on mice to investigate whether the ARB candesartan would mitigate any effects of TBI. We administered candesartan or vehicle to mice 5 h before CCI injury. Candesartan treatment reduced the lesion volume after CCI injury by approximately 50%, decreased the number of dying neurons, lessened the number of activated microglial cells, protected cerebral blood flow (CBF), and reduced the expression of the cytokine TGFβ1 while increasing expression of TGFβ3. Candesartan-treated mice also showed better motor skills on the rotarod 3 days after injury, and improved performance in the Morris water maze 4 weeks after injury. These results indicate that candesartan is neuroprotective, reducing neuronal injury, decreasing lesion volume and microglial activation, protecting CBF and improving functional behavior in a mouse model of TBI. Co-treatment with a peroxisome proliferator-activated receptor-gamma (PPARγ) antagonist significantly reduced some of the beneficial effects of candesartan after CCI, suggesting that PPARγ activation may contribute to part or to all of the neuroprotective effect of candesartan. Overall, our data suggest that ARBs with dual AT₁R-blocking and PPARγ activation properties may have therapeutic value in treating TBI.

  20. 5-HT2 Receptor Regulation of Mitochondrial Genes: Unexpected Pharmacological Effects of Agonists and Antagonists.

    PubMed

    Harmon, Jennifer L; Wills, Lauren P; McOmish, Caitlin E; Demireva, Elena Y; Gingrich, Jay A; Beeson, Craig C; Schnellmann, Rick G

    2016-04-01

    In acute organ injuries, mitochondria are often dysfunctional, and recent research has revealed that recovery of mitochondrial and renal functions is accelerated by induction of mitochondrial biogenesis (MB). We previously reported that the nonselective 5-HT2 receptor agonist DOI [1-(4-iodo-2,5-dimethoxyphenyl)propan-2-amine] induced MB in renal proximal tubular cells (RPTCs). The goal of this study was to determine the role of 5-HT2 receptors in the regulation of mitochondrial genes and oxidative metabolism in the kidney. The 5-HT2C receptor agonist CP-809,101 [2-[(3-chlorophenyl)methoxy]-6-(1-piperazinyl)pyrazine] and antagonist SB-242,084 [6-chloro-2,3-dihydro-5-methyl-N-[6-[(2-methyl-3-pyridinyl)oxy]-3-pyridinyl]-1H-indole-1-carboxyamide dihydrochloride] were used to examine the induction of renal mitochondrial genes and oxidative metabolism in RPTCs and in mouse kidneys in the presence and absence of the 5-HT2C receptor. Unexpectedly, both CP-809,101 and SB-242,084 increased RPTC respiration and peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) mRNA expression in RPTCs at 1-10 nM. In addition, CP-809,101 and SB-242,084 increased mRNA expression of PGC-1α and the mitochondrial proteins NADH dehydrogenase subunit 1 and NADH dehydrogenase (ubiquinone) β subcomplex 8 in mice. These compounds increased mitochondrial genes in RPTCs in which the 5-HT2C receptor was downregulated with small interfering RNA and in the renal cortex of mice lacking the 5-HT2C receptor. By contrast, the ability of these compounds to increase PGC-1α mRNA and respiration was blocked in RPTCs treated with 5-HT2A receptor small interfering RNA or the 5-HT2A receptor antagonist eplivanserin. In addition, the 5-HT2A receptor agonist NBOH-2C-CN [4-[2-[[(2-hydroxyphenyl)methyl]amino]ethyl]-2,5-dimethoxybenzonitrile] increased RPTC respiration at 1-100 nM. These results suggest that agonism of the 5-HT2A receptor induces MB and that the classic 5-HT2C receptor agonist CP

  1. Caffeine withdrawal syndrome in social interaction test in mice: effects of the NMDA receptor channel blockers, memantine and neramexane.

    PubMed

    Sukhotina, I A; Zvartau, E E; Danysz, W; Bespalov, A Y

    2004-05-01

    Antagonists acting at N-methyl-D-aspartate (NMDA) receptors have been demonstrated repeatedly to attenuate the expression of drug and alcohol withdrawal syndromes. The present study aimed to evaluate the effects of NMDA receptor blockade on the expression of behavioural signs of caffeine withdrawal syndrome, assessed using the social interaction paradigm. Adult male Swiss mice were treated with increasing doses of caffeine (40-100 mg/kg, i.p., twice daily) for 8 days. Twenty-four hours after the last injection of caffeine, there were significant increases in duration and frequency of defensive behaviours, as well as decreased locomotor activity. These changes faded within 72 hours. Pretreatment with a single dose of caffeine (1 mg/kg; 24 h after the end of repeated caffeine administration and 30 min prior to the test) completely reversed these withdrawal-related changes. Separate groups of mice were treated i.p. with different doses of memantine (1, 3 or 10 mg/kg) or neramexane (MRZ 2/579; 1, 3 or 10 mg/kg) 24 h after the last caffeine injection. Both compounds dose-dependently reduced the expression of defensive behaviours while increasing motor activity. These data suggest that NMDA receptor blockade may counteract the acute behavioural effects of caffeine withdrawal.

  2. Characterisation of human 5-hydroxytryptamine2A and 5-hydroxytryptamine2C receptors expressed in the human neuroblastoma cell line SH-SY5Y: comparative stimulation by hallucinogenic drugs.

    PubMed

    Newton, R A; Phipps, S L; Flanigan, T P; Newberry, N R; Carey, J E; Kumar, C; McDonald, B; Chen, C; Elliott, J M

    1996-12-01

    Stable transfection of the human neuroblastoma cell line SH-SY5Y with the human 5-hydroxytryptamine2A (5-HT2A) or 5-HT2C receptor cDNA produced cell lines demonstrating ligand affinities that correlated closely with those for the corresponding endogenous receptors in human frontal cortex and choroid plexus, respectively. Stimulation of the recombinant receptors by 5-HT induced phosphoinositide hydrolysis with higher potency but lower efficacy at the 5-HT2C receptor (pEC50 = 7.80 +/- 0.06) compared with the 5-HT2A receptor (pEC50 = 7.30 +/- 0.08). Activation of the 5-HT2A receptor caused a transient fourfold increase in intracellular Ca2+ concentration. Whole-cell recordings of cells clamped at -50 mV demonstrated a small inward current (2 pA) in response to 10 microM 5-HT for both receptors. There were no differences in potency or efficacy of phosphoinositide hydrolysis among four hallucinogenic [d-lysergic acid diethylamide (LSD), 1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane (DOI), 5-methoxy-N,N-dimethyltryptamine, and mescaline] and three nonhallucinogenic drugs (m-chlorophenylpiperazine, quipazine, and ergotamine). Comparison of equipotent doses producing 20% of the maximal response induced by 5-HT revealed selective activation of the 5-HT2A receptor by LSD and to a lesser degree by DOI, mescaline, and ergotamine. Quipazine and 5-methoxy-N,N-dimethyltryptamine were relatively nonselective, whereas m-chlorophenylpiperazine selectively activated the 5-HT2C receptor. It is unlikely therefore that hallucinosis is mediated primarily by activity at the 5-HT2C receptor, whereas activity at the 5-HT2A receptor may represent an important but not unique mechanism associated with hallucinogenic drug action.

  3. Spironolactone and chlorthalidone in uncontrolled elderly hypertensive patients treated with calcium antagonists and angiotensin II receptor-blocker: effects on endothelial function, inflammation, and oxidative stress.

    PubMed

    Yamanari, Hiroshi; Nakamura, Kazufumi; Miura, Daiji; Yamanari, Shuichi; Ohe, Tohru

    2009-10-01

    The side effects of thiazide-type diuretics include metabolic abnormality and increased oxidative stress, which might cause endothelial dysfunction despite blood pressure reduction. In hypertensive patients with heart failure, treatment with an aldosterone antagonist resulted in improvements in endothelial function and significant blood pressure reduction. The purpose of the present study was to evaluate the differences between spironolactone and chlorthalidone in hypertensive elderly patients treated with calcium antagonists and angiotensin II receptor blockers. Fourteen uncontrolled hypertensive patients treated with amlodipine and candesartan were included in this study. The study was an open-label randomized crossover comparison of 16 weeks treatment with spironolactone against chlorthalidone added to amlodipine and candesartan. Blood pressure significantly decreased in patients treated with both spironolactone and chlorthalidone. Chlorthalidone reduced flow mediated dilation significantly compared to the baseline condition and spironolactone. Serum high sensitively C-reactive protein and uric acid increased significantly in chlorthalidone-treated patients compared to spironolactone treated patients. We conclude that spironolactone may be a more useful add-on therapy than chlorthalidone in hypertensive patients inadequately controlled on candesartan and amlodipine, because spironolactone preserves endothelial function and reduces inflammation compared to chlorthalidone.

  4. Beneficial effects of candesartan, an angiotensin II type 1 receptor blocker, on beta-cell function and morphology in db/db mice.

    PubMed

    Shao, Jiaqing; Iwashita, Noseki; Ikeda, Fuki; Ogihara, Takeshi; Uchida, Toyoyoshi; Shimizu, Tomoaki; Uchino, Hiroshi; Hirose, Takahisa; Kawamori, Ryuzo; Watada, Hirotaka

    2006-06-16

    Several epidemiological studies suggested that treatment with angiotensin II type 1 receptor blocker (ARB) provided a risk reduction of developing type 2 diabetes. In this study, we investigated whether and how ARB treatment can improve abnormalities of pancreatic islets in diabetes state. We randomized db/db mice, a model of type 2 diabetes with obesity, at the age of 8 weeks to receive candesartan, an ARB, for 6 weeks. We also studied age-matched db/misty mice as control. Glucose tolerance test revealed that candesartan treatment improved glucose tolerance with the modest increase in serum insulin level in db/db mice. Concurrently, candesartan increased beta-cell mass, increased staining intensity of insulin, and decreased staining intensity of components of NAD(P)H oxidase, p22phox and gp91phox, and those of oxidative stress markers in beta-cells. These changes were accompanied by reduction of mitochondrial volume. Treatment with candesartan also reduced fibrosis in and around the islets and prevented the loss of endothelial cells in islets. Our results showed that candesartan partially prevented deterioration of glucose tolerance by providing protection against progressive beta-cell damage in diabetes. PMID:16650382

  5. Additive Effect of Qidan Dihuang Grain, a Traditional Chinese Medicine, and Angiotensin Receptor Blockers on Albuminuria Levels in Patients with Diabetic Nephropathy: A Randomized, Parallel-Controlled Trial

    PubMed Central

    Xiang, Lei; Jiang, Pingping; Zhou, Lin; Sun, Xiaomin; Bi, Jianlu; Cui, Lijuan; Nie, Xiaoli; Luo, Ren; Liu, Yanyan

    2016-01-01

    Albuminuria is characteristic of early-stage diabetic nephropathy (DN). The conventional treatments with angiotensin receptor blockers (ARB) are unable to prevent the development of albuminuria in normotensive individuals with type 2 diabetes mellitus (T2DM). Purpose. The present study aimed to evaluate the effect of ARB combined with a Chinese formula Qidan Dihuang grain (QDDHG) in improving albuminuria and Traditional Chinese Medicine Symptom (TCMS) scores in normotensive individuals with T2DM. Methods. Eligible patients were randomized to the treatment group and the control group. Results. Compared with baseline (week 0), both treatment and control groups markedly improved the 24-hour albuminuria, total proteinuria (TPU), and urinary albumin to creatinine ratio (A/C) at 4, 8, and 12 weeks. Between treatment and the control group, the levels of albuminuria in the treatment group were significantly lower than in the control group at 8 and 12 weeks (p < 0.05). In addition, treatment group markedly decreased the scores of TCMS after treatment. Conclusion. This trial suggests that QDDHG combined with ARB administration decreases the levels of albuminuria and the scores for TCMS in normotensive individuals with T2DM. PMID:27375762

  6. Depressor and Anti-Inflammatory Effects of Angiotensin II Receptor Blockers in Metabolic and/or Hypertensive Patients With Coronary Artery Disease: A Randomized, Prospective Study (DIAMOND Study)

    PubMed Central

    Adachi, Sen; Miura, Shin-ichiro; Shiga, Yuhei; Arimura, Tadaaki; Kuwano, Takashi; Kitajima, Ken; Ike, Amane; Sugihara, Makoto; Iwata, Atsushi; Nishikawa, Hiroaki; Morito, Natsumi; Saku, Keijiro

    2016-01-01

    Background We compared the efficacy and safety of azilsartan to those of olmesartan in a prospective, randomized clinical trial. Methods Forty-four hypertensive patients who had coronary artery disease (CAD) were enrolled. We randomly assigned patients to changeover from their prior angiotensin II receptor blockers (ARBs) to either azilsartan or olmesartan, and followed the patients for 12 weeks. Results Office systolic blood pressure (SBP) in the azilsartan group was significantly decreased after 12 weeks. SBP and diastolic blood pressure (DBP) after 12 weeks in the azilsartan group were significantly lower than those in the olmesartan group. The percentage of patients who reached the target BP at 12 weeks (78%) in the azilsartan group was significantly higher than that at 12 weeks (45%) in the olmesartan group. There were no significant changes in pentraxin-3, high-sensitively C-reactive protein or adiponectin in blood after 12 weeks in either group. Although serum levels of creatinine (Cr) in the azilsartan group significantly increased, these changes were within the respective normal range. Conclusion In conclusion, the ability of azilsartan to reduce BP may be superior to that of prior ARBs with equivalent safety in hypertensive patients with CAD.

  7. Depressor and Anti-Inflammatory Effects of Angiotensin II Receptor Blockers in Metabolic and/or Hypertensive Patients With Coronary Artery Disease: A Randomized, Prospective Study (DIAMOND Study)

    PubMed Central

    Adachi, Sen; Miura, Shin-ichiro; Shiga, Yuhei; Arimura, Tadaaki; Kuwano, Takashi; Kitajima, Ken; Ike, Amane; Sugihara, Makoto; Iwata, Atsushi; Nishikawa, Hiroaki; Morito, Natsumi; Saku, Keijiro

    2016-01-01

    Background We compared the efficacy and safety of azilsartan to those of olmesartan in a prospective, randomized clinical trial. Methods Forty-four hypertensive patients who had coronary artery disease (CAD) were enrolled. We randomly assigned patients to changeover from their prior angiotensin II receptor blockers (ARBs) to either azilsartan or olmesartan, and followed the patients for 12 weeks. Results Office systolic blood pressure (SBP) in the azilsartan group was significantly decreased after 12 weeks. SBP and diastolic blood pressure (DBP) after 12 weeks in the azilsartan group were significantly lower than those in the olmesartan group. The percentage of patients who reached the target BP at 12 weeks (78%) in the azilsartan group was significantly higher than that at 12 weeks (45%) in the olmesartan group. There were no significant changes in pentraxin-3, high-sensitively C-reactive protein or adiponectin in blood after 12 weeks in either group. Although serum levels of creatinine (Cr) in the azilsartan group significantly increased, these changes were within the respective normal range. Conclusion In conclusion, the ability of azilsartan to reduce BP may be superior to that of prior ARBs with equivalent safety in hypertensive patients with CAD. PMID:27635180

  8. The H1 histamine receptor blocker, chlorpheniramine, completely prevents the increase in REM sleep induced by immobilization stress in rats.

    PubMed

    Rojas-Zamorano, J A; Esqueda-Leon, E; Jimenez-Anguiano, A; Cintra-McGlone, L; Mendoza Melendez, M A; Velazquez Moctezuma, J

    2009-01-01

    Chlorpheniramine is a selective antagonist of the H1 histaminergic receptor subtype and its effects in humans include somnolence. Chlorpheniramine affects sleep in rats, mainly by decreasing REM sleep. On the other hand, stress by immobilization induces an important increase in the percentage of REM sleep. In this study we analyzed the effects of blocking histaminergic receptors on REM sleep induced by immobilization stress. Adult male Wistar rats were chronically implanted for sleep recording. Immobilization stress was induced by placing the rat in a small cylinder for 2 h. Experimental conditions were: A. Control; B. Stress; C. Stress plus vehicle and D. Stress plus chlorpheniramine. Independent experiments were done both in the dark, as well as the light period. Results showed that the increase in REM sleep observed after immobilization stress was completely abolished by chlorpheniramine, both in the dark and in the light phase. Furthermore, the decrease in REM sleep was significant even when compared to the non-stressed control rats. REM sleep latency was also significantly longer during both light phases. The present results suggest that REM sleep is quite sensitive to histaminergic blockage. It is possible that chlorpheniramine is also blocking the cholinergic mechanisms generating REM sleep.

  9. An angiotensin II receptor blocker–calcium channel blocker combination prevents cardiovascular events in elderly high-risk hypertensive patients with chronic kidney disease better than high-dose angiotensin II receptor blockade alone

    PubMed Central

    Kim-Mitsuyama, Shokei; Ogawa, Hisao; Matsui, Kunihiko; Jinnouchi, Tomio; Jinnouchi, Hideaki; Arakawa, Kikuo

    2013-01-01

    The OSCAR study was a multicenter, prospective randomized open-label blinded end-point study of 1164 Japanese elderly hypertensive patients comparing the efficacy of angiotensin II receptor blocker (ARB) uptitration to an ARB plus calcium channel blocker (CCB) combination. In this prospective study, we performed prespecified subgroup analysis according to baseline estimated glomerular filtration rate (eGFR) with chronic kidney disease (CKD) defined as an eGFR <60 ml/min per 1.73 m2. Blood pressure was lower in the combined therapy than in the high-dose ARB cohort in both groups with and without CKD. In patients with CKD, significantly more primary events (a composite of cardiovascular events and noncardiovascular death) occurred in the high-dose ARB group than in the combination group (30 vs. 16, respectively, hazard ratio 2.25). Significantly more cerebrovascular and more heart failure events occurred in the high-dose ARB group than in the combination group. In patients without CKD, however, the incidence of primary events was similar between the two treatments. The treatment-by-subgroup interaction was significant. Allocation to the high-dose ARB was a significant independent prognostic factor for primary events in patients with CKD. Thus, the ARB plus CCB combination conferred greater benefit in prevention of cardiovascular events in patients with CKD compared with high-dose ARB alone. Our findings provide new insight into the antihypertensive strategy for elderly hypertensive patients with CKD. PMID:23051740

  10. Antagonism of lateral saphenous vein serotonin receptors from steers grazing endophyte-free, wild-type, or novel endophyte-infected tall fescue

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Pharmacologic profiling of 5-hydroxytryptamine (5HT) receptors of bovine lateral saphenous vein has shown that cattle grazing endophyte-infected (Neotyphodium coenophialum) tall fescue (Lolium arundinaceum) have altered responses to ergovaline (ERV), 5HT, 5HT2A and 5HT7 agonists. To determine if 5HT...

  11. Angiotensin II receptor blocker candesartan cilexetil, but not hydralazine hydrochloride, protects against mouse cardiac enlargement resulting from undernutrition in utero.

    PubMed

    Kawamura, Makoto; Itoh, Hiroaki; Yura, Shigeo; Mogami, Haruta; Fujii, Tsuyoshi; Kanayama, Naohiro; Konishi, Ikuo

    2009-10-01

    Epidemiologic studies have shown that malnutrition in utero is a risk factor for cardiovascular disease (CVD) in adulthood. Recently, we reported a mouse animal model of 30% maternal caloric reduction, in which adult offspring (undernourished [UN] offspring) showed a significant increase in cardiac remodeling-associated parameters, such as cardiac enlargement (CE) and coronary perivascular fibrosis (CPVF), as risk factors for CVD. To investigate the possible involvement of the angiotensin system, an angiotensin II receptor antagonist, candesartan cilexetil, or a nonspecific vasodilator, hydralazine hydrochloride, was administrated via a subcutaneously implanted miniosmotic pump to the UN offspring from 9 to 17 weeks after birth. Administration of candesartan cilexetil, but not hydralazine hydrochloride, significantly protected against CE. While administration of not only candesartan cilexetil but also hydralazine hydrochloride prevented an augmentation of CPVF. The angiotensin system seems to make a critical contribution to the developmental origins of cardiac enlargement.

  12. Structure of the high-affinity binding site for noncompetitive blockers of the acetylcholine receptor: (/sup 3/H)chlorpromazine labels homologous residues in the. beta. and delta chains

    SciTech Connect

    Giraudat, J.; Dennis, M.; Heidmann, T.; Haumont, P.Y.; Lederer, F.; Changeux, J.P.

    1987-05-05

    The membrane-bound acetylcholine receptor from Torpedo marmorata was photolabeled by the noncompetitive channel blocker (/sup 3/H)chlorpromazine under equilibrium conditions in the presence of the agonist carbamoylcholine. The amount of radioactivity incorporated into all subunits was reduced by addition of phencyclidine, a specific ligand for the high-affinity site for noncompetitive blockers. The labeled ..beta.. chain was purified and digested with trypsin or CNBr, and the resulting fragments were fractionated by high-performance liquid chromatography. Sequence analysis resulted in the identification of Ser-254 and Leu-257 as residues labeled by (/sup 3/H)chlorpromazine in a phencyclidine-sensitive manner. These residues are located in the hydrophobic and potentially transmembrane segment M II of the ..beta.. chain, a region homologous to that containing the chlorpromazine-labeled Ser-262 in the delta chain. These results show that homologous regions of different receptor subunits contribute to the unique high-affinity site for noncompetitive blockers, a finding consistent with the location of this site on the axis of symmetry of the receptor molecule.

  13. G protein receptor kinase 4 polymorphisms: β-blocker pharmacogenetics and treatment-related outcomes in hypertension.

    PubMed

    Vandell, Alexander G; Lobmeyer, Maximilian T; Gawronski, Brian E; Langaee, Taimour Y; Gong, Yan; Gums, John G; Beitelshees, Amber L; Turner, Stephen T; Chapman, Arlene B; Cooper-DeHoff, Rhonda M; Bailey, Kent R; Boerwinkle, Eric; Pepine, Carl J; Liggett, Stephen B; Johnson, Julie A

    2012-10-01

    G protein-coupled receptor kinases (GRKs) are important regulatory proteins for many G protein-coupled receptors, but little is known about GRK4 pharmacogenetics. We hypothesized that 3 nonsynonymous GRK4 single-nucleotide polymorphisms, R65L (rs2960306), A142V (rs1024323), and A486V (rs1801058), would be associated with blood pressure response to atenolol, but not hydrochlorothiazide, and would be associated with long-term cardiovascular outcomes (all-cause death, nonfatal myocardial infarction, nonfatal stroke) in participants treated with an atenolol-based versus verapamil-SR-based antihypertensive strategy. GRK4 single-nucleotide polymorphisms were genotyped in 768 hypertensive participants from the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) trial. In whites and blacks, increasing copies of the variant 65L-142V haplotype were associated with significantly reduced atenolol-induced diastolic blood pressure lowering (-9.1±6.8 versus -6.8±7.1 versus -5.3±6.4 mm Hg in participants with 0, 1, and 2 copies of 65L-142V, respectively; P=0.0088). One thousand four hundred sixty participants with hypertension and coronary artery disease from the INternational VErapamil SR/Trandolapril STudy (INVEST) were genotyped, and variant alleles of all 3 GRK4 single-nucleotide polymorphisms were associated with increased risk for adverse cardiovascular outcomes in an additive fashion, with 486V homozygotes reaching statistical significance (odds ratio, 2.29 [1.48-3.55]; P=0.0002). These effects on adverse cardiovascular outcomes were independent of antihypertensive treatment. These results suggest that the presence of GRK4 variant alleles may be important determinants of blood pressure response to atenolol and risk for adverse cardiovascular events. The associations with GRK4 variant alleles were stronger in patients who were also ADRB1 389R homozygotes, suggesting a potential interaction between these 2 genes.

  14. Differential Effects of β-Blockers, Angiotensin II Receptor Blockers, and a Novel AT2R Agonist NP-6A4 on Stress Response of Nutrient-Starved Cardiovascular Cells.

    PubMed

    Mahmood, Abuzar; Pulakat, Lakshmi

    2015-01-01

    In order to determine differences in cardiovascular cell response during nutrient stress to different cardiovascular protective drugs, we investigated cell responses of serum starved mouse cardiomyocyte HL-1 cells and primary cultures of human coronary artery vascular smooth muscles (hCAVSMCs) to treatment with β-blockers (atenolol, metoprolol, carvedilol, nebivolol, 3 μM each), AT1R blocker losartan (1 μM) and AT2R agonists (CGP42112A and novel agonist NP-6A4, 300 nM each). Treatment with nebivolol, carvedilol, metoprolol and atenolol suppressed Cell Index (CI) of serum-starved HL-1 cells (≤17%, ≤8%, ≤15% and ≤15% respectively) as measured by the Xcelligence Real-Time Cell Analyzer (RTCA). Conversely, CI was increased by Ang II (≥9.6%), CGP42112A (≥14%), and NP-6A4 (≥25%) respectively and this effect was blocked by AT2R antagonist PD123319, but not by AT1R antagonist losartan. Thus, the CI signature for each drug could be unique. MTS cell proliferation assay showed that NP-6A4, but not other drugs, increased viability (≥20%) of HL-1 and hCAVSMCs. Wheat Germ Agglutinin (WGA) staining showed that nebivolol was most effective in reducing cell sizes of HL-1 and hCAVSMCs. Myeloid Cell Leukemia 1 (MCL-1) is a protein critical for cardiovascular cell survival and implicated in cell adhesion. β-blockers significantly suppressed and NP-6A4 increased MCL-1 expression in HL-1 and hCAVSMCs as determined by immunofluorescence. Thus, reduction in cell size and/or MCL-1 expression might underlie β-blocker-induced reduction in CI of HL-1. Conversely, increase in cell viability and MCL-1 expression by NP-6A4 through AT2R could have resulted in NP-6A4 mediated increase in CI of HL-1. These data show for the first time that activation of the AT2R-MCL-1 axis by NP-6A4 in nutrient-stressed mouse and human cardiovascular cells (mouse HL-1 cells and primary cultures of hCAVSMCs) might underlie improved survival of cells treated by NP-6A4 compared to other drugs

  15. Efficacy of a dose range of surinabant, a cannabinoid receptor blocker, for smoking cessation: a randomized controlled clinical trial.

    PubMed

    Tonstad, Serena; Aubin, Henri-Jean

    2012-07-01

    A hyperactive endocannabinoid signalling system may contribute to addictions. We tested the efficacy and safety of surinabant, a novel selective CB₁ cannabinoid receptor antagonist, for smoking cessation. In a randomized, double-blind, placebo-controlled, parallel-group clinical trial, participants were assigned to brief counselling and one of three doses of surinabant, 2.5 mg/day (n = 199), 5 mg/day (n = 204), or 10 mg/day (n = 205) or placebo (n = 202) orally for 8 weeks with 6 weeks of non-drug follow-up. For weeks 5 through 8, the 4-week continuous abstinence rates were 25.2% for placebo vs. 22.6%, 22.1% and 21.5% for 2.5 mg/day, 5 mg/day and 10 mg/day doses of surinabant (p for trend, 0.4). The gain in body weight from baseline was reduced with surinabant 2.5 mg/day, 5 mg/day and 10 mg/day (0.75 kg [SE, 0.13], 0.53 kg [SE, 0.13], and 0.24 kg [SE, 0.13], respectively, versus 1.19 kg [SE, 0.13] for placebo; p for trend, < 0.001). The most common adverse events for participants receiving active drug with a greater incidence than placebo were headache, nausea, insomnia, anxiety, nasopharyngitis, diarrhoea and hyperhidrosis. Surinabant did not improve smoking cessation rates compared with placebo, but had a small effect on reducing post-cessation weight gain. PMID:22219220

  16. Losartan/hydrochlorothiazide combination therapy surpasses high-dose angiotensin receptor blocker in the reduction of morning home blood pressure in patients with morning hypertension.

    PubMed

    Hanayama, Yoshihisa; Uchida, Haruhito Adam; Nakamura, Yoshio; Makino, Hirofumi

    2012-01-01

    Angiotensin receptor blockers (ARBs) are the first-line antihypertensive agents. In clinical practice, it is often difficult to achieve the recommended blood pressure level by ARBs in their ordinal dosages alone. This study examined the practical efficacy of a combination therapy of ARB with thiazide diuretics for lowering morning home blood pressure (MHBP) in comparison to high-dose ARB therapy in patients with morning hypertension administered an ordinal dosage of ARB. This study was performed in a prospective, randomized, open-labeled and blind-endpoint fashion. Patients were considered to have morning hypertension when their self-measured systolic MHBPs were 135mmHg or higher, irrespective of their diastolic MHBP and office blood pressures (OBPs). Forty-eight outpatients with morning hypertension receiving the ordinal dosage of ARB were given either losartan/hydrochlorothiazide (n = 26) or high-dose ARB (n = 22) in place of their previously prescribed ARB. No change in any medication was permitted during this period. Decreases of both systolic and diastolic MHBP after 3 months of treatment were significantly greater in the losartan/hydrochlorothiazide group than in the high-dose ARB group (p < 0.05, respectively). The ratio of adverse events was somewhat high (23.1% in the losartan/hydrochlorothiazide group, 9.1% in the high-dose ARB group, respectively). However, there were no significant differences in any particular adverse event between groups. This study suggested losartan/hydrochlorothiazide might be superior to high-dose ARB for reducing morning home blood pressure. PMID:23254579

  17. Effect of Angiotensin Converting Enzyme Inhibitors and Receptor Blockers on Appropriate Implantable Cardiac Defibrillator Shock in Patients with Severe Systolic Heart Failure (From the GRADE Multicenter Study)

    PubMed Central

    AlJaroudi, Wael A.; Refaat, Marwan M.; Habib, Robert H.; Al-Shaar, Laila; Singh, Madhurmeet; Gutmann, Rebecca; Bloom, Heather L.; Dudley, Samuel C.; Ellinor, Patrick T.; Saba, Samir F.; Shalaby, Alaa A.; Weiss, Raul; McNamara, Dennis M.; Halder, Indrani; London, Barry

    2015-01-01

    Sudden cardiac death (SCD) is a leading cause of mortality in patients with cardiomyopathy. While angiotensin converting enzyme inhibitors (ACEi) and receptor blockers (ARB) decrease cardiac mortality in these cohorts, their role in preventing SCD has not been well established. We sought to determine whether the use of ACEi or ARB in patients with cardiomyopathy is associated with a lower incidence of appropriate implantable cardiac defibrillator (ICD) shocks in the Genetic Risk Assessment of Defibrillator Events (GRADE) study which included subjects with an ejection fraction of ≤30% and ICDs. Treatment with ACEi/ARB versus no ACEi/ARB was physician dependent. There were 1509 patients (mean age [SD] 63[12] years, 80% male, mean [SD] EF 21% [6%]) with 1213 (80%) on ACEi/ARB, and 296 (20%) not on ACEi/ARB. We identified 574 propensity matched patients (287 in each group). After a mean (SD) of 2.5(1.9) years, there were 334 (22%) appropriate shocks in the entire cohort. The use of ACEi/ARB was associated with lower incidence of shocks at 1, 3 and 5 years in the matched cohort (7.7%, 16.7%, 18.5% vs. 13.2%, 27.5%, and 32.0% (RR= 0.61[0.43–0.86], p =0.005). Among patients with GFR >60 and 30–60 ml/min/1.73m2, those on no-ACEi/ARB were at 45% and 77% increased risk of ICD shock as compared to those on ACEi/ARB, respectively. ACEi/ARB were associated with significant lower incidence of appropriate ICD shock in patients with cardiomyopathy and GFR ≥30 ml/min/1.73m2, and with neutral effect among those GFR <30 ml/min/1.73m2. PMID:25682436

  18. Addition of hydrochlorothiazide to angiotensin receptor blocker therapy can achieve a lower sodium balance with no acceleration of intrarenal renin angiotensin system in patients with chronic kidney disease

    PubMed Central

    Fuwa, Daisuke; Fukuda, Michio; Ogiyama, Yoshiaki; Sato, Ryo; Mizuno, Masashi; Miura, Toshiyuki; Abe-Dohmae, Sumiko; Michikawa, Makoto; Kobori, Hiroyuki; Ohte, Nobuyuki

    2016-01-01

    Objective Angiotensin receptor blockers (ARBs) produce a lower sodium (Na) balance, and the natriuretic effect is enhanced under Na deprivation, despite falls in blood pressure (BP) and glomerular filtration rate (GFR). Methods The effect of additional hydrochlorothiazide (HCTZ; 12.5 mg/day) to ARB treatment (valsartan; 80 mg/day) on glomerulotubular Na balance was evaluated in 23 patients with chronic kidney disease. Results Add-on HCTZ decreased GFR, tubular Na load, and tubular Na reabsorption (tNa), although 24-hour urinary Na excretion (UNaV) remained constant. Daily urinary angiotensinogen excretion (UAGTV, 152±10→82±17 μg/g Cre) reduced (p=0.02). Changes in tubular Na load (r2=0.26) and tNa (r2=0.25) correlated with baseline 24-hour UAGTV. Changes in filtered Na load correlated with changes in nighttime systolic BP (r2=0.17), but not with changes in daytime systolic BP. The change in the tNa to filtered Na load ratio was influenced by the change in daytime UNaV (β=−0.67, F=16.8), rather than the change in nighttime UNaV. Conclusions Lower Na balance was produced by add-on HCTZ to ARB treatment without an increase of intra-renal renin-angiotensin system activity, leading to restoration of nocturnal hypertension. A further study is needed to demonstrate that the reduction of UAGTV by additional diuretics to ARBs prevents the progression of nephropathy or cardiovascular events. PMID:27283968

  19. In Vitro Biliary Clearance of Angiotensin II Receptor Blockers and HMG-CoA Reductase Inhibitors in Sandwich-Cultured Rat Hepatocytes: Comparison to In Vivo Biliary Clearance

    PubMed Central

    Abe, Koji; Bridges, Arlene S.; Yue, Wei; Brouwer, Kim L. R.

    2008-01-01

    Previous reports have indicated that in vitro biliary clearance (Clbiliary) determined in sandwich-cultured hepatocytes correlates well with in vivo Clbiliary for limited sets of compounds. This study was designed to estimate the in vitro Clbiliary in sandwich-cultured rat hepatocytes (SCRH) of angiotensin II receptor blockers and HMG-CoA reductase inhibitors that undergo limited metabolism, to compare the estimated Clbiliary values with published in vivo Clbiliary data in rats, and to characterize the mechanism(s) of basolateral uptake and canalicular excretion of these drugs in rats. Average biliary excretion index (BEI) and in vitro Clbiliary of olmesartan, valsartan, pravastatin, rosuvastatin, and pitavastatin were 15%, 19%, 43%, 45%, and 20%, respectively, and 1.7, 3.2, 4.4, 46.1, and 34.6 ml/min/kg, respectively. Clbiliary predicted from SCRH, accounting for plasma unbound fraction, correlated with reported in vivo Clbiliary for these drugs. The rank order of Clbiliary values predicted from SCRH was consistent with in vivo Clbiliary values. Bromosulfophthalein inhibited the uptake of all drugs. BEI and Clbiliary values of olmesartan, valsartan, pravastatin, and rosuvastatin, known multidrug resistance-associated protein (Mrp)2 substrates, were reduced in SCRH from Mrp2-deficient (TR−) compared to wild-type (WT) rats. Although Mrp2 plays a minor role in pitavastatin biliary excretion, pitavastatin BEI and Clbiliary were reduced in TR− compared to WT SCRH; Bcrp expression in SCRH from TR− rats was decreased. In conclusion, in vitro Clbiliary determined in SCRH can be used to estimate and compare in vivo Clbiliary of compounds in rats, and to characterize transport proteins responsible for their hepatic uptake and excretion. PMID:18574002

  20. Blood pressure outcomes in patients receiving angiotensin II receptor blockers in primary care: a comparative effectiveness analysis from electronic medical record data.

    PubMed

    Ram, C Venkata S; Ramaswamy, Krishnan; Qian, Chunlin; Biskupiak, Joe; Ryan, Amy; Quah, Ruth; Russo, Patricia A

    2011-11-01

    The authors examined the comparative effectiveness of 4 angiotensin receptor blockers (ARBs) in patients with hypertension using a large electronic medical record database. Analysis of covariance and logistic multivariate regression models were used to estimate the blood pressure (BP) outcomes of 73,012 patients during 13 months of treatment with olmesartan, losartan, valsartan, and irbesartan. Results were adjusted by baseline BP, starting dose, year, age, sex, race, body mass index, comorbid conditions, and concomitant medications of patients. All ARBs led to sustained reductions in BP, but with significant differences in the magnitude of BP reduction. Raw mean systolic BP/diastolic BP reductions with losartan, valsartan, irbesartan, and olmesartan were 9.3/4.9 mm Hg, 10.4/5.6 mm Hg, 10.1/5.3 mm Hg, and 12.4/6.8 mm Hg, respectively. Adjusting for all covariates, the overall BP reductions with olmesartan were 1.88/0.86 mm Hg, 1.21/0.52 mm Hg, and 0.89/0.51 mm Hg greater than for losartan, valsartan, and irbesartan, respectively, and mean differences were higher for monotherapy: 2.43/1.16 mm Hg; 2.18/0.93 mm Hg; 1.44/0.91 mm Hg, respectively (all P values <.0001). Adjusted odds ratios of the JNC 7 goal attainment for losartan, valsartan, and irbesartan compared with olmesartan were 0.76, 0.86, and 0.91 (P<.05). Differences were also found in subpopulations: African Americans, diabetics, and obese/overweight patients but not all of these reached statistical significance. A broad choice of ARBs may be required to get patients to treatment goals. PMID:22051424

  1. Comparative Effectiveness of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers in Terms of Major Cardiovascular Disease Outcomes in Elderly Patients

    PubMed Central

    Chien, Shu-Chen; Ou, Shuo-Ming; Shih, Chia-Jen; Chao, Pei-Wen; Li, Szu-Yuan; Lee, Yi-Jung; Kuo, Shu-Chen; Wang, Shuu-Jiun; Chen, Tzeng-Ji; Tarng, Der-Cherng; Chu, Hsi; Chen, Yung-Tai

    2015-01-01

    Abstract Renin and aldosterone activity levels are low in elderly patients, raising concerns about the benefits and risks of angiotensin-converting-enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARB) use. However, data from direct comparisons of the effects of ACEIs on ARBs in the elderly population remain inconclusive. In this nationwide study, all patients aged ≥ 70 years were retrieved from the Taiwan National Health Insurance database for the period 2000 to 2009 and were followed up until the end of 2010. The ARB cohort (12,347 patients who continuously used ARBs for ≥ 90 days) was matched to ACEI cohort using high-dimensional propensity score (hdPS). Intention-to-treat (ITT) and as-treated (AT) analyses were conducted. In the ITT analysis, after considering death as a competing risk, the ACEI cohort had similar risks of myocardial infarction (hazard ratio [HR] 0.92, 95% confidence interval [CI] 0.79–1.06), ischemic stroke (HR 0.98, 95% CI 0.90–1.07), and heart failure (HR 0.93, 95% CI 0.83–1.04) compared with the ARB cohort. No difference in adverse effects, such as acute kidney injury (HR 0.99, 95% CI 0.89–1.09) and hyperkalemia (HR 1.02, 95% CI 0.87–1.20), was observed between cohorts. AT analysis produced similar results to those of ITT analysis. We were unable to demonstrate a survival difference between cohorts (HR 1.03, 95% CI 0.88–1.21) after considering drug discontinuation as a competing risk in AT analysis. Our study supports the notion that ACEI and ARB users have similar risks of major adverse cardiovascular events (MACE), even in elderly populations. PMID:26512568

  2. Activation of serotonin2A receptors in the medial septum-diagonal band of Broca complex enhanced working memory in the hemiparkinsonian rats.

    PubMed

    Li, Li-Bo; Zhang, Li; Sun, Yi-Na; Han, Ling-Na; Wu, Zhong-Heng; Zhang, Qiao-Jun; Liu, Jian

    2015-04-01

    Serotonin2A (5-HT2A) receptors are highly expressed in the medial septum-diagonal band of Broca complex (MS-DB), especially in parvalbumin (PV)-positive neurons linked to hippocampal theta rhythm, which is involved in cognition. Cognitive impairments commonly occur in Parkinson's disease. Here we performed behavioral, electrophysiological, neurochemical and immunohistochemical studies in rats with complete unilateral 6-hydroxydopamine lesions of the medial forebrain bundle (MFB) to assess the importance of dopamine (DA) depletion and MS-DB 5-HT2A receptors for working memory. The MFB lesions resulted in working memory impairment and decreases in firing rate and density of MS-DB PV-positive neurons, peak frequency of hippocampal theta rhythm, and DA levels in septohippocampal system and medial prefrontal cortex (mPFC) compared to control rats. Intra-MS-DB injection of high affinity 5-HT2A receptor agonist TCB-2 enhanced working memory, increased firing rate of PV-positive neurons and peak frequency of hippocampal theta rhythm, elevated DA levels in the hippocampus and mPFC, and decreased 5-HT level in the hippocampus in control and lesioned rats. Compared to control rats, the duration of the excitatory effect produced by TCB-2 on the firing rate of PV-positive neurons was markedly shortened in lesioned rats, indicating dysfunction of 5-HT2A receptors. These findings suggest that unilateral lesions of the MFB in rats induced working memory deficit, and activation of MS-DB 5-HT2A receptors enhanced working memory, which may be due to changes in the activity of septohippocampal network and monoamine levels in the hippocampus and mPFC. PMID:25486618

  3. Activation of serotonin2A receptors in the medial septum-diagonal band of Broca complex enhanced working memory in the hemiparkinsonian rats.

    PubMed

    Li, Li-Bo; Zhang, Li; Sun, Yi-Na; Han, Ling-Na; Wu, Zhong-Heng; Zhang, Qiao-Jun; Liu, Jian

    2015-04-01

    Serotonin2A (5-HT2A) receptors are highly expressed in the medial septum-diagonal band of Broca complex (MS-DB), especially in parvalbumin (PV)-positive neurons linked to hippocampal theta rhythm, which is involved in cognition. Cognitive impairments commonly occur in Parkinson's disease. Here we performed behavioral, electrophysiological, neurochemical and immunohistochemical studies in rats with complete unilateral 6-hydroxydopamine lesions of the medial forebrain bundle (MFB) to assess the importance of dopamine (DA) depletion and MS-DB 5-HT2A receptors for working memory. The MFB lesions resulted in working memory impairment and decreases in firing rate and density of MS-DB PV-positive neurons, peak frequency of hippocampal theta rhythm, and DA levels in septohippocampal system and medial prefrontal cortex (mPFC) compared to control rats. Intra-MS-DB injection of high affinity 5-HT2A receptor agonist TCB-2 enhanced working memory, increased firing rate of PV-positive neurons and peak frequency of hippocampal theta rhythm, elevated DA levels in the hippocampus and mPFC, and decreased 5-HT level in the hippocampus in control and lesioned rats. Compared to control rats, the duration of the excitatory effect produced by TCB-2 on the firing rate of PV-positive neurons was markedly shortened in lesioned rats, indicating dysfunction of 5-HT2A receptors. These findings suggest that unilateral lesions of the MFB in rats induced working memory deficit, and activation of MS-DB 5-HT2A receptors enhanced working memory, which may be due to changes in the activity of septohippocampal network and monoamine levels in the hippocampus and mPFC.

  4. Nifedipine, a calcium channel blocker, inhibits advanced glycation end product (AGE)-elicited mesangial cell damage by suppressing AGE receptor (RAGE) expression via peroxisome proliferator-activated receptor-gamma activation

    SciTech Connect

    Matsui, Takanori; Yamagishi, Sho-ichi; Takeuchi, Masayoshi; Ueda, Seiji; Fukami, Kei; Okuda, Seiya

    2009-07-24

    The interaction between advanced glycation end products (AGE) and their receptor RAGE mediates the progressive alteration in renal architecture and loss of renal function in diabetic nephropathy. Oxidative stress generation and inflammation also play a central role in diabetic nephropathy. This study investigated whether and how nifedipine, a calcium channel blocker (CCB), blocked the AGE-elicited mesangial cell damage in vitro. Nifedipine, but not amlodipine, a control CCB, down-regulated RAGE mRNA levels and subsequently reduced reactive oxygen species (ROS) generation in AGE-exposed mesangial cells. AGE increased mRNA levels of vascular cell adhesion molecule-1 (VCAM-1) and induced monocyte chemoattractant protein-1 (MCP-1) production in mesangial cells, both of which were prevented by the treatment with nifedipine, but not amlodipine. The beneficial effects of nifedipine on AGE-exposed mesangial cells were blocked by the simultaneous treatment of GW9662, an inhibitor of peroxisome proliferator-activated receptor-{gamma} (PPAR-{gamma}). Although nifedipine did not affect expression levels of PPAR-{gamma}, it increased the PPAR-{gamma} transcriptional activity in mesangial cells. Our present study provides a unique beneficial aspect of nifedipine on diabetic nephropathy; it could work as an anti-inflammatory agent against AGE by suppressing RAGE expression in cultured mesangial cells via PPAR-{gamma} activation.

  5. Inhibition of alpha oscillations through serotonin-2A receptor activation underlies the visual effects of ayahuasca in humans.

    PubMed

    Valle, Marta; Maqueda, Ana Elda; Rabella, Mireia; Rodríguez-Pujadas, Aina; Antonijoan, Rosa Maria; Romero, Sergio; Alonso, Joan Francesc; Mañanas, Miquel Àngel; Barker, Steven; Friedlander, Pablo; Feilding, Amanda; Riba, Jordi

    2016-07-01

    Ayahuasca is an Amazonian psychotropic plant tea typically obtained from two plants, Banisteriopsis caapi and Psychotria viridis. It contains the psychedelic 5-HT2A and sigma-1 agonist N,N-dimethyltryptamine (DMT) plus β-carboline alkaloids with monoamine-oxidase (MAO)-inhibiting properties. Although the psychoactive effects of ayahuasca have commonly been attributed solely to agonism at the 5-HT2A receptor, the molecular target of classical psychedelics, this has not been tested experimentally. Here we wished to study the contribution of the 5-HT2A receptor to the neurophysiological and psychological effects of ayahuasca in humans. We measured drug-induced changes in spontaneous brain oscillations and subjective effects in a double-blind randomized placebo-controlled study involving the oral administration of ayahuasca (0.75mg DMT/kg body weight) and the 5-HT2A antagonist ketanserin (40mg). Twelve healthy, experienced psychedelic users (5 females) participated in four experimental sessions in which they received the following drug combinations: placebo+placebo, placebo+ayahuasca, ketanserin+placebo and ketanserin+ayahuasca. Ayahuasca induced EEG power decreases in the delta, theta and alpha frequency bands. Current density in alpha-band oscillations in parietal and occipital cortex was inversely correlated with the intensity of visual imagery induced by ayahuasca. Pretreatment with ketanserin inhibited neurophysiological modifications, reduced the correlation between alpha and visual effects, and attenuated the intensity of the subjective experience. These findings suggest that despite the chemical complexity of ayahuasca, 5-HT2A activation plays a key role in the neurophysiological and visual effects of ayahuasca in humans. PMID:27039035

  6. Inhibition of alpha oscillations through serotonin-2A receptor activation underlies the visual effects of ayahuasca in humans.

    PubMed

    Valle, Marta; Maqueda, Ana Elda; Rabella, Mireia; Rodríguez-Pujadas, Aina; Antonijoan, Rosa Maria; Romero, Sergio; Alonso, Joan Francesc; Mañanas, Miquel Àngel; Barker, Steven; Friedlander, Pablo; Feilding, Amanda; Riba, Jordi

    2016-07-01

    Ayahuasca is an Amazonian psychotropic plant tea typically obtained from two plants, Banisteriopsis caapi and Psychotria viridis. It contains the psychedelic 5-HT2A and sigma-1 agonist N,N-dimethyltryptamine (DMT) plus β-carboline alkaloids with monoamine-oxidase (MAO)-inhibiting properties. Although the psychoactive effects of ayahuasca have commonly been attributed solely to agonism at the 5-HT2A receptor, the molecular target of classical psychedelics, this has not been tested experimentally. Here we wished to study the contribution of the 5-HT2A receptor to the neurophysiological and psychological effects of ayahuasca in humans. We measured drug-induced changes in spontaneous brain oscillations and subjective effects in a double-blind randomized placebo-controlled study involving the oral administration of ayahuasca (0.75mg DMT/kg body weight) and the 5-HT2A antagonist ketanserin (40mg). Twelve healthy, experienced psychedelic users (5 females) participated in four experimental sessions in which they received the following drug combinations: placebo+placebo, placebo+ayahuasca, ketanserin+placebo and ketanserin+ayahuasca. Ayahuasca induced EEG power decreases in the delta, theta and alpha frequency bands. Current density in alpha-band oscillations in parietal and occipital cortex was inversely correlated with the intensity of visual imagery induced by ayahuasca. Pretreatment with ketanserin inhibited neurophysiological modifications, reduced the correlation between alpha and visual effects, and attenuated the intensity of the subjective experience. These findings suggest that despite the chemical complexity of ayahuasca, 5-HT2A activation plays a key role in the neurophysiological and visual effects of ayahuasca in humans.

  7. Serotonin 2A Receptors in Obsessive-Compulsive Disorder: a Positron Emission Tomography Study with [11C]MDL 100907

    PubMed Central

    Simpson, H. Blair; Slifstein, Mark; Bender, James; Xu, Xiaoyan; Hackett, Elizabeth; Maher, Michael J.; Abi-Dargham, Anissa

    2014-01-01

    Background Serotonergic abnormalities are hypothesized to contribute to obsessive-compulsive disorder (OCD). This study used positron emission tomography (PET) with the radioligand [11C]MDL 100907 to examine whether the distribution of one of the serotonin receptors, the 5-HT2A receptor, is altered in OCD. Methods Nineteen OCD subjects, free of psychiatric medications and depression, and 19 matched healthy controls underwent PET scans following injection of [11C]MDL 100907. Total distribution volumes (VT) were derived by kinetic analysis using the arterial input function. Two measures of 5-HT2A availability were computed (BPND and BPP). Groups were compared using a region of interest (ROI) analysis and voxelwise analysis of spatially normalized parametric maps. ROIs included cortical regions (orbitofrontal, dorsolateral prefrontal, medial prefrontal, anterior cingulate, temporal, parietal, occipital, and insular cortex) and limbic regions (entorhinal cortex, parahippocampal gyrus, and medial temporal lobe). Results No significant group differences were observed in [11C]MDL 100907 BPND or BPP in the ROIs or in the voxelwise analysis of BPND maps. There was a significant correlation in the orbitofrontal cortex between [11C] MDL 100907 binding and age of onset, with earlier age of onset associated with higher binding. Conclusions In contrast to prior reports, people with OCD (free of psychiatric medications and depression) are not characterized as a group by major changes in 5-HT2A availability in cortical or limbic brain regions. Further research is warranted to examine potential differences in 5-HT2A availability between early and late onset OCD and to assess 5-HT2A function in relation to other neurotransmitter systems implicated in OCD. PMID:21855857

  8. Impact of drug price adjustments on utilization of and expenditures on angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in Taiwan

    PubMed Central

    2012-01-01

    Background A previous study has suggested that drug price adjustments allow physicians in Taiwan to gain greater profit by prescribing generic drugs. To better understand the effect of price adjustments on physician choice, this study used renin-angiotensin drugs (including angiotensin-converting enzyme inhibitors [ACEIs] and angiotensin receptor blockers [ARBs]) to examine the impact of price adjustments on utilization of and expenditures on patented and off-patent drugs with the same therapeutic indication. Methods Using the Taiwan’s Longitudinal Health Insurance Database (2005), we identified 147,157 patients received ACEIs and/or ARBs between 1997 and 2008. The annual incident and prevalent users of ACEIs, ARBs and overall renin-angiotensin drugs were examined. Box-Tiao intervention analysis was applied to assess the impact of price adjustments on monthly utilization of and expenditures on these drugs. ACEIs were divided into patented and off-patent drugs, off-patent ACEIs were further divided into original brands and generics, and subgroup analyses were performed. Results The number of incident renin-angiotensin drug users decreased over the study period. The number of prevalent ARB users increased and exceeded the cumulative number of first-time renin-angiotensin drug users starting on ARBs, implying that some patients switched from ACEIs to ARBs. After price adjustments, long term trend increases in utilization were observed for patented ACEIs and ARBs; a long-term trend decrease was observed for off-patent ACEIs; long-term trend change was not significant for overall renin-angiotensin drugs. Significant long-term trend increases in expenditures were observed for patented ACEIs after price adjustment in 2007 (200.9%, p = 0.0088) and in ARBs after price adjustments in 2001 (173.4%, p < 0.0001) and 2007 (146.3%, p < 0.0001). A significant long-term trend decrease in expenditures was observed for off-patent ACEIs after 2004 price adjustment (

  9. Effect of angiotensin-converting enzyme inhibitors and receptor blockers on appropriate implantable cardiac defibrillator shock in patients with severe systolic heart failure (from the GRADE Multicenter Study).

    PubMed

    AlJaroudi, Wael A; Refaat, Marwan M; Habib, Robert H; Al-Shaar, Laila; Singh, Madhurmeet; Gutmann, Rebecca; Bloom, Heather L; Dudley, Samuel C; Ellinor, Patrick T; Saba, Samir F; Shalaby, Alaa A; Weiss, Raul; McNamara, Dennis M; Halder, Indrani; London, Barry

    2015-04-01

    Sudden cardiac death (SCD) is a leading cause of mortality in patients with cardiomyopathy. Although angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs) decrease cardiac mortality in these cohorts, their role in preventing SCD has not been well established. We sought to determine whether the use of ACEi or ARB in patients with cardiomyopathy is associated with a lower incidence of appropriate implantable cardiac defibrillator (ICD) shocks in the Genetic Risk Assessment of Defibrillator Events study that included subjects with an ejection fraction of ≤30% and ICDs. Treatment with ACEi/ARB versus no-ACEi/ARB was physician dependent. There were 1,509 patients (mean age [SD] 63 [12] years, 80% men, mean [SD] EF 21% [6%]) with 1,213 (80%) on ACEi/ARB and 296 (20%) not on ACEi/ARB. We identified 574 propensity-matched patients (287 in each group). After a mean (SD) of 2.5 (1.9) years, there were 334 (22%) appropriate shocks in the entire cohort. The use of ACEi/ARB was associated with lower incidence of shocks at 1, 3, and 5 years in the matched cohort (7.7%, 16.7%, and 18.5% vs 13.2%, 27.5%, and 32.0%; RR = 0.61 [0.43 to 0.86]; p = 0.005). Among patients with glomerular filtration rate (GFR) >60 and 30 to 60 ml/min/1.73 m(2), those on no-ACEi/ARB were at 45% and 77% increased risk of ICD shock compared with those on ACEi/ARB, respectively. ACEi/ARB were associated with significant lower incidence of appropriate ICD shock in patients with cardiomyopathy and GFR ≥30 ml/min/1.73 m(2) and with neutral effect in those with GFR <30 ml/min/1.73 m(2). PMID:25682436

  10. Comparative effectiveness of angiotensin-converting-enzyme inhibitors and angiotensin II receptor blockers in patients with type 2 diabetes and retinopathy

    PubMed Central

    Shih, Chia-Jen; Chen, Hung-Ta; Kuo, Shu-Chen; Li, Szu-Yuan; Lai, Pi-Hsiang; Chen, Shu-Chen; Ou, Shuo-Ming; Chen, Yung-Tai

    2016-01-01

    Background: Angiotensin-converting-enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) are effective treatments for diabetic retinopathy, but randomized trials and meta-analyses comparing their effects on macrovascular complications have yielded conflicting results. We compared the effectiveness of these drugs in patients with pre-existing diabetic retinopathy in a large population-based cohort. Methods: We conducted a propensity score–matched cohort study using Taiwan’s National Health Insurance Research Database. We included adult patients prescribed an ACE inhibitor or ARB within 90 days after diagnosis of diabetic retinopathy between 2000 and 2010. Primary outcomes were all-cause death and major adverse cardiovascular events (myocardial infarction, ischemic stroke or cardiovascular death). Secondary outcomes were hospital admissions with acute kidney injury or hyperkalemia. Results: We identified 11 246 patients receiving ACE inhibitors and 15 173 receiving ARBs, of whom 9769 patients in each group were matched successfully by propensity scores. In the intention-to-treat analyses, ARBs were similar to ACE inhibitors in risk of all-cause death (hazard ratio [HR] 0.94, 95% confidence interval [CI] 0.87–1.01) and major adverse cardiovascular events (HR 0.95, 95% CI 0.87–1.04), including myocardial infarction (HR 1.03, 95% CI 0.88–1.20), ischemic stroke (HR 0.94, 95% CI 0.85–1.04) and cardiovascular death (HR 1.01, 95% CI 0.88–1.16). They also did not differ from ACE inhibitors in risk of hospital admission with acute kidney injury (HR 1.01, 95% CI 0.91–1.13) and hospital admission with hyperkalemia (HR 1.01, 95% CI 0.86–1.18). Results were similar in as-treated analyses. Interpretation: Our study showed that ACE inhibitors were similar to ARBs in risk of all-cause death, major adverse cardiovascular events and adverse effects among patients with pre-existing diabetic retinopathy. PMID:27001739

  11. The telmisartan renoprotective study from incipient nephropathy to overt nephropathy--rationale, study design, treatment plan and baseline characteristics of the incipient to overt: angiotensin II receptor blocker, telmisartan, Investigation on Type 2 Diabetic Nephropathy (INNOVATION) Study.

    PubMed

    Makino, H; Haneda, M; Babazono, T; Moriya, T; Ito, S; Iwamoto, Y; Kawamori, R; Takeuchi, M; Katayama, S

    2005-01-01

    We planned the INNOVATION study to determine whether telmisartan, an angiotensin-2-receptor blocker, delays the progression of renal disease from incipient nephropathy to overt nephropathy in hypertensive or normotensive Japanese patients with type 2 diabetes mellitus. The INNOVATION study is a randomized, double-blind, placebo-controlled trial. Eligible patients must have incipient nephropathy (defined as a urinary albumin to creatinine ratio of 100-300 mg/g creatinine) and a serum creatinine concentration of < 1.5 mg/dl for men and < 1.3 mg/dl for women. Patients who need treatment with angiotensin II receptor blockers or angiotensin-converting enzyme inhibitors are excluded. Eligible patients are randomly assigned to three groups: telmisartan titrated to 40 mg; telmisartan titrated to 80 mg; or placebo. The primary endpoint is the time from baseline visit to first detection of overt nephropathy (defined by a urinary albumin to creatinine ratio that is > 300 mg/g creatinine and 30% higher than the baseline on at least two consecutive visits). A total of 1855 patients have been enrolled from 160 study centres. In 527 randomized patients (28.4% of the enrolled patients), mean (SD) urinary albumin to creatinine ratio and serum creatinine concentration at baseline were 173.3 (47.2) mg/g creatinine and 0.78 (0.19) mg/dl. Sixty-eight per cent of the patients had hypertension at baseline. Mean (SD) systolic and diastolic blood pressures at baseline were 137.1 (14.6) and 77.5 (10.3) mmHg. The INNOVATION study will determine whether telmisartan, an angiotensin II receptor blocker, provides clinical benefits in hypertensive or normotensive patients with diabetes mellitus and diabetic nephropathy.

  12. Concurrent use of diuretics, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers with non-steroidal anti-inflammatory drugs and risk of acute kidney injury: nested case-control study

    PubMed Central

    Lapi, Francesco; Azoulay, Laurent; Yin, Hui; Nessim, Sharon J

    2013-01-01

    Objectives To assess whether a double therapy combination consisting of diuretics, angiotensin converting enzyme inhibitors, or angiotensin receptor blockers with addition of non-steroidal anti-inflammatory drugs (NSAIDs) and the triple therapy combination of two of the aforementioned antihypertensive drugs to which NSAIDs are added are associated with an increased risk of acute kidney injury. Design Retrospective cohort study using nested case-control analysis. Setting General practices contributing data to the UK Clinical Practice Research Datalink linked to the Hospital Episodes Statistics database. Participants A cohort of 487 372 users of antihypertensive drugs. Main outcome measures Rate ratios with 95% confidence intervals of acute kidney injury associated with current use of double and triple therapy combinations of antihypertensive drugs with NSAIDs. Results During a mean follow-up of 5.9 (SD 3.4) years, 2215 cases of acute kidney injury were identified (incidence rate 7/10 000 person years). Overall, current use of a double therapy combination containing either diuretics or angiotensin converting enzyme inhibitors or angiotensin receptor blockers with NSAIDs was not associated with an increased rate of acute kidney injury. In contrast, current use of a triple therapy combination was associated with an increased rate of acute kidney injury (rate ratio 1.31, 95% confidence interval 1.12 to 1.53). In secondary analyses, the highest risk was observed in the first 30 days of use (rate ratio 1.82, 1.35 to 2.46). Conclusions A triple therapy combination consisting of diuretics with angiotensin converting enzyme inhibitors or angiotensin receptor blockers and NSAIDs was associated with an increased risk of acute kidney injury. The risk was greatest at the start of treatment. Although antihypertensive drugs have cardiovascular benefits, vigilance may be warranted when they are used concurrently with NSAIDs. PMID:23299844

  13. The 5-hydroxytryptamine2A receptor antagonist R-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl-4-piperidinemethanol (M100907) attenuates impulsivity after both drug-induced disruption (dizocilpine) and enhancement (antidepressant drugs) of differential-reinforcement-of-low-rate 72-s behavior in the rat.

    PubMed

    Ardayfio, Paul A; Benvenga, Mark J; Chaney, Stephen F; Love, Patrick L; Catlow, John; Swanson, Steven P; Marek, Gerard J

    2008-12-01

    Previous work has suggested that N-methyl-d-aspartate (NMDA) receptor antagonism and 5-hydroxytryptamine (5-HT)(2A) receptor blockade may enhance and attenuate, respectively, certain types of impulsivity mediated by corticothalamostriatal circuits. More specifically, past demonstrations of synergistic "antidepressant-like" effects of a 5-HT(2A) receptor antagonist and fluoxetine on differential-reinforcement-of-low-rate (DRL) 72-s schedule of operant reinforcement may speak to the role of 5-HT(2A) receptor blockade with respect to response inhibition as an important prefrontal cortical executive function relating to motor impulsivity. To examine the dynamic range over which 5-HT(2A) receptor blockade may exert effects on impulsivity, [R-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl-4-piperidinemethanol] (M100907) was examined both alone and in combination with the psychotomimetic NMDA receptor antagonist dizocilpine [e.g., (-)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate; MK-801] and two different antidepressants, the tricyclic antidepressant desmethylimipramine (DMI) and the monoamine oxidase inhibitor tranylcypromine in rats performing under a DRL 72-s schedule. MK-801 increased the response rate, decreased the number of reinforcers obtained, and exerted a leftward shift in the inter-response time (IRT) distribution as expected. A dose of M100907 that exerted minimal effect on DRL behavior by itself attenuated the psychotomimetic effects of MK-801. Extending previous M100907-fluoxetine observations, addition of a minimally active dose of M100907 to low doses of DMI and tranylcypromine enhanced the antidepressant-like effect of the antidepressants. Therefore, it may be that a tonic excitation of 5-HT(2A) receptors modulates impulsivity and function of corticothalamostriatal circuits over an extensive dynamic range. PMID:18772320

  14. Activation of mGlu2/3 metabotropic glutamate receptors negatively regulates the stimulation of inositol phospholipid hydrolysis mediated by 5-hydroxytryptamine2A serotonin receptors in the frontal cortex of living mice.

    PubMed

    Molinaro, G; Traficante, A; Riozzi, B; Di Menna, L; Curto, M; Pallottino, S; Nicoletti, F; Bruno, V; Battaglia, G

    2009-08-01

    The interaction between 5-hydroxytryptamine(2A) (5-HT(2A)) serotonin receptors and metabotropic glutamate (mGlu) 2/3 receptors underlies the antipsychotic activity of mGlu2/3 receptor agonists in experimental animals and humans. The molecular nature of this interaction is only partially known. We here report for the first time that pharmacological activation of mGlu2/3 receptors attenuates the stimulation of polyphosphoinositide (PI) hydrolysis mediated by 5-HT(2A) receptors in the frontal cortex of living mice. Mice were injected intracerebroventricularly with [myo-(3)H]inositol and treated with drugs 1 h after a pretreatment with lithium, which blocks the conversion of inositol monophosphate into free inositol. Systemic injection of the mGlu2/3 receptor agonist (-)-2-oxa-4-aminocyclo[3.1.0]hexane-4,6-dicarboxylic acid (LY379268) inhibited the stimulation of PI hydrolysis induced by the hallucinogenic 5-HT(2A) receptor agonist (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) without affecting the stimulation by mGlu1/5 or muscarinic receptors. The action of LY379268 was prevented by the preferential mGlu2/3 receptor antagonist (2S,1'S,2'S)-2-(9-xanthylmethyl)-2-(2'-carboxycyclopropyl)glycine (LY341495). N-(4'-cyano-biphenyl-3-yl)-N-(3-pyridinylmethyl)-ethanesulfonamide hydrochloride (LY566332), a selective mGlu2 receptor enhancer, also reduced DOI-stimulated PI hydrolysis when combined with subthreshold doses of LY379268. Systemic LY379268 inhibited DOI-stimulated PI hydrolysis in mice lacking either mGlu2 or mGlu3 receptors but was inactive in double mGlu2/mGlu3 receptor knockout mice, suggesting that both mGlu2 and mGlu3 receptors interact with 5-HT(2A) receptors. Surprisingly, contrasting results were obtained in cortical slice preparations, where LY379268 amplified both DOI- and 3,5-dihydroxyphenylglycine-stimulated PI hydrolysis. Amplification was abrogated by the mGlu5 receptor antagonist 2-methyl-6-(phenylethynyl)pyridine, suggesting that

  15. [AT1-blockers in the treatment of hypertension: summary].

    PubMed

    Jr, Jiří Widimský

    2016-02-01

    Angiotensin receptor antagonists (AT(1)-blockers) are considered as one of the major classes of antihypertensive drugs suitable for monotherapy as well as for combination treatment. AT(1)-blockers have comparable antihypertensive efficacy with other major classes of antihypertensive drugs. AT(1)-blockers are considered by current guidelines of Czech society of hypertension altogether with ACE-inhibitors and calcium channel blockers as universal antihypertensive drug class. AT(1)-blockers has the lowest profile of side-effects among all antihypertensive drug classes and thus very high persistence to therapy. Mechanisms of antihypertensive effects of AT(1)-blockers are discussed altogether with the results of large clinical trials and indications in the treatment of hypertension. PMID:27172437

  16. The noncompetitive blocker ( sup 3 H)chlorpromazine labels three amino acids of the acetylcholine receptor gamma subunit: Implications for the alpha-helical organization of regions MII and for the structure of the ion channel

    SciTech Connect

    Revah, F.; Galzi, J.L.; Giraudat, J.; Haumont, P.Y.; Lederer, F.; Changeux, J.P. )

    1990-06-01

    Labeling studies of Torpedo marmorata nicotinic acetylcholine receptor with the noncompetitive channel blocker ({sup 3}H)chlorpromazine have led to the initial identification of amino acids plausibly participating to the walls of the ion channel on the alpha, beta, and delta subunits. We report here results obtained with the gamma subunit, which bring additional information on the structure of the channel. After photolabeling of the membrane-bound receptor under equilibrium conditions in the presence of agonist and with or without phencyclidine (a specific ligand for the high-affinity site for noncompetitive blockers), the purified labeled gamma subunit was digested with trypsin, and the resulting fragments were fractionated by HPLC. Sequence analysis of peptide mixtures containing various amounts of highly hydrophobic fragments showed that three amino acids are labeled by ({sup 3}H)chlorpromazine in a phencyclidine-sensitive manner: Thr-253, Ser-257, and Leu-260. These residues all belong to the hydrophobic and putative transmembrane region MII of the gamma subunit. Their distribution along the sequence is consistent with an alpha-helical organization of this segment. The ({sup 3}H)chlorpromazine-labeled amino acids are conserved at homologous positions in the known sequences of other ligand-gated ion channels and may, thus, play a critical role in ion-transport mechanisms.

  17. Aromatic interactions impact ligand binding and function at serotonin 5-HT2C G protein-coupled receptors: receptor homology modelling, ligand docking, and molecular dynamics results validated by experimental studies

    NASA Astrophysics Data System (ADS)

    Córdova-Sintjago, Tania; Villa, Nancy; Fang, Lijuan; Booth, Raymond G.

    2014-02-01

    The serotonin (5-hydroxytryptamine, 5-HT) 5-HT2 G protein-coupled receptor (GPCR) family consists of types 2A, 2B, and 2C that share ∼75% transmembrane (TM) sequence identity. Agonists for 5-HT2C receptors are under development for psychoses; whereas, at 5-HT2A receptors, antipsychotic effects are associated with antagonists - in fact, 5-HT2A agonists can cause hallucinations and 5-HT2B agonists cause cardiotoxicity. It is known that 5-HT2A TM6 residues W6.48, F6.51, and F6.52 impact ligand binding and function; however, ligand interactions with these residues at the 5-HT2C receptor have not been reported. To predict and validate molecular determinants for 5-HT2C-specific activation, results from receptor homology modelling, ligand docking, and molecular dynamics simulation studies were compared with experimental results for ligand binding and function at wild type and W6.48A, F6.51A, and F6.52A point-mutated 5-HT2C receptors.

  18. In silico optimization of pharmacokinetic properties and receptor binding affinity simultaneously: a 'parallel progression approach to drug design' applied to β-blockers.

    PubMed

    Advani, Poonam; Joseph, Blessy; Ambre, Premlata; Pissurlenkar, Raghuvir; Khedkar, Vijay; Iyer, Krishna; Gabhe, Satish; Iyer, Radhakrishnan P; Coutinho, Evans

    2016-01-01

    The present work exploits the potential of in silico approaches for minimizing attrition of leads in the later stages of drug development. We propose a theoretical approach, wherein 'parallel' information is generated to simultaneously optimize the pharmacokinetics (PK) and pharmacodynamics (PD) of lead candidates. β-blockers, though in use for many years, have suboptimal PKs; hence are an ideal test series for the 'parallel progression approach'. This approach utilizes molecular modeling tools viz. hologram quantitative structure activity relationships, homology modeling, docking, predictive metabolism, and toxicity models. Validated models have been developed for PK parameters such as volume of distribution (log Vd) and clearance (log Cl), which together influence the half-life (t1/2) of a drug. Simultaneously, models for PD in terms of inhibition constant pKi have been developed. Thus, PK and PD properties of β-blockers were concurrently analyzed and after iterative cycling, modifications were proposed that lead to compounds with optimized PK and PD. We report some of the resultant re-engineered β-blockers with improved half-lives and pKi values comparable with marketed β-blockers. These were further analyzed by the docking studies to evaluate their binding poses. Finally, metabolic and toxicological assessment of these molecules was done through in silico methods. The strategy proposed herein has potential universal applicability, and can be used in any drug discovery scenario; provided that the data used is consistent in terms of experimental conditions, endpoints, and methods employed. Thus the 'parallel progression approach' helps to simultaneously fine-tune various properties of the drug and would be an invaluable tool during the drug development process.

  19. Effects of serotonin 2A/1A receptor stimulation on social exclusion processing.

    PubMed

    Preller, Katrin H; Pokorny, Thomas; Hock, Andreas; Kraehenmann, Rainer; Stämpfli, Philipp; Seifritz, Erich; Scheidegger, Milan; Vollenweider, Franz X

    2016-05-01

    Social ties are crucial for physical and mental health. However, psychiatric patients frequently encounter social rejection. Moreover, an increased reactivity to social exclusion influences the development, progression, and treatment of various psychiatric disorders. Nevertheless, the neuromodulatory substrates of rejection experiences are largely unknown. The preferential serotonin (5-HT) 2A/1A receptor agonist, psilocybin (Psi), reduces the processing of negative stimuli, but whether 5-HT2A/1A receptor stimulation modulates the processing of negative social interactions remains unclear. Therefore, this double-blind, randomized, counterbalanced, cross-over study assessed the neural response to social exclusion after the acute administration of Psi (0.215 mg/kg) or placebo (Pla) in 21 healthy volunteers by using functional magnetic resonance imaging (fMRI) and resting-state magnetic resonance spectroscopy (MRS). Participants reported a reduced feeling of social exclusion after Psi vs. Pla administration, and the neural response to social exclusion was decreased in the dorsal anterior cingulate cortex (dACC) and the middle frontal gyrus, key regions for social pain processing. The reduced neural response in the dACC was significantly correlated with Psi-induced changes in self-processing and decreased aspartate (Asp) content. In conclusion, 5-HT2A/1A receptor stimulation with psilocybin seems to reduce social pain processing in association with changes in self-experience. These findings may be relevant to the normalization of negative social interaction processing in psychiatric disorders characterized by increased rejection sensitivity. The current results also emphasize the importance of 5-HT2A/1A receptor subtypes and the Asp system in the control of social functioning, and as prospective targets in the treatment of sociocognitive impairments in psychiatric illnesses.

  20. Effects of serotonin 2A/1A receptor stimulation on social exclusion processing.

    PubMed

    Preller, Katrin H; Pokorny, Thomas; Hock, Andreas; Kraehenmann, Rainer; Stämpfli, Philipp; Seifritz, Erich; Scheidegger, Milan; Vollenweider, Franz X

    2016-05-01

    Social ties are crucial for physical and mental health. However, psychiatric patients frequently encounter social rejection. Moreover, an increased reactivity to social exclusion influences the development, progression, and treatment of various psychiatric disorders. Nevertheless, the neuromodulatory substrates of rejection experiences are largely unknown. The preferential serotonin (5-HT) 2A/1A receptor agonist, psilocybin (Psi), reduces the processing of negative stimuli, but whether 5-HT2A/1A receptor stimulation modulates the processing of negative social interactions remains unclear. Therefore, this double-blind, randomized, counterbalanced, cross-over study assessed the neural response to social exclusion after the acute administration of Psi (0.215 mg/kg) or placebo (Pla) in 21 healthy volunteers by using functional magnetic resonance imaging (fMRI) and resting-state magnetic resonance spectroscopy (MRS). Participants reported a reduced feeling of social exclusion after Psi vs. Pla administration, and the neural response to social exclusion was decreased in the dorsal anterior cingulate cortex (dACC) and the middle frontal gyrus, key regions for social pain processing. The reduced neural response in the dACC was significantly correlated with Psi-induced changes in self-processing and decreased aspartate (Asp) content. In conclusion, 5-HT2A/1A receptor stimulation with psilocybin seems to reduce social pain processing in association with changes in self-experience. These findings may be relevant to the normalization of negative social interaction processing in psychiatric disorders characterized by increased rejection sensitivity. The current results also emphasize the importance of 5-HT2A/1A receptor subtypes and the Asp system in the control of social functioning, and as prospective targets in the treatment of sociocognitive impairments in psychiatric illnesses. PMID:27091970

  1. Effects of serotonin 2A/1A receptor stimulation on social exclusion processing

    PubMed Central

    Preller, Katrin H.; Pokorny, Thomas; Hock, Andreas; Kraehenmann, Rainer; Stämpfli, Philipp; Seifritz, Erich; Scheidegger, Milan; Vollenweider, Franz X.

    2016-01-01

    Social ties are crucial for physical and mental health. However, psychiatric patients frequently encounter social rejection. Moreover, an increased reactivity to social exclusion influences the development, progression, and treatment of various psychiatric disorders. Nevertheless, the neuromodulatory substrates of rejection experiences are largely unknown. The preferential serotonin (5-HT) 2A/1A receptor agonist, psilocybin (Psi), reduces the processing of negative stimuli, but whether 5-HT2A/1A receptor stimulation modulates the processing of negative social interactions remains unclear. Therefore, this double-blind, randomized, counterbalanced, cross-over study assessed the neural response to social exclusion after the acute administration of Psi (0.215 mg/kg) or placebo (Pla) in 21 healthy volunteers by using functional magnetic resonance imaging (fMRI) and resting-state magnetic resonance spectroscopy (MRS). Participants reported a reduced feeling of social exclusion after Psi vs. Pla administration, and the neural response to social exclusion was decreased in the dorsal anterior cingulate cortex (dACC) and the middle frontal gyrus, key regions for social pain processing. The reduced neural response in the dACC was significantly correlated with Psi-induced changes in self-processing and decreased aspartate (Asp) content. In conclusion, 5-HT2A/1A receptor stimulation with psilocybin seems to reduce social pain processing in association with changes in self-experience. These findings may be relevant to the normalization of negative social interaction processing in psychiatric disorders characterized by increased rejection sensitivity. The current results also emphasize the importance of 5-HT2A/1A receptor subtypes and the Asp system in the control of social functioning, and as prospective targets in the treatment of sociocognitive impairments in psychiatric illnesses. PMID:27091970

  2. Deletion of CB2 cannabinoid receptor induces schizophrenia-related behaviors in mice.

    PubMed

    Ortega-Alvaro, Antonio; Aracil-Fernández, Auxiliadora; García-Gutiérrez, María S; Navarrete, Francisco; Manzanares, Jorge

    2011-06-01

    The possible role of the CB(2) receptor (CB(2)r) in psychiatric disorders has been considered. Several animal models use knockout (KO) mice that display schizophrenia-like behaviors and this study evaluated the role of CB(2)r in the regulation of such behaviors. Mice lacking the CB(2)r (CB(2)KO) were challenged in open field, light-dark box, elevated plus-maze, tail suspension, step down inhibitory avoidance, and pre-pulse inhibition tests (PPI). Furthermore, the effects of treatment with cocaine and risperidone were evaluated using the OF and the PPI test. Gene expression of dopamine D(2) (D(2)r), adrenergic-α(2C) (α(2C)r), serotonergic 5-HT(2A) and 5-HT(2C) receptors (5-HT(2A)r and 5-HT(2C)r) were studied by RT-PCR in brain regions related to schizophrenia. Deletion of CB(2)r decreased motor activity in the OF test, but enhanced response to acute cocaine and produced mood-related alterations, PPI deficit, and cognitive impairment. Chronic treatment with risperidone tended to impair PPI in WT mice, whereas it 'normalized' the PPI deficit in CB(2)KO mice. CB(2)KO mice presented increased D(2)r and α(2C)r gene expressions in the prefrontal cortex (PFC) and locus coeruleus (LC), decreased 5-HT(2C)r gene expression in the dorsal raphe (DR), and 5-HT(2A)r gene expression in the PFC. Chronic risperidone treatment in WT mice left α(2C)r gene expression unchanged, decreased D(2)r gene expression (15 μg/kg), and decreased 5-HT(2C)r and 5-HT(2A)r in PFC and DR. In CB(2)KO, the gene expression of D(2)r in the PFC, of α(2C)r in the LC, and of 5-HT(2C)r and 5-HT(2A)r in PFC was reduced; 5-HT(2C)r and 5-HT(2A)r gene expressions in DR were increased after treatment with risperidone. These results suggest that deletion of CB(2)r has a relation with schizophrenia-like behaviors. Pharmacological manipulation of CB(2)r may merit further study as a potential therapeutic target for the treatment of schizophrenia-related disorders. PMID:21430651

  3. Differential contributions of serotonin receptors to the behavioral effects of indoleamine hallucinogens in mice.

    PubMed

    Halberstadt, Adam L; Koedood, Liselore; Powell, Susan B; Geyer, Mark A

    2011-11-01

    Psilocin (4-hydroxy-N,N-dimethyltryptamine) is a hallucinogen that acts as an agonist at 5-HT(1A), 5-HT(2A), and 5-HT(2C) receptors. Psilocin is the active metabolite of psilocybin, a hallucinogen that is currently being investigated clinically as a potential therapeutic agent. In the present investigation, we used a combination of genetic and pharmacological approaches to identify the serotonin (5-HT) receptor subtypes responsible for mediating the effects of psilocin on head twitch response (HTR) and the behavioral pattern monitor (BPM) in C57BL/6J mice. We also compared the effects of psilocin with those of the putative 5-HT(2C) receptor-selective agonist 1-methylpsilocin and the hallucinogen and non-selective serotonin receptor agonist 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT). Psilocin, 1-methylpsilocin, and 5-MeO-DMT induced the HTR, effects that were absent in mice lacking the 5-HT(2A) receptor gene. When tested in the BPM, psilocin decreased locomotor activity, holepoking, and time spent in the center of the chamber, effects that were blocked by the selective 5-HT(1A) antagonist WAY-100635 but were not altered by the selective 5-HT(2C) antagonist SB 242,084 or by 5-HT(2A) receptor gene deletion. 5-MeO-DMT produced similar effects when tested in the BPM, and the action of 5-MeO-DMT was significantly attenuated by WAY-100635. Psilocin and 5-MeO-DMT also decreased the linearity of locomotor paths, effects that were mediated by 5-HT(2C) and 5-HT(1A) receptors, respectively. In contrast to psilocin and 5-MeO-DMT, 1-methylpsilocin (0.6-9.6 mg/kg) was completely inactive in the BPM. These findings confirm that psilocin acts as an agonist at 5-HT(1A), 5-HT(2A), and 5-HT(2C) receptors in mice, whereas the behavioral effects of 1-methylpsilocin indicate that this compound is acting at 5-HT(2A) sites but is inactive at the 5-HT(1A) receptor. The fact that 1-methylpsilocin displays greater pharmacological selectivity than psilocin indicates that 1-methylpsilocin

  4. Effect of angiotensin II type 1 receptor blocker on renal function, arterial blood pressure and parathyroid hormone related protein over expression in cadmium induced nephrotoxicity in adult male rats

    PubMed Central

    Ahmed, Marwa A

    2013-01-01

    Objective: To study the possible effect of angiotensin II type 1 Receptor blocker (AT1 blocker) on renal function, arterial blood pressure and parathyroid hormone related protein over expression in cadmium induced nephrotoxicity in adult male rats. Forty five rats were divided randomly into a control (group I), group II, received cadmium chloride at a dose of 5 mg/kg/day, orally, for nine weeks, group III received telmisartan (TEL) treatment (1 mg/kg/day, orally) one week before cadmium administration and continued for ten weeks. Results: Telmisartan significantly reduced blood urea nitrogen (BUN) and serum creatinine levels which were increased significantly by cadmium. Telmisartan significantly suppressed lipid peroxidation, compensated deficits in the antioxidant defenses (super oxide dismutase (SOD) level and catalase activity), decreased the elevations of nitric oxide (NO) and cadmium ion concentrations in renal tissue observed in Cd-treated rats. Group III had a significant decrease of urinary levels of total protein, N-acetyl-β-d-glucosaminidase (NAG), alkaline phosphatase (ALP) and γ-glutamyl-transpeptidase (GGT) and urinary 8-isoprostanes than those of group II. Telmisartan decreased the systolic blood pressure significantly than those of group II. Histopathological examination revealed that cadmium-induced renal tissue damage was ameliorated by telmisartan treatment. Immunohistochemical analysis revealed that telmisartan significantly decreased the cadmium-induced overexpression of parathyroid hormone receptor 1 (PTHR1) in renal tissue. RT-PCR analysis showed that Cd increased renal expression of PTHrP; however telmisartan could decrease the expression of PTHrP in group III. Conclusion: Blocking AT1 receptors significantly decreases PTHrP over expression and ameliorates renal dysfunction in Cd induced nephrotoxicity. These data suggest that Ang II might contribute to pathophysiology and deleterious effects in cadmium nephrotoxicity. PMID:23750309

  5. Serotonin 5-hydroxytryptamine(2A) receptor activation suppresses tumor necrosis factor-alpha-induced inflammation with extraordinary potency.

    PubMed

    Yu, Bangning; Becnel, Jaime; Zerfaoui, Mourad; Rohatgi, Rasika; Boulares, A Hamid; Nichols, Charles D

    2008-11-01

    The G protein-coupled serotonin 5-hydroxytryptamine (5-HT)(2A) receptor is primarily recognized for its role in brain neurotransmission, where it mediates a wide variety of functions, including certain aspects of cognition. However, there is significant expression of this receptor in peripheral tissues, where its importance is largely unknown. We have now discovered that activation of 5-HT(2A) receptors in primary aortic smooth muscle cells provides a previously unknown and extremely potent inhibition of tumor necrosis factor (TNF)-alpha-mediated inflammation. 5-HT(2A) receptor stimulation with the agonist (R)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane [(R)-DOI] rapidly inhibits a variety of TNF-alpha-mediated proinflammatory markers, including intracellular adhesion molecule 1 (ICAM-1), vascular adhesion molecule 1 (VCAM-1), and interleukin (IL)-6 gene expression, nitric-oxide synthase activity, and nuclear translocation of nuclear factor kappaB, with IC(50) values of only 10 to 20 pM. It is significant that proinflammatory markers can also be inhibited by (R)-DOI hours after treatment with TNF-alpha. With the exception of a few natural toxins, no current drugs or small molecule therapeutics demonstrate a comparable potency for any physiological effect. TNF-alpha-mediated inflammatory pathways have been strongly implicated in a number of diseases, including atherosclerosis, rheumatoid arthritis, psoriasis, type II diabetes, depression, schizophrenia, and Alzheimer's disease. Our results indicate that activation of 5-HT(2A) receptors represents a novel, and extraordinarily potent, potential therapeutic avenue for the treatment of disorders involving TNF-alpha-mediated inflammation. Note that because (R)-DOI can significantly inhibit the effects of TNF-alpha many hours after the administration of TNF-alpha, potential therapies could be aimed not only at preventing inflammation but also treating inflammatory injury that has already occurred or is ongoing. PMID

  6. N-Benzyl-5-methoxytryptamines as Potent Serotonin 5-HT2 Receptor Family Agonists and Comparison with a Series of Phenethylamine Analogues

    PubMed Central

    2015-01-01

    A series of N-benzylated-5-methoxytryptamine analogues was prepared and investigated, with special emphasis on substituents in the meta position of the benzyl group. A parallel series of several N-benzylated analogues of 2,5-dimethoxy-4-iodophenethylamine (2C-I) also was included for comparison of the two major templates (i.e., tryptamine and phenethylamine). A broad affinity screen at serotonin receptors showed that most of the compounds had the highest affinity at the 5-HT2 family receptors. Substitution at the para position of the benzyl group resulted in reduced affinity, whereas substitution in either the ortho or the meta position enhanced affinity. In general, introduction of a large lipophilic group improved affinity, whereas functional activity often followed the opposite trend. Tests of the compounds for functional activity utilized intracellular Ca2+ mobilization. Function was measured at the human 5-HT2A, 5-HT2B, and 5-HT2C receptors, as well as at the rat 5-HT2A and 5-HT2C receptors. There was no general correlation between affinity and function. Several of the tryptamine congeners were very potent functionally (EC50 values from 7.6 to 63 nM), but most were partial agonists. Tests in the mouse head twitch assay revealed that many of the compounds induced the head twitch and that there was a significant correlation between this behavior and functional potency at the rat 5-HT2A receptor. PMID:25547199

  7. Single cell laser dissection with molecular beacon polymerase chain reaction identifies 2A as the predominant serotonin receptor subtype in hypoglossal motoneurons.

    PubMed

    Zhan, G; Shaheen, F; Mackiewicz, M; Fenik, P; Veasey, S C

    2002-01-01

    We hypothesize that sleep state-dependent withdrawal of serotonin (5-hydroxytryptamine, 5-HT) at upper airway (UAW) dilator motoneurons contributes significantly to sleep-related suppression of dilator muscle activity in obstructive sleep apnea. Identification of 5-HT receptor subtypes involved in postsynaptic facilitation of UAW motoneuron activity may provide pharmacotherapies for this prevalent disorder. We have adapted two assays to provide semi-quantitative measurements of mRNA copy numbers for 5-HT receptor subtypes in single UAW motoneurons. Specifically, soma of 111 hypoglossal (XII) motoneurons in 10 adult male rats were captured using a laser dissection microscope, and then used individually in single round molecular beacon polymerase chain reaction (PCR) for real-time quantitation of 5-HT(2A), 5-HT(2C), 5-HT(3), 5-HT(4), 5-HT(5A), 5-HT(5B), 5-HT(6) or 5-HT(7) receptor. Receptor mRNA copy numbers from single XII motoneurons were compared to control samples from within the XII nucleus and lateral medulla. All 20 motoneuronal soma assayed for the 5-HT(2A) receptor had measurable copy numbers (7028+/-2656 copies/cell). In contrast, copy numbers for the 5-HT(2A) receptor in XII non-motoneuronal (n=17) and lateral medulla (n=15) samples were 81+/-51 copies and 83+/-35 copies, respectively, P<0.05. Seven of 13 XII motoneurons assayed had measurable 5-HT(2C) receptor copy numbers of mRNA (287+/-112 copies/cell). XII soma had minimal 5-HT(3), 5-HT(4), 5-HT(5A), 5-HT(5B), 5-HT(6) or 5-HT(7) receptor mRNA. 5-HT(2A) receptor mRNA presence within XII motoneurons was confirmed with digoxigenin-labeled in situ hybridization. In summary, combined use of laser dissection and molecular beacon PCR revealed 5-HT(2A) receptor as the predominant 5-HT receptor mRNA in XII motoneurons, and identified small quantities of 5-HT(2C) receptor. This information will allow a more complete understanding of serotonergic control of respiratory activity.

  8. Pharmacogenetics of β-Blockers

    PubMed Central

    Shin, Jaekyu; Johnson, Julie A.

    2009-01-01

    β-Blockers are an important cardiovascular drug class, recommended as first-line treatment of numerous diseases such as heart failure, hypertension, and angina, as well as treatment after myocardial infarction. However, responses to a β-blocker are variable among patients. Results of numerous studies now suggest that genetic polymorphisms may contribute to variability in responses to β-blockers. This review summarizes the pharmacogenetic data for β-blockers in patients with various diseases and discusses the potential implications of β-blocker pharmacogenetics in clinical practice. PMID:17542770

  9. Antidepressant- and anxiolytic-like activity of 7-phenylpiperazinylalkyl-1,3-dimethyl-purine-2,6-dione derivatives with diversified 5-HT₁A receptor functional profile.

    PubMed

    Partyka, Anna; Chłoń-Rzepa, Grażyna; Wasik, Anna; Jastrzębska-Więsek, Magdalena; Bucki, Adam; Kołaczkowski, Marcin; Satała, Grzegorz; Bojarski, Andrzej J; Wesołowska, Anna

    2015-01-01

    Continuing our earlier study in a group of purine-2,6-dione derivatives of long chain arylpiperazines (LCAPs), a series of 8-unsubstituted 7-phenylpiperazin-4-yl-alkyl (4-14) and 7-tetrahydroisoquinolinyl-alkyl (15-17) analogues were synthesized and their serotonin 5-HT1A, 5-HT2A, 5-HT6, 5-HT7 and dopamine D2 receptor affinities were determined. The study allowed us to identify some potent 5-HT1A receptor ligands with additional moderate affinity for 5-HT2A, 5-HT7 and dopamine D2 receptors. Compounds 9, 12, 13 and 14, with the highest 5HT1A receptor affinity, were selected for further functional in vivo studies and behavioural evaluation of antidepressant- and antianxiety-like activity. Compounds 9, 12 and 13 showed features of agonists of pre- and/or post-synaptic 5-HT1A receptors, whereas 14 was classified as an antagonist of postsynaptic sites. Moreover, derivatives 9 and 14 acted as antagonists of 5-HT2A receptors. In behavioural studies, compounds 9 and 13 showed antidepressant-like activity in the mouse forced swim test, and their effects were similar or stronger than those of imipramine. Compounds 9, 12 and 14 displayed potential anxiolytic-like properties in the mouse four-plate test, similar or even greater than those of the reference anxiolytic drug, diazepam.

  10. Aminergic receptors in astrogliotic plaques from patients with multiple sclerosis.

    PubMed

    Zeinstra, Esther; te Riele, Paula; Langlois, Xavier; Wilczak, Nadine; Leysen, Josée; de Keyser, Jacques

    2002-10-11

    Cultured astrocytes express a spectrum of neurotransmitter receptors. However, little is known about these receptors in situ. We previously reported the absence of beta(2) adrenergic receptors on astrocytes in multiple sclerosis (MS). Here we used [(3)H]-radioligands and receptor autoradiography to screen for a variety of other aminergic receptors in six silent chronic astrogliotic plaques in brain tissue obtained from five patients with MS. Dopamine D(1) and histamine H(1) receptors were absent. We detected specific binding for cholinergic muscarinic receptors > dopamine D(2), alpha(1-) and alpha(2)-adrenergic receptors > 5-HT(1A), 5-HT(1B/D), 5-HT(2A), 5-HT(2c), 5-HT(4), and dopamine D(3) receptors. Radiotracers for these aminergic receptors might be useful for studying astrogliosis in patients with MS, and compounds acting at some of these receptors may have potential to modulate astroglial function in MS. PMID:12361847

  11. New halogenated tris-(phenylalkyl)amines as h5-HT2B receptor ligands.

    PubMed

    Kapadia, Nirav; Ahmed, Shahrear; Harding, Wayne W

    2016-07-15

    A series of compounds in which various halogen substituents were incorporated into a phenyl ring of a tris-(phenylalkyl)amine scaffold, was synthesized and evaluated for affinity to h5-HT2 receptors. In general, all compounds were found to have good affinity for the 5-HT2B receptor and were selective over 5-HT2A and 5-HT2C receptors. Compound 9i was the most selective compound in this study and is the highest affinity 5-HT2B receptor ligand bearing a tris-(phenylalkyl)amine scaffold to date. PMID:27261181

  12. Changes in Intensity of Serotonin Syndrome Caused by Adverse Interaction between Monoamine Oxidase Inhibitors and Serotonin Reuptake Blockers

    PubMed Central

    Tao, Rui; Rudacille, Mary; Zhang, Gongliang; Ma, Zhiyuan

    2014-01-01

    Drug interaction between inhibitors of monoamine oxidase (MAOIs) and selective serotonin (5-hydroxytryptamine, 5-HT) reuptake (SSRIs) induces serotonin syndrome, which is usually mild but occasionally severe in intensity. However, little is known about neural mechanisms responsible for the syndrome induction and intensification. In this study, we hypothesized that the syndrome induction and intensity utilize two different but inter-related mechanisms. Serotonin syndrome is elicited by excessive 5-HT in the brain (presynaptic mechanism), whereas syndrome intensity is attributed to neural circuits involving 5-HT2A and NMDA receptors (postsynaptic mechanism). To test this hypothesis, basal 5-HT efflux and postsynaptic circuits were pharmacologically altered in rats by once daily pretreatment of the MAOI clorgyline for 3, 6, or 13 days. Syndrome intensity was estimated by measuring 5-HT efflux, neuromuscular activity, and body-core temperature in response to challenge injection of clorgyline combined with the SSRI paroxetine. Results showed that the onset of serotonin syndrome is caused by 5-HT efflux exceeding 10-fold above baseline, confirming the presynaptic hypothesis. The neuromuscular and body-core temperature abnormalities, which were otherwise mild in drug-naive rats, were significantly intensified to a severe level in rats pretreated with daily clorgyline for 3 and 6 days but not in rats pretreated for 13 days. The intensified effect was blocked by M100907 and MK-801, suggesting that variation in syndrome intensity was mediated through a 5-HT2A and NMDA receptor-engaged circuit. Therefore, we concluded that pretreatments of MAOI pharmacologically alter the activity of postsynaptic circuits, which is responsible for changes in syndrome intensity. PMID:24577320

  13. Occurrence and fate of the angiotensin II receptor antagonist transformation product valsartan acid in the water cycle--a comparative study with selected β-blockers and the persistent anthropogenic wastewater indicators carbamazepine and acesulfame.

    PubMed

    Nödler, Karsten; Hillebrand, Olav; Idzik, Krzysztof; Strathmann, Martin; Schiperski, Ferry; Zirlewagen, Johannes; Licha, Tobias

    2013-11-01

    The substantial transformation of the angiotensin II receptor antagonist valsartan to the transformation product 2'-(2H-tetrazol-5-yl)-[1,1'-biphenyl]-4-carboxylic acid (referred to as valsartan acid) during the activated sludge process was demonstrated in the literature and confirmed in the here presented study. However, there was a severe lack of knowledge regarding the occurrence and fate of this compound in surface water and its behavior during drinking water treatment. In this work a comparative study on the occurrence and persistency of valsartan acid, three frequently used β-blockers (metoprolol, atenolol, and sotalol), atenolol acid (one significant transformation product of atenolol and metoprolol), and the two widely distributed persistent anthropogenic wastewater indicators carbamazepine and acesulfame in raw sewage, treated wastewater, surface water, groundwater, and tap water is presented. Median concentrations of valsartan acid in the analyzed matrices were 101, 1,310, 69, <1.0, and 65 ng L(-1), respectively. Treated effluents from wastewater treatment plants were confirmed as significant source. Regarding concentration levels of pharmaceutical residues in surface waters valsartan acid was found just as relevant as the analyzed β-blockers and the anticonvulsant carbamazepine. Regarding its persistency in surface waters it was comparable to carbamazepine and acesulfame. Furthermore, removal of valsartan acid during bank filtration was poor, which demonstrated the relevance of this compound for drinking water suppliers. Regarding drinking water treatment (Muelheim Process) the compound was resistant to ozonation but effectively eliminated (≥90%) by subsequent activated carbon filtration. However, without applying activated carbon filtration the compound may enter the drinking water distribution system as it was demonstrated for Berlin tap water.

  14. Enriched Expression of Serotonin 1B and 2A Receptor Genes in Macaque Visual Cortex and their Bidirectional Modulatory Effects on Neuronal Responses

    PubMed Central

    Watakabe, Akiya; Komatsu, Yusuke; Sadakane, Osamu; Shimegi, Satoshi; Takahata, Toru; Higo, Noriyuki; Tochitani, Shiro; Hashikawa, Tsutomu; Naito, Tomoyuki; Osaki, Hironobu; Sakamoto, Hiroshi; Okamoto, Masahiro; Ishikawa, Ayako; Hara, Shin-ichiro; Akasaki, Takafumi; Sato, Hiromichi

    2009-01-01

    To study the molecular mechanism how cortical areas are specialized in adult primates, we searched for area-specific genes in macaque monkeys and found striking enrichment of serotonin (5-hydroxytryptamine, 5-HT) 1B receptor mRNA, and to a lesser extent, of 5-HT2A receptor mRNA, in the primary visual area (V1). In situ hybridization analyses revealed that both mRNA species were highly concentrated in the geniculorecipient layers IVA and IVC, where they were coexpressed in the same neurons. Monocular inactivation by tetrodotoxin injection resulted in a strong and rapid (<3 h) downregulation of these mRNAs, suggesting the retinal activity dependency of their expression. Consistent with the high expression level in V1, clear modulatory effects of 5-HT1B and 5-HT2A receptor agonists on the responses of V1 neurons were observed in in vivo electrophysiological experiments. The modulatory effect of the 5-HT1B agonist was dependent on the firing rate of the recorded neurons: The effect tended to be facilitative for neurons with a high firing rate, and suppressive for those with a low firing rate. The 5-HT2A agonist showed opposite effects. These results suggest that this serotonergic system controls the visual response in V1 for optimization of information processing toward the incoming visual inputs. PMID:19056862

  15. Effects of chronic fluoxetine treatment on catalepsy and the immune response in mice with a genetic predisposition to freezing reactions: the roles of types 1A and 2A serotonin receptors and the tph2 and SERT genes.

    PubMed

    Tikhonova, M A; Alperina, E L; Tolstikova, T G; Bazovkina, D V; Di, V Y; Idova, G V; Kulikov, A V; Popova, N K

    2010-06-01

    ASC (Antidepressant-Sensitive Catalepsy) mice, bred for a high predisposition to catalepsy, are characterized by depression-like behavior and decreased immune responses. Chronic administration of fluoxetine, which is a selective serotonin reuptake inhibitor antidepressant widely used in clinical practice, to mice of this strain weakened catalepsy and normalized the number of rosette-forming cells in the spleen. In mice of the parental cataleptic strain CBA/Lac, fluoxetine had no effect on the level of catalepsy or the immune response. Analysis of the effects of fluoxetine on the functional activity of 5-HT(1A) and 5-HT(2A) receptors, and the expression of 5-HT(1A) receptor genes in the frontal cortex and midbrain and 5-HT(2A) receptors in the frontal cortex, as well as the tryptophan hydroxylase-2 and the serotonin transporter genes in the midbrain showed that the antidepressant had no effect on these parameters in ASC mice, but decreased the functional activity of 5-HT(2A) receptors in CBA/Lac mice. The possibility that the actions of fluoxetine on catalepsy and the immune response in mice with depression-like states are mediated via other serotoninergic mechanisms is discussed.

  16. Safety and Tolerability of the Direct Renin Inhibitor Aliskiren in Combination with Angiotensin Receptor Blockers and Thiazide Diuretics: A Pooled Analysis of Clinical Experience of 12,942 Patients

    PubMed Central

    White, William B.; Bresalier, Robert; Kaplan, Allen P.; Palmer, Biff F.; Riddell, Robert H.; Lesogor, Anastasia; Chang, William; Keefe, Deborah L.

    2011-01-01

    Combinations of the direct renin inhibitor aliskiren with angiotensin receptor blockers (ARBs) or diuretics are effective therapeutic regimens for the treatment of hypertension. A large database of safety information has become available during the past several years with aliskiren in combination trials. Data were pooled from nine short-term (8-week) and four longer-term (26–52-week) randomized, controlled trials of aliskiren in patients with hypertension. Adverse event (AE) rates were assessed for aliskiren combination therapy compared to component monotherapies. In short-term studies, overall AE rates were similar for those receiving aliskiren/valsartan or aliskiren/diuretic combinations (32.2–39.8%) and those receiving the component monotherapies (30.0–39.6%). In longer-term studies, AE rates with aliskiren/losartan (55.5%) and aliskiren/diuretic (45.0%) combination therapy were similar to those with losartan (53.9%) and diuretic (48.9%) alone. Angioedema and hyperkalemia occurred in similar proportions of patients on combination therapies versus monotherapy. In conclusion, the safety and tolerability profile of aliskiren in combination with the ARBs valsartan or losartan, or diuretic is similar to aliskiren, ARBs or diuretic alone. PMID:21029339

  17. Cardiovascular characterization of pyrrolo[2,1-d][1,5]benzothiazepine derivatives binding selectively to the peripheral-type benzodiazepine receptor (PBR): from dual PBR affinity and calcium antagonist activity to novel and selective calcium entry blockers.

    PubMed

    Campiani, G; Fiorini, I; De Filippis, M P; Ciani, S M; Garofalo, A; Nacci, V; Giorgi, G; Sega, A; Botta, M; Chiarini, A; Budriesi, R; Bruni, G; Romeo, M R; Manzoni, C; Mennini, T

    1996-07-19

    The synthesis and cardiovascular characterization of a series of novel pyrrolo[2,1-d][1,5]-benzothiazepine derivatives (54-68) are described. Selective peripheral-type benzodiazepine receptor (PBR) ligands, such as PK 11195 and Ro 5-4864, have recently been found to possess low but significant inhibitory activity of L-type calcium channels, and this property is implicated in the cardiovascular effects observed with these compounds. In functional studies both PK 11195 (1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxa mide) and Ro 5-4864 (4'-chlorodiazepam) did not display selectivity between cardiac and vascular tissue. Therefore, several 7-(acyloxy)-6-arylpyrrolo[2,1-d][1,5]benzothiazepines, potent and selective peripheral-type benzodiazepine receptor ligands recently developed by us (3, 7-20), were subjected to calcium channel receptor binding assay. Some of these compounds showed an unexpected potency in displacing the binding of [3H]nitrendipine from L-type calcium channels, much higher than that reported for PK 11195 and Ro 5-4864 and equal to or higher than that of reference calcium antagonists such as verapamil and (+)-cis-diltiazem. Specifically, in rat cortex homogenate, our prototypic PBR ligand 7-acetoxy-6-(p-methoxyphenyl)pyrrolo[2,1-d][1,5]benzothiazepine (3) showed an IC50 equal to 0.13 nM for inhibition of [3H]nitrendipine binding. Furthermore, in functional studies this compound displayed a clear-cut selectivity for cardiac over vascular tissue. Comparison of calcium antagonist activity on guinea pig aorta strips with the negative inotropic activity, determined by using isolated guinea pig left atria, revealed that 3 displayed higher selectivity than the reference (+)-cis-diltiazem. Thus, the pyrrolobenzothiazepine 3 might represent a new tool for characterizing the relationship between the PBR and cardiac function. Furthermore, we have also investigated the structural dependence of binding to PBR and L-type calcium channels, and

  18. The role of 5-HT7 receptor antagonism in the amelioration of MK-801-induced learning and memory deficits by the novel atypical antipsychotic drug lurasidone.

    PubMed

    Horisawa, Tomoko; Nishikawa, Hiroyuki; Toma, Satoko; Ikeda, Atsushi; Horiguchi, Masakuni; Ono, Michiko; Ishiyama, Takeo; Taiji, Mutsuo

    2013-05-01

    Lurasidone is a novel atypical antipsychotic with high affinity for dopamine D2, serotonin 5-HT7 and 5-HT2A receptors. We previously reported that lurasidone and the selective 5-HT7 receptor antagonist, SB-656104-A improved learning and memory deficits induced by MK-801, an N-methyl-d-aspartate (NMDA) receptor antagonist, in the rat passive avoidance test. In this study, we first examined the role of the 5-HT7 receptor antagonistic activity of lurasidone in its pro-cognitive effect to ameliorate MK-801-induced deficits in the rat passive avoidance test. The 5-HT7 receptor agonist, AS19, (2S)-(+)-5-(1,3,5-trimethylpyrazol-4-yl)-2-(dimethylamino) tetralin, (3 mg/kg, s.c.) completely blocked the attenuating effects of lurasidone (3 mg/kg, p.o.), highlighting the importance of 5-HT7 receptor antagonism in the pro-cognitive effect of lurasidone. AS19 (3 mg/kg, s.c.) also blocked the ameliorating effect of SB-656104-A (10 mg/kg, i.p.) in the same experimental paradigm. To further extend our observation, we next tested whether 5-HT7 receptor antagonism still led to the amelioration of MK-801-induced deficits when combined with D2 and 5-HT2A receptor antagonists, and found that SB-656104-A (10 mg/kg, i.p.) significantly ameliorated MK-801-induced deficits even in the presence of the D2 receptor antagonist raclopride (0.1 mg/kg, s.c.) and 5-HT2A receptor antagonist ketanserin (1 mg/kg, s.c.). Taken together, these results suggest that the 5-HT7 receptor antagonistic activity of lurasidone plays an important role in its effectiveness against MK-801-induced deficits, and may contribute to its pharmacological actions in patients with schizophrenia.

  19. Multiple receptor subtypes mediate the effects of serotonin on rat subfornical organ neurons

    NASA Technical Reports Server (NTRS)

    Scrogin, K. E.; Johnson, A. K.; Schmid, H. A.

    1998-01-01

    The subfornical organ (SFO) receives significant serotonergic innervation. However, few reports have examined the functional effects of serotonin on SFO neurons. This study characterized the effects of serotonin on spontaneously firing SFO neurons in the rat brain slice. Of 31 neurons tested, 80% responded to serotonin (1-100 microM) with either an increase (n = 15) or decrease (n = 10) in spontaneous activity. Responses to serotonin were dose dependent and persisted after synaptic blockade. Excitatory responses could also be mimicked by the 5-hydroxytryptamine (5-HT)2A/2C receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI; 1-10 microM) and could be blocked by the 5-HT2A/2C-receptor antagonist LY-53,857 (10 microM). LY-53,857 unmasked inhibitory responses to serotonin in 56% of serotonin-excited cells tested. Serotonin-inhibited cells were also inhibited by the 5-HT1A-receptor agonist 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT; 1-10 microM; n = 7). The data indicate that SFO neurons are responsive to serotonin via postsynaptic activation of multiple receptor subtypes. The results suggest that excitatory responses to serotonin are mediated by 5-HT2A or 5-HT2C receptors and that inhibitory responses may be mediated by 5-HT1A receptors. In addition, similar percentages of serotonin-excited and -inhibited cells were also sensitive to ANG II. As such the functional relationship between serotonin and ANG II in the SFO remains unclear.

  20. Support for 5-HT2C receptor functional selectivity in vivo utilizing structurally diverse, selective 5-HT2C receptor ligands and the 2,5-dimethoxy-4-iodoamphetamine elicited head-twitch response model

    PubMed Central

    Canal, Clinton E.; Booth, Raymond G.; Morgan, Drake

    2013-01-01

    There are seemingly conflicting data in the literature regarding the role of serotonin (5-HT) 5-HT2C receptors in the mouse head-twitch response (HTR) elicited by the hallucinogenic 5-HT2A/2B/2C receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI). Namely, both 5-HT2C receptor agonists and antagonists, regarding 5-HT2C receptor-mediated Gq-phospholipase C (PLC) signaling, reportedly attenuate the HTR response. The present experiments tested the hypothesis that both classes of 5-HT2C receptor compounds could attenuate the DOI-elicited-HTR in a single strain of mice, C57Bl/6J. The expected results were considered in accordance with ligand functional selectivity. Commercially-available 5-HT2C agonists (CP 809101, Ro 60-0175, WAY 161503, mCPP, and 1-methylpsilocin), novel 4-phenyl-2-N,N-dimethyl-aminotetralin (PAT)-type 5-HT2C agonists (with 5-HT2A/2B antagonist activity), and antagonists selective for 5-HT2A (M100907), 5-HT2C (SB-242084), and 5-HT2B/2C (SB-206553) receptors attenuated the DOI-elicited-HTR. In contrast, there were differential effects on locomotion across classes of compounds. The 5-HT2C agonists and M100907 decreased locomotion, SB-242084 increased locomotion, SB-206553 resulted in dose-dependent biphasic effects on locomotion, and the PATs did not alter locomotion. In vitro molecular pharmacology studies showed that 5-HT2C agonists potent for attenuating the DOI-elicited-HTR also reduced the efficacy of DOI to activate mouse 5-HT2C receptor-mediated PLC signaling in HEK cells. Although there were differences in affinities of a few compounds at mouse compared to human 5-HT2A or 5-HT2C receptors, all compounds tested retained their selectivity for either receptor, regardless of receptor species. Results indicate that 5-HT2C receptor agonists and antagonists attenuate the DOI-elicited-HTR in C57Bl/6J mice, and suggest that structurally diverse 5-HT2C ligands result in different 5-HT2C receptor signaling outcomes compared to DOI. PMID:23353901

  1. The ryanodine receptor pore blocker neomycin also inhibits channel activity via a previously undescribed high-affinity Ca(2+) binding site.

    PubMed

    Laver, Derek R; Hamada, Tomoyo; Fessenden, James D; Ikemoto, Noriaki

    2007-12-01

    In this study, we present evidence for the mechanism of neomycin inhibition of skeletal ryanodine receptors (RyRs). In single-channel recordings, neomycin produced monophasic inhibition of RyR open probability and biphasic inhibition of [(3)H]ryanodine binding. The half-maximal inhibitory concentration (IC(50)) for channel blockade by neomycin was dependent on membrane potential and cytoplasmic [Ca(2+)], suggesting that neomycin acts both as a pore plug and as a competitive antagonist at a cytoplasmic Ca(2+) binding site that causes allosteric inhibition. This novel Ca(2+)/neomycin binding site had a neomycin affinity of 100 nM: and a Ca(2+) affinity of 35 nM,: which is 30-fold higher than that of the well-described cytoplasmic Ca(2+) activation site. Therefore, a new high-affinity class of Ca(2+) binding site(s) on the RyR exists that mediates neomycin inhibition. Neomycin plugging of the channel pore induced brief (1-2 ms) conductance substates at 30% of the fully open conductance, whereas allosteric inhibition caused complete channel closure with durations that depended on the neomycin concentration. We quantitatively account for these results using a dual inhibition model for neomycin that incorporates voltage-dependent pore plugging and Ca(2+)-dependent allosteric inhibition.

  2. The discovery of potent blockers of the canonical transient receptor channels, TRPC3 and TRPC6, based on an anilino-thiazole pharmacophore.

    PubMed

    Washburn, David G; Holt, Dennis A; Dodson, Jason; McAtee, Jeff J; Terrell, Lamont R; Barton, Linda; Manns, Sharada; Waszkiewicz, Anna; Pritchard, Christina; Gillie, Dan J; Morrow, Dwight M; Davenport, Elizabeth A; Lozinskaya, Irina M; Guss, Jeffrey; Basilla, Jonathan B; Negron, Lorena Kallal; Klein, Michael; Willette, Robert N; Fries, Rusty E; Jensen, Timothy C; Xu, Xiaoping; Schnackenberg, Christine G; Marino, Joseph P

    2013-09-01

    Lead optimization of piperidine amide HTS hits, based on an anilino-thiazole core, led to the identification of analogs which displayed low nanomolar blocking activity at the canonical transient receptor channels 3 and 6 (TRPC3 & 6) based on FLIPR (carbachol stimulated) and electrophysiology (OAG stimulated) assays. In addition, the anilino-thiazole amides displayed good selectivity over other TRP channels (TRPA1, TRPV1, and TRPV4), as well as against cardiac ion channels (CaV1.2, hERG, and NaV1.5). The high oxidation potential of the aliphatic piperidine and aniline groups, as well as the lability of the thiazole amide group contributed to the high clearance observed for this class of compounds. Conversion of an isoquinoline amide to a naphthyridine amide markedly reduced clearance for the bicyclic piperidines, and improved oral bioavailability for this compound series, however TRPC3 and TRPC6 blocking activity was reduced substantially. Although the most potent anilino-thiazole amides ultimately lacked oral exposure in rodents and were not suitable for chronic dosing, analogs such as 14-19, 22, and 23 are potentially valuable in vitro tool compounds for investigating the role of TRPC3 and TRPC6 in cardiovascular disease.

  3. Conjugates of γ-Carbolines and Phenothiazine as new selective inhibitors of butyrylcholinesterase and blockers of NMDA receptors for Alzheimer Disease.

    PubMed

    Makhaeva, Galina F; Lushchekina, Sofya V; Boltneva, Natalia P; Sokolov, Vladimir B; Grigoriev, Vladimir V; Serebryakova, Olga G; Vikhareva, Ekaterina A; Aksinenko, Alexey Yu; Barreto, George E; Aliev, Gjumrakch; Bachurin, Sergey O

    2015-08-18

    Alzheimer disease is a multifactorial pathology and the development of new multitarget neuroprotective drugs is promising and attractive. We synthesized a group of original compounds, which combine in one molecule γ-carboline fragment of dimebon and phenothiazine core of methylene blue (MB) linked by 1-oxo- and 2-hydroxypropylene spacers. Inhibitory activity of the conjugates toward acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and structurally close to them carboxylesterase (CaE), as well their binding to NMDA-receptors were evaluated in vitro and in silico. These newly synthesized compounds showed significantly higher inhibitory activity toward BChE with IC50 values in submicromolar and micromolar range and exhibited selective inhibitory action against BChE over AChE and CaE. Kinetic studies for the 9 most active compounds indicated that majority of them were mixed-type BChE inhibitors. The main specific protein-ligand interaction is π-π stacking of phenothiazine ring with indole group of Trp82. These compounds emerge as promising safe multitarget ligands for the further development of a therapeutic approach against aging-related neurodegenerative disorders such as Alzheimer and/or other pathological conditions.

  4. Mineralocorticoid receptor blocker eplerenone reduces pain behaviors in vivo and decreases excitability in small diameter sensory neurons from local inflamed dorsal root ganglia in vitro

    PubMed Central

    Dong, Fei; Xie, Wenrui; Strong, Judith A.; Zhang, Jun-Ming

    2012-01-01

    Background Inflammation of the dorsal root ganglia (DRG) may contribute to low back pain, postherpetic neuralgia, and neuropathic pain. The mineralocorticoid receptor (MR) plays a pro-inflammatory role in many non-renal tissues, but its role in peripheral pain at the DRG level is not well studied. Methods Local inflammation of the L5 DRG with the immune activator zymosan rapidly leads to mechanical hypersensitivity and increased excitability of sensory neurons. Using this pain model, we applied the MR antagonist eplerenone locally to the inflamed DRG. Excitability of small diameter sensory neurons was examined in acute primary culture, using patch clamp techniques. Results Local eplerenone significantly reduced the mechanical hypersensitivity and shortened its duration. The same dose was ineffective systemically. Immunohistochemical studies showed the MR was present in most neurons, and rapidly translocated to the nucleus 1 day after local DRG inflammation. Activation of satellite glia (defined by expression of glial fibrillary acidic protein) in the inflamed DRG was also reduced by local eplerenone. Increased excitability of small diameter sensory neurons 1 day after inflammation could be observed in vitro. Eplerenone applied in vitro (8 – 12 hours) could reverse this increased excitability. Eplerenone had no effect in neurons isolated from normal, uninflamed DRG. The MR agonist aldosterone (10 nM) applied in vitro increased excitability of neurons isolated from normal DRG. Conclusions The MR may have a pro-nociceptive role in the DRG. Some of its effects may be mediated by neuronal MR. The MR may represent a novel therapeutic target in some pain syndromes. PMID:23023156

  5. A comparison between diuretics and angiotensin-receptor blocker agents in patients with stage I hypertension (PREVER-treatment trial): study protocol for a randomized double-blind controlled trial

    PubMed Central

    2011-01-01

    Background Cardiovascular disease is the leading cause of death in Brazil, and hypertension is its major risk factor. The benefit of its drug treatment to prevent major cardiovascular events was consistently demonstrated. Angiotensin-receptor blockers (ARB) have been the preferential drugs in the management of hypertension worldwide, despite the absence of any consistent evidence of advantage over older agents, and the concern that they may be associated with lower renal protection and risk for cancer. Diuretics are as efficacious as other agents, are well tolerated, have longer duration of action and low cost, but have been scarcely compared with ARBs. A study comparing diuretic and ARB is therefore warranted. Methods/design This is a randomized, double-blind, clinical trial, comparing the association of chlorthalidone and amiloride with losartan as first drug option in patients aged 30 to 70 years, with stage I hypertension. The primary outcomes will be variation of blood pressure by time, adverse events and development or worsening of microalbuminuria and of left ventricular hypertrophy in the EKG. The secondary outcomes will be fatal or non-fatal cardiovascular events: myocardial infarction, stroke, heart failure, evidence of new subclinical atherosclerosis and sudden death. The study will last 18 months. The sample size will be of 1200 participants for group in order to confer enough power to test for all primary outcomes. The project was approved by the Ethics committee of each participating institution. Discussion The putative pleiotropic effects of ARB agents, particularly renal protection, have been disputed, and they have been scarcely compared with diuretics in large clinical trials, despite that they have been at least as efficacious as newer agents in managing hypertension. Even if the null hypothesis is not rejected, the information will be useful for health care policy to treat hypertension in Brazil. Clinical trials registration number Clinical

  6. Investigation of the role of 5-HT2 receptor subtypes in the control of the bladder and the urethra in the anaesthetized female rat

    PubMed Central

    Mbaki, Y; Ramage, A G

    2008-01-01

    Background and purpose: Micturition is controlled by central 5-HT-containing pathways. 5-HT2 receptors have been implicated in this system especially in control of the urethra, which is a drug target for treating urinary incontinence. This study investigates the role of each of the three subtypes of this receptor with emphasis on sphincter regulation. Experimental approach: Recordings of urethral and bladder pressure, external urethral sphincter (EUS) EMG, as well as the micturition reflex induced by bladder distension along with blood pressure and heart rate were made in anaesthetized rats. The effects of agonists and antagonists for 5-HT2 receptor subtypes were studied on these variables. Key results: The 5-HT2C agonists Ro 60-0175, WAY 161503 and mCPP, i.v., activated the EUS, increased urethral pressure and inhibited the micturition reflex. The effects of Ro 60-0175 on the EUS were blocked by the 5-HT2C antagonist SB 242084 and the 5-HT2A antagonists, ketanserin and MDL 100907. SB 242084 also blocked the inhibitory action on the reflex, while the 5-HT2B antagonist RS 127445 only blocked the increase in urethral pressure. The 5-HT2A receptor agonist DOI given i.v. or i.t. but not i.c.v. activated the EUS. Conclusions and implications: 5-HT2A/2C receptors located in the sacral spinal cord activate the EUS, while central 5-HT2C receptors inhibit the micturition reflex and 5-HT2B receptors, probably at the level of the urethra, increase urethral smooth muscle tone. Furthermore, 5-HT2B and 5-HT2C receptors do not seem to play an important role in the physiological regulation of micturition. PMID:18604238

  7. Role of CRH in the effects of 5-HT-receptor agonists on food intake and metabolic rate.

    PubMed

    Bovetto, S; Rouillard, C; Richard, D

    1996-11-01

    Two series of experiments were conducted to investigate the role of corticotropin-releasing hormone (CRH) in the effects of 5-hydroxytryptamine (5-HT) on energy intake and energy expenditure. The first set of experiments was carried out to confirm the influence of 5-HT1A-, 5-HT1B-, 5-HT2A/2C-receptor agonists on the activation of the hypothalamic-pituitary-adrenal axis. Plasma corticosterone levels were measured, and a double-immunolabeling procedure was used to determine whether the neuronal activity marker, c-Fos protein (Fos), could be found within brain neurons containing CRH after treatments with 5-HT1A-, 5-HT1B-, 5-HT2A/2C-receptor agonists. The second series of experiments was conducted to assess the involvement of CRH in the effects of 5-HT on food intake and metabolic rate (VO2). The effects of the 5-HT1A-, 5-HT1B-, 5-HT2A/2C-receptor agonists on food intake and VO2 were measured in rats treated with the CRH antagonist, alpha-helical CRH-(9-41). In both experiments rats were intraperitoneally injected with either a vehicle (NaCl 0.9%), the 5-HT1A-receptor agonist (+/-)-8-hydroxy-2-(di-n-propylamino) tetralin hydrobromide (8-OH-DPAT), the 5-HT1B-receptor agonist 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole succinate (RU-24969), or the 5-HT2A/2C-receptor agonist (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl (DOI). Fos immunoreactivity was detectable within the CRH-containing neurons of the paraventricular nucleus of the hypothalamus (PVH) after injection of each of the 5-HT-receptor agonists used. The CRH antagonist alpha-helical CRH-(9-41) attenuated the increases in metabolic rate induced by DOI and 8-OH-DPAT. alpha-Helical CRH did not, however, prevent the effects of RU-24969 and DOI on either nocturnal metabolic rate or food intake. The present results provide further evidence for a role of CRH in 5-HT-mediated thermogenic effect, which likely involves the 5-HT2A/2C receptor during the day and the 5-HT1A receptor during the night

  8. Decreased striatal dopamine receptor binding in primary focal dystonia: a D2 or D3 defect?

    PubMed Central

    Karimi, Morvarid; Moerlein, Stephen M.; Videen, Tom O.; Luedtke, Robert R.; Taylor, Michelle; Mach, Robert H.; Perlmutter, Joel S.

    2010-01-01

    Dystonia is an involuntary movement disorder characterized by repetitive patterned or sustained muscle contractions causing twisting or abnormal postures. Several lines of evidence suggest that abnormalities of dopaminergic pathways contribute to the pathophysiology of dystonia. In particular dysfunction of D2-like receptors that mediate function of the indirect pathway in the basal ganglia may play a key role. We have demonstrated with positron emission tomography (PET) that patients with primary focal cranial or hand dystonia have reduced putamenal specific binding of [18F]spiperone a non-selective D2-like radioligand with nearly equal affinity for serotonergic 5-HT(2A) sites. We then repeated the study with [18F]N-methyl-benperidol (NMB), a more selective D2-like receptor radioligand with minimal affinity for 5-HT(2A). Surprisingly, there was no decrease in NMB binding in the putamen of subjects with dystonia. Our findings excluded reductions of putamenal uptake greater than 20% with 95% confidence intervals. Following analysis of the in vitro selectivity of NMB and spiperone demonstrated that NMB was highly selective for D2 receptors relative to D3 receptors (200-fold difference in affinity), whereas spiperone has similar affinity for all three of the D2-like receptor subtypes. These findings coupled with other literature suggest that a defect in D3, rather than D2, receptor expression may be associated with primary focal dystonia. PMID:20960437

  9. Pyrrolo[1,3]benzothiazepine-based serotonin and dopamine receptor antagonists. Molecular modeling, further structure-activity relationship studies, and identification of novel atypical antipsychotic agents.

    PubMed

    Campiani, Giuseppe; Butini, Stefania; Fattorusso, Caterina; Catalanotti, Bruno; Gemma, Sandra; Nacci, Vito; Morelli, Elena; Cagnotto, Alfredo; Mereghetti, Ilario; Mennini, Tiziana; Carli, Miriana; Minetti, Patrizia; Di Cesare, M Assunta; Mastroianni, Domenico; Scafetta, Nazzareno; Galletti, Bruno; Stasi, M Antonietta; Castorina, Massimo; Pacifici, Licia; Vertechy, Mario; Di Serio, Stefano; Ghirardi, Orlando; Tinti, Ornella; Carminati, Paolo

    2004-01-01

    Recently we reported the pharmacological characterization of the 9,10-dihydropyrrolo[1,3]benzothiazepine derivative (S)-(+)-8 as a novel atypical antipsychotic agent. This compound had an optimum pK(i) 5-HT(2A)/D(2) ratio of 1.21 (pK(i) 5-HT(2A) = 8.83; pK(i) D(2) = 7.79). The lower D(2) receptor affinity of (S)-(+)-8 compared to its enantiomer was explained by the difficulty in reaching the conformation required to optimally fulfill the D(2) pharmacophore. With the aim of finding novel atypical antipsychotics we further investigated the core structure of (S)-(+)-8, synthesizing analogues with specific substituents; the structure-activity relationship (SAR) study was also expanded with the design and synthesis of other analogues characterized by a pyrrolo[2,1-b][1,3]benzothiazepine skeleton, substituted on the benzo-fused ring or on the pyrrole system. On the 9,10-dihydro analogues the substituents introduced on the pyrrole ring were detrimental to affinity for dopamine and for 5-HT(2A) receptors, but the introduction of a double bond at C-9/10 on the structure of (S)-(+)-8 led to a potent D(2)/5-HT(2A) receptor ligand with a typical binding profile (9f, pK(i) 5-HT(2A)/D(2) ratio of 1.01, log Y = 8.43). Then, to reduce D(2) receptor affinity and restore atypicality on unsaturated analogues, we exploited the effect of specific substitutions on the tricyclic system of 9f. Through a molecular modeling approach we generated a novel series of potential atypical antipsychotic agents, with optimized 5HT(2A)/D(2) receptor affinity ratios and that were easier to synthesize and purify than the reference compound (S)-(+)-8. A number of SAR trends were identified, and among the analogues synthesized and tested in binding assays, 9d and 9m were identified as the most interesting, giving atypical log Y scores respectively 4.98 and 3.18 (pK(i) 5-HT(2A)/D(2) ratios of 1.20 and 1.30, respectively). They had a multireceptor affinity profile and could be promising atypical agents

  10. Stimulation of glutamate receptors in the ventral tegmental area is necessary for serotonin-2 receptor-induced increases in mesocortical dopamine release.

    PubMed

    Pehek, E A; Hernan, A E

    2015-04-01

    Modulation of dopamine (DA) released by serotonin-2 (5-HT2) receptors has been implicated in the mechanism of action of antipsychotic drugs. The mesocortical DA system has been implicated particularly in the cognitive deficits observed in schizophrenia. Agonism at 5-HT2A receptors in the prefrontal cortex (PFC) is associated with increases in cortical DA release. Evidence indicates that 5-HT2A receptors in the cortex regulate mesocortical DA release through stimulation of a "long-loop" feedback system from the PFC to the ventral tegmental area (VTA) and back. However, a causal role for VTA glutamate in the 5-HT2-induced increases in PFC DA has not been established. The present study does so by measuring 5-HT2 agonist-induced DA release in the cortex after infusions of glutamate antagonists into the VTA of the rat. Infusions of a combination of a N-methyl-d-aspartic acid (NMDA) (AP-5: 2-amino-5-phosphopentanoic acid) and an AMPA/kainate (CNQX: 6-cyano-7-nitroquinoxaline-2,3-dione) receptor antagonist into the VTA blocked the increases in cortical DA produced by administration of the 5-HT2 agonist DOI [(±)-2,5-dimethoxy-4-iodoamphetamine] (2.5mg/kg s.c.). These results demonstrate that stimulation of glutamate receptors in the VTA is necessary for 5-HT2 agonist-induced increases in cortical DA.

  11. Stimulation of glutamate receptors in the ventral tegmental area is necessary for serotonin-2 receptor-induced increases in mesocortical dopamine release.

    PubMed

    Pehek, E A; Hernan, A E

    2015-04-01

    Modulation of dopamine (DA) released by serotonin-2 (5-HT2) receptors has been implicated in the mechanism of action of antipsychotic drugs. The mesocortical DA system has been implicated particularly in the cognitive deficits observed in schizophrenia. Agonism at 5-HT2A receptors in the prefrontal cortex (PFC) is associated with increases in cortical DA release. Evidence indicates that 5-HT2A receptors in the cortex regulate mesocortical DA release through stimulation of a "long-loop" feedback system from the PFC to the ventral tegmental area (VTA) and back. However, a causal role for VTA glutamate in the 5-HT2-induced increases in PFC DA has not been established. The present study does so by measuring 5-HT2 agonist-induced DA release in the cortex after infusions of glutamate antagonists into the VTA of the rat. Infusions of a combination of a N-methyl-d-aspartic acid (NMDA) (AP-5: 2-amino-5-phosphopentanoic acid) and an AMPA/kainate (CNQX: 6-cyano-7-nitroquinoxaline-2,3-dione) receptor antagonist into the VTA blocked the increases in cortical DA produced by administration of the 5-HT2 agonist DOI [(±)-2,5-dimethoxy-4-iodoamphetamine] (2.5mg/kg s.c.). These results demonstrate that stimulation of glutamate receptors in the VTA is necessary for 5-HT2 agonist-induced increases in cortical DA. PMID:25637799

  12. Tuning Photochromic Ion Channel Blockers

    PubMed Central

    2011-01-01

    Photochromic channel blockers provide a conceptually simple and convenient way to modulate neuronal activity with light. We have recently described a family of azobenzenes that function as tonic blockers of Kv channels but require UV-A light to unblock and need to be actively switched by toggling between two different wavelengths. We now introduce red-shifted compounds that fully operate in the visible region of the spectrum and quickly turn themselves off in the dark. Furthermore, we have developed a version that does not block effectively in the dark-adapted state, can be switched to a blocking state with blue light, and reverts to the inactive state automatically. Photochromic blockers of this type could be useful for the photopharmacological control of neuronal activity under mild conditions. PMID:22860175

  13. SSRI augmentation of antipsychotic alters expression of GABA(A) receptor and related genes in PMC of schizophrenia patients.

    PubMed

    Silver, Henry; Susser, Ehud; Danovich, Lena; Bilker, Warren; Youdim, Moussa; Goldin, Vladimir; Weinreb, Orly

    2011-06-01

    Clinical studies have shown that negative symptoms of schizophrenia unresponsive to antipsychotic given alone can improve after augmentation with SSRI antidepressant. Laboratory investigations into the mechanism of this synergism showed that co-administration of SSRI and antipsychotic produces changes in GABA(A) receptor and related systems, which differ from the effects of each drug alone. To examine the clinical relevance of these findings, the current study examined the effects of SSRI augmentation treatment on GABA(A) receptor and related systems in schizophrenia patients. Schizophrenia patients with high levels of negative symptoms unresponsive to antipsychotic treatment received add-on fluvoxamine (100 mg/d). Blood was taken before and 1, 3 and 6 wk after adding fluvoxamine and peripheral mononuclear cells (PMC) isolated. RNA encoding for GABA(A)β3, 5-HT2A, and 5-HT7 receptors, PKCβ2, and brain-derived neurotrophic factor (BDNF) was assayed with real-time RT-PCR. Plasma BDNF protein was assayed using ELISA. Clinical symptoms were assessed with validated rating scales. We found significant increase in mRNA encoding for GABA(A)β3 and 5-HT2A, 5-HT7 receptors and BDNF and a reduction in PKCβ2 mRNA. Plasma BDNF protein concentrations were increased. There were significant correlations among the genes. Clinical symptoms improved significantly. mRNA expression of PKCβ2, 5-HT2A and 5-HT7 showed significant associations with clinical symptoms. Combined SSRI+antipsychotic treatment is associated with changes in GABA(A) receptor and in related signalling systems in patients. These changes may be part of the mechanism of clinically effective drug action and may prove to be biomarkers of pharmacological response.

  14. A case of 25I-NBOMe (25-I) intoxication: a new potent 5-HT2A agonist designer drug

    PubMed Central

    Rose, S. Rutherfoord; Poklis, Justin L.; Poklis, Alphonse

    2014-01-01

    Context Abuse of synthetic stimulant compounds resulting in significant toxicity is being increasingly reported by poison centers. Toxicologic assessment is complicated by inconsistent manufacturing processes and limited laboratory testing. We describe a case of self-reported exposure to 25-I (25I-NBOMe), a novel phenethylamine derivative, with subsequent quantification in serum. Case details An 18-year-old male presented to the emergency department (ED) with severe agitation and hallucinations after jumping out of a moving car. He was tachycardiac (150–160 bpm) and hypertensive (150–170 mm Hg systolic and 110 mg Hg diastolic), and required physical restraints and treatment with intravenous lorazepam administration. His symptoms gradually improved and vital signs returned to normal over 48 h, though he continued to have episodes of aggressiveness. An assay was developed by our analytical toxicology laboratory for 25-I, and serum obtained during ED evaluation and treatment was found to contain 0.76 ng/ml of 25-I. Case discussion For 25I-NBOMe, 25-I is a common abbreviation for 25I-NBOMe, which is a (n-benzyl) phenethylamine in the 2C “family.” Initially synthesized for research, cases of self-reported use of 25-I have recently appeared in the literature, some of which contain qualitative urine conf rmation. There are no commercially available quantitative assays, and no previous reports have published serum concentrations. 25-I is a potent new synthetic drug with apparent significant behavioral toxicity that can be detected and quantified in serum. PMID:23473462

  15. Short and Long-Term Effects of the Angiotensin II Receptor Blocker Irbesartan on Intradialytic Central Hemodynamics: A Randomized Double-Blind Placebo-Controlled One-Year Intervention Trial (the SAFIR Study)

    PubMed Central

    Peters, Christian Daugaard; Kjaergaard, Krista Dybtved; Jensen, Jens Dam; Christensen, Kent Lodberg; Strandhave, Charlotte; Tietze, Ida Noerager; Novosel, Marija Kristina; Bibby, Bo Martin; Jespersen, Bente

    2015-01-01

    Background and Aim Little is known about the tolerability of antihypertensive drugs during hemodialysis treatment. The present study evaluated the use of the angiotensin II receptor blocker (ARB) irbesartan. Design Randomized, double-blind, placebo-controlled, one-year intervention trial. Setting and Participants Eighty-two hemodialysis patients with urine output >300 mL/day and dialysis vintage <1 year. Intervention Irbesartan/placebo 300 mg/day for 12 months administered as add-on to antihypertensive treatment using a predialytic systolic blood pressure target of 140 mmHg in all patients. Outcomes and Measurements Cardiac output, stroke volume, central blood volume, total peripheral resistance, mean arterial blood pressure, and frequency of intradialytic hypotension. Results At baseline, the groups were similar regarding age, comorbidity, blood pressure, antihypertensive medication, ultrafiltration volume, and dialysis parameters. Over the one-year period, predialytic systolic blood pressure decreased significantly, but similarly in both groups. Mean start and mean end cardiac output, stroke volume, total peripheral resistance, heart rate, and mean arterial pressure were stable and similar in the two groups, whereas central blood volume increased slightly but similarly over time. The mean hemodynamic response observed during a dialysis session was a drop in cardiac output, in stroke volume, in mean arterial pressure, and in central blood volume, whereas heart rate increased. Total peripheral resistance did not change significantly. Overall, this pattern remained stable over time in both groups and was uninfluenced by ARB treatment. The total number of intradialytic hypotensive episodes was (placebo/ARB) 50/63 (P = 0.4). Ultrafiltration volume, left ventricular mass index, plasma albumin, and change in intradialytic total peripheral resistance were significantly associated with intradialytic hypotension in a multivariate logistic regression analysis based on

  16. Behavioral tolerance to lysergic acid diethylamide is associated with reduced serotonin-2A receptor signaling in rat cortex.

    PubMed

    Gresch, Paul J; Smith, Randy L; Barrett, Robert J; Sanders-Bush, Elaine

    2005-09-01

    Tolerance is defined as a decrease in responsiveness to a drug after repeated administration. Tolerance to the behavioral effects of hallucinogens occurs in humans and animals. In this study, we used drug discrimination to establish a behavioral model of lysergic acid diethylamide (LSD) tolerance and examined whether tolerance to the stimulus properties of LSD is related to altered serotonin receptor signaling. Rats were trained to discriminate 60 microg/kg LSD from saline in a two-lever drug discrimination paradigm. Two groups of animals were assigned to either chronic saline treatment or chronic LSD treatment. For chronic treatment, rats from each group were injected once per day with either 130 microg/kg LSD or saline for 5 days. Rats were tested for their ability to discriminate either saline or 60 microg/kg LSD, 24 h after the last chronic injection. Rats receiving chronic LSD showed a 44% reduction in LSD lever selection, while rats receiving chronic vehicle showed no change in percent choice on the LSD lever. In another group of rats receiving the identical chronic LSD treatment, LSD-stimulated [35S]GTPgammaS binding, an index of G-protein coupling, was measured in the rat brain by autoradiography. After chronic LSD, a significant reduction in LSD-stimulated [35S]GTPgammaS binding was observed in the medial prefrontal cortex and anterior cingulate cortex. Furthermore, chronic LSD produced a significant reduction in 2,5-dimethoxy-4-iodoamphetamine-stimulated [35S]GTPgammaS binding in medial prefrontal cortex and anterior cingulate cortex, which was blocked by MDL 100907, a selective 5-HT2A receptor antagonist, but not SB206553, a 5-HT2C receptor antagonist, indicating a reduction in 5-HT2A receptor signaling. 125I-LSD binding to 5-HT2A receptors was reduced in cortical regions, demonstrating a reduction in 5-HT2A receptor density. Taken together, these results indicate that adaptive changes in LSD-stimulated serotonin receptor signaling may mediate tolerance

  17. Tyrosine kinase blockers: new hope for successful cancer therapy.

    PubMed

    Pytel, Dariusz; Sliwinski, Tomasz; Poplawski, Tomasz; Ferriola, Deborah; Majsterek, Ireneusz

    2009-01-01

    Tyrosine kinases (TKs) are attractive targets for cancer therapy, as quite often their abnormal signaling has been linked with tumor development and growth. Constitutive activated TKs stimulate multiple signaling pathways responsible for DNA repair, apoptosis, and cell proliferation. During the last few years, thorough analysis of the mechanism underlying tyrosine kinase's activity led to novel cancer therapy using TKs blockers. These drugs are remarkably effective in the treatment of various human tumors including head and neck, gastric, prostate and breast cancer and leukemias. The most successful example of kinase blockers is Imatinib (Imatinib mesylate, Gleevec, STI571), the inhibitor of Bcr/Abl oncoprotein, which has become a first-line therapy for chronic myelogenous leukemia. The introduction of STI571 for the treatment of leukemia in clinical oncology has had a dramatic impact on how this disease is currently managed. Others kinase inhibitors used recently in cancer therapy include Dasatinib (BMS-354825) specific for ABL non-receptor cytoplasmic kinase, Gefitinib (Iressa), Erlotinib (OSI-774, Tarceva) and Sunitinib (SU 11248, Sutent) specific for VEGF receptor kinase, AMN107 (Nilotinib) and INNO-406 (NS-187) specific for c-KIT kinase. The following TK blockers for treatment of various human tumors are in clinical development: Lapatinib (Lapatinib ditosylate, Tykerb, GW-572016), Canertinib (CI-1033), Zactima (ZD6474), Vatalanib (PTK787/ZK 222584), Sorafenib (Bay 43-9006, Nexavar), and Leflunomide (SU101, Arava). Herein, we discuss the chemistry, biological activity and clinical potential of new drugs with tyrosine kinase blockers for cancer treatment.

  18. Beta-Blockers and Nitrates: Pharmacotherapy and Indications.

    PubMed

    Facchini, Emanuela; Degiovanni, Anna; Cavallino, Chiara; Lupi, Alessandro; Rognoni, Andrea; Bongo, Angelo S

    2015-01-01

    Many clinically important differences exist between beta blockers. B1-selectivity is of clinical interest because at clinically used doses, b1- selective agents block cardiac b-receptors while having minor effects on bronchial and vascular b-receptors. Beta-adrenergic blocking agents significantly decrease the frequency and duration of angina pectoris, instead the prognostic benefit of beta-blockers in stable angina has been extrapolated from studies of post myocardial infarction but has not yet been documented without left ventricular disfunction or previous myocardial infarction. Organic nitrates are among the oldest drugs, but they still remain a widely used adjuvant in the treatment of symptomatic coronary artery disease. While their efficacy in relieving angina pectoris symptoms in acute settings and in preventing angina before physical or emotional stress is undisputed, the chronic use of nitrates has been associated with potentially important side effects such as tolerance and endothelial dysfunction. B-blockers are the firstline anti-anginal therapy in stable stable angina patients without contraindications, while nitrates are the secondline anti-anginal therapy. Despite 150 years of clinical practice, they remain fascinating drugs, which in a chronic setting still deserve investigation. This review evaluated pharmacotherapy and indications of Beta-blockers and nitrates in stable angina.

  19. Optimization of 2-phenylcyclopropylmethylamines as selective serotonin 2C receptor agonists and their evaluation as potential antipsychotic agents.

    PubMed

    Cheng, Jianjun; Giguère, Patrick M; Onajole, Oluseye K; Lv, Wei; Gaisin, Arsen; Gunosewoyo, Hendra; Schmerberg, Claire M; Pogorelov, Vladimir M; Rodriguiz, Ramona M; Vistoli, Giulio; Wetsel, William C; Roth, Bryan L; Kozikowski, Alan P

    2015-02-26

    The discovery of a new series of compounds that are potent, selective 5-HT2C receptor agonists is described herein as we continue our efforts to optimize the 2-phenylcyclopropylmethylamine scaffold. Modifications focused on the alkoxyl substituent present on the aromatic ring led to the identification of improved ligands with better potency at the 5-HT2C receptor and excellent selectivity against the 5-HT2A and 5-HT2B receptors. ADMET studies coupled with a behavioral test using the amphetamine-induced hyperactivity model identified four compounds possessing drug-like profiles and having antipsychotic properties. Compound (+)-16b, which displayed an EC50 of 4.2 nM at 5-HT2C, no activity at 5-HT2B, and an 89-fold selectivity against 5-HT2A, is one of the most potent and selective 5-HT2C agonists reported to date. The likely binding mode of this series of compounds to the 5-HT2C receptor was also investigated in a modeling study, using optimized models incorporating the structures of β2-adrenergic receptor and 5-HT2B receptor. PMID:25633969

  20. Dynamic alterations of serotonergic metabolism and receptors during social isolation of low- and high-active mice.

    PubMed

    Rilke, O; Freier, D; Jähkel, M; Oehler, J

    1998-04-01

    Alterations induced by social isolation (1 day to 18 weeks) in low- and high-active mice (LAM and HAM) were studied in respect to serotonin metabolism, [3H]-8-OH-DPAT binding of presynaptic (midbrain), postsynaptic (hippocampus) 5-HT1A receptors and [3H]-ketanserin binding of cortical 5-HT2A receptors. Individual housing of mice was associated with reduction of serotonin metabolism, depending on isolation time and brain structure. Whereas a transient decrease in the striatum and cortex was detected between 1 week and 6 weeks, reduction of cerebellar and hippocampal serotonin metabolism was found later (12-18 weeks). Serotonergic systems of HAM were found to be more reactive to environmental disturbances, and their serotonin metabolism was more affected by social isolation. Isolation-induced upregulation of cortical 5-HT2A receptors was measured only in HAM. Densities of postsynaptic 5-HT1A receptors in the hippocampus did differ either in grouped or isolated mice. However, there were significant differences in hippocampal 5-HT1A receptor affinity, especially between 1 day and 3 weeks. Transient downregulation of presynaptic 5-HT1A receptors in the midbrain was found in isolated mice between 3 and 6 weeks. These results are discussed in terms of interactions between serotonergic alterations and isolation-induced aggression.

  1. Partial role of 5-HT2 and 5-HT3 receptors in the activity of antidepressants in the mouse forced swimming test.

    PubMed

    Redrobe, J P; Bourin, M

    1997-05-01

    The present study was designed to evaluate the roles of 5-HT2 and 5-HT3 receptors in the mouse forced swimming test, by using selective agonists and antagonists of 5-HT(2A/C) and 5-HT3 receptor sites. Agonists/antagonists and antidepressants were administered 45 min and 30 min, respectively, prior to testing. Pretreatment with (+/-)-2,5-dimethoxy-4-iodoamphetamine (DOI) (4 mg/kg, i.p.) or 2-methyl-5-HT (4 mg/kg, i.p.) had no effect on the anti-immobility effects of any antidepressant tested. Prior administration of ritanserin (4 mg/kg, i.p.) or ketanserin (8 mg/kg, i.p.), on the other hand, potentiated the effects of sub-active doses of imipramine (8 mg/kg, i.p.) and desipramine (16 mg/kg, i.p.) but not of maprotiline (8 mg/kg, i.p.), fluoxetine (16 mg/kg, i.p.), citalopram (16 mg/kg, i.p.) or fluvoxamine (8 mg/kg, i.p.). Pretreatment with ondansetron (1 X 10(-5) mg/kg, i.p.) enhanced the antidepressant-like effects of sub-active doses of the selective serotonin reuptake inhibitors. The results of the present study suggested that, in the forced swimming test, the selective serotonin reuptake inhibitors act partially through 5-HT3 receptor sites, whereas the tricyclic antidepressants exert effects at 5-HT(2A/C) receptor sites. Anti-immobility effects of the selective noradrenaline reuptake inhibitor, maprotiline, do not seem to be mediated by 5-HT(2A/C) or 5-HT3 receptor function.

  2. Anticonvulsant effects of N-arachidonoyl-serotonin, a dual fatty acid amide hydrolase enzyme and transient receptor potential vanilloid type-1 (TRPV1) channel blocker, on experimental seizures: the roles of cannabinoid CB1 receptors and TRPV1 channels.

    PubMed

    Vilela, Luciano R; Medeiros, Daniel C; de Oliveira, Antonio Carlos P; Moraes, Marcio F; Moreira, Fabricio A

    2014-10-01

    Selective blockade of anandamide hydrolysis, through the inhibition of the FAAH enzyme, has anticonvulsant effects, which are mediated by CB1 receptors. Anandamide, however, also activates TRPV1 channels, generally with an opposite outcome on neuronal modulation. Thus, we suggested that the dual FAAH and TRPV1 blockade with N-arachidonoyl-serotonin (AA-5-HT) would be efficacious in inhibiting pentylenetetrazole (PTZ)-induced seizures in mice. We also investigated the contribution of CB1 activation and TRPV1 blockade to the overt effect of AA-5-HT. In the first experiment, injection of AA-5-HT (0.3-3.0 mg/kg) delayed the onset and reduced the duration of PTZ (60 mg)-induced seizures in mice. These effects were reversed by pre-treatment with the CB1 antagonist, AM251 (1.0-3.0 mg/kg). Finally, we observed that administration of the selective TRPV1 antagonist, SB366791 (0.1-1 mg/kg), did not entirely mimic AA-5-HT effects. In conclusion, AA-5-HT alleviates seizures in mice, an effect inhibited by CB1 antagonism, but not completely mimicked by TRPV1 blockage, indicating that the overall effect of AA-5-HT seems to depend mainly on CB1 receptors. This may represent a new strategy for the development of drugs against seizures, epilepsies and related syndromes.

  3. [Changes of circulation, blood gases, acid-base-and metabolism during neurolept-analgesia with and without beta-receptor blockers in electro coagulation of Gasser's ganglion (author's transl)].

    PubMed

    Knitza, R; Olbermann, M; Fischer, F; Bässler, K H

    1978-05-01

    The cardiovascular, blood gas, acid-base and metabolic changes occurring during operative stress were studied in 10 elderly, metabolically healthy patients, suffering from idiopathic trigeminal neuralgia, who underwent electrocoagulation of the gasserian ganglion under neuroleptanalgesia. In a group of 12 patients undergoing the same operative procedure and anesthesthetic management, we investigated the effects of administration of a beta blocking agent on these parameters. Intraoperative rises of blood pressure and tachycardia were prevented by intravenous administration of 0.4 mg Pindolol (Visken), whereas increases in the blood glucose levels at the end of the operation were the same. The increase of glycerol, free fatty acids and ketone bodies was markedly reduced after pretreatment with the beta blocker compared with the controlgroup. In the patients without beta blocker treatment pH and standard bicarbonate at the end of the operation were lower as the result of the stimulation of ketogenesis. PMID:27127

  4. [Changes of circulation, blood gases, acid-base-and metabolism during neurolept-analgesia with and without beta-receptor blockers in electro coagulation of Gasser's ganglion (author's transl)].

    PubMed

    Knitza, R; Olbermann, M; Fischer, F; Bässler, K H

    1978-05-01

    The cardiovascular, blood gas, acid-base and metabolic changes occurring during operative stress were studied in 10 elderly, metabolically healthy patients, suffering from idiopathic trigeminal neuralgia, who underwent electrocoagulation of the gasserian ganglion under neuroleptanalgesia. In a group of 12 patients undergoing the same operative procedure and anesthesthetic management, we investigated the effects of administration of a beta blocking agent on these parameters. Intraoperative rises of blood pressure and tachycardia were prevented by intravenous administration of 0.4 mg Pindolol (Visken), whereas increases in the blood glucose levels at the end of the operation were the same. The increase of glycerol, free fatty acids and ketone bodies was markedly reduced after pretreatment with the beta blocker compared with the controlgroup. In the patients without beta blocker treatment pH and standard bicarbonate at the end of the operation were lower as the result of the stimulation of ketogenesis.

  5. Clinical Impact of Selective and Non-selective Beta Blockers on Survival in Ovarian Cancer Patients

    PubMed Central

    Watkins, Jack L.; Thaker, Premal H.; Nick, Alpa M.; Ramondetta, Lois M.; Kumar, Sanjeev; Urbauer, Diana L.; Matsuo, Koji; Squires, Kathryn; Lutgendorf, Susan K.; Ramirez, Pedro T.; Sood, Anil K.

    2015-01-01

    BACKGROUND Preclinical evidence suggests that sustained adrenergic activation can promote ovarian cancer growth and metastasis. We examined the impact of beta-adrenergic blockade on clinical outcome of women with epithelial ovarian, primary peritoneal or fallopian tube cancers (collectively, EOC). METHODS A multicenter review of 1,425 women with histopathologically confirmed EOC was performed. Comparisons were made between patients with documented beta blocker use during chemotherapy and those without beta blocker use. RESULTS The median age of patients in this study was 63 years (range, 21–93 years). The sample included 269 patients who received beta blockers. Of those, 193 (71.7%) were receiving beta-1 adrenergic receptor (ADRB1) selective agents, and the remaining patients were receiving non-selective beta antagonists. The primary indication for beta blocker use was hypertension but also included arrhythmia and post-myocardial infarction management. For patients receiving any beta blocker, the median overall survival (OS) was 47.8 months versus42 months (P = 0.04) for non-users. The median OS based on beta blocker receptor selectivity was 94.9 months for those receiving non-selective beta blockers versus 38 months for those receiving ADRB1 selective agents (P < 0.001). Hypertension was associated with decreased OS compared to no hypertension across all groups. However, even in patients with hypertension, users of a non-selective beta blocker had a longer median OS than non-users observed (38.2 vs 90 months, P < 0.001). CONCLUSION Use of non-selective beta blockers in epithelial ovarian cancer patients was associated with longer OS. These findings may have implications for new therapeutic approaches. PMID:26301456

  6. Multiple microvascular and astroglial 5-hydroxytryptamine receptor subtypes in human brain: molecular and pharmacologic characterization.

    PubMed

    Cohen, Z; Bouchelet, I; Olivier, A; Villemure, J G; Ball, R; Stanimirovic, D B; Hamel, E

    1999-08-01

    Physiologic and anatomic evidence suggest that 5-hydroxytryptamine (5-HT) neurons regulate local cerebral blood flow and blood-brain barrier permeability. To evaluate the possibility that some of these effects occur directly on the blood vessels, molecular and/or pharmacologic approaches were used to assess the presence of 5-HT receptors in human brain microvascular fractions, endothelial and smooth muscle cell cultures, as well as in astroglial cells which intimately associate with intraparenchymal blood vessels. Isolated microvessels and capillaries consistently expressed messages for the h5-HT1B, h5-HT1D, 5-HT1F, 5-HT2A but not 5-HT7 receptors. When their distribution within the vessel wall was studied in more detail, it was found that capillary endothelial cells exhibited mRNA for the h5-HT1D and for the 5-HT7 receptors whereas microvascular smooth muscle cells, in addition to h5-HT1D and 5-HT7, also showed polymerase chain reaction products for h5-HT1B receptors. Expression of 5-HT1F and 5-HT2A receptor mRNAs was never detected in any of the microvascular cell cultures. In contrast, messages for all 5-HT receptors tested were detected in human brain astrocytes with a predominance of the 5-HT2A and 5-HT7 subtypes. In all cultures, sumatriptan inhibited (35-58%, P < .05) the forskolin-stimulated production of cyclic AMP, an effect blocked by the 5-HT1B/1D receptor antagonists GR127935 and GR55562. In contrast, 5-carboxamidotryptamine induced strong increases (> or = 400%, P < .005) in basal cyclic AMP levels that were abolished by mesulergine, a nonselective 5-HT7 receptor antagonist. Only astroglial cells showed a ketanserin-sensitive increase (177%, P < .05) in IP3 formation when exposed to 5-HT. These results show that specific populations of functional 5-HT receptors are differentially distributed within the various cellular compartments of the human cortical microvascular bed, and that human brain astroglial cells are endowed with multiple 5-HT receptors

  7. Up-regulation of 5-HT2B receptor density and receptor-mediated glycogenolysis in mouse astrocytes by long-term fluoxetine administration.

    PubMed

    Kong, Ebenezer K C; Peng, Liang; Chen, Ye; Yu, Albert C H; Hertz, Leif

    2002-02-01

    The effects were studied of short-term (1 week) versus long-term (2-3 weeks) fluoxetine treatment of primary cultures of mouse astrocytes, differentiated by treatment with dibutyryl cyclic AMP. From previous experiments it is known that acute treatment with fluoxetine stimulates glycogenolysis and increases free cytosolic Ca2+ concentration ([Ca2+]i]) in these cultures, whereas short-term (one week) treatment with 10 microM down-regulates the effects on glycogen and [Ca2+]i, when fluoxetine administration is renewed (or when serotonin is administered). Moreover, antagonist studies have shown that these responses are evoked by activation of a 5-HT2, receptor that is different from the 5-HT2A receptor and therefore at that time tentatively were interpreted as being exerted on 5-HT2C receptors. In the present study the cultures were found by RT-PCR to express mRNA for 5-HT2A and 5-HT2B receptors, but not for the 5-HT2C receptor, identifying the 5-HT2 receptor activated by fluoxetine as the 5-HT2B receptor, the most recently cloned 5-Ht2 receptor and a 5-HT receptor known to be more abundant in human, than in rodent, brain. Both short-term and long-term treatment with fluoxetine increased the specific binding of [3H]mesulergine, a ligand for alL three 5-HT2 receptors. Long-term treatment with fluoxetine caused an agonist-induced up-regulation of the glycogenolytic response to renewed administration of fluoxetine, whereas short-term treatment abolished the fluoxetine-induced hydrolysis of glycogen. Thus, during a treatment period similar to that required for fluoxetine's clinical response to occur, 5-HT2B-mediated effects are initially down-regulated and subsequently up-regulated. PMID:11930908

  8. Serotonin 2A Receptors Differentially Contribute to Abuse-Related Effects of Cocaine and Cocaine-Induced Nigrostriatal and Mesolimbic Dopamine Overflow in Nonhuman Primates

    PubMed Central

    Murnane, Kevin S.; Winschel, Jake; Schmidt, Karl T.; Stewart, LaShaya M.; Rose, Samuel J.; Cheng, Kejun; Rice, Kenner C.

    2013-01-01

    Two of the most commonly used procedures to study the abuse-related effects of drugs in laboratory animals are intravenous drug self-administration and reinstatement of extinguished behavior previously maintained by drug delivery. Intravenous self-administration is widely accepted to model ongoing drug-taking behavior, whereas reinstatement procedures are accepted to model relapse to drug taking following abstinence. Previous studies indicate that 5-HT2A receptor antagonists attenuate the reinstatement of cocaine-maintained behavior but not cocaine self-administration in rodents. Although the abuse-related effects of cocaine have been closely linked to brain dopamine systems, no previous study has determined whether this dissociation is related to differential regulation of dopamine neurotransmission. To elucidate the neuropharmacological and neuroanatomical mechanisms underlying this phenomenon, we evaluated the effects of the selective 5-HT2A receptor antagonist M100907 on intravenous cocaine self-administration and drug- and cue-primed reinstatement in rhesus macaques (Macaca mulatta). In separate subjects, we evaluated the role of 5-HT2A receptors in cocaine-induced dopamine overflow in the nucleus accumbens (n = 4) and the caudate nucleus (n = 5) using in vivo microdialysis. Consistent with previous studies, M100907 (0.3 mg/kg, i.m.) significantly attenuated drug- and cue-induced reinstatement but had no significant effects on cocaine self-administration across a range of maintenance doses. Importantly, M100907 (0.3 mg/kg, i.m.) attenuated cocaine-induced (1.0 mg/kg, i.v.) dopamine overflow in the caudate nucleus but not in the nucleus accumbens. These data suggest that important abuse-related effects of cocaine are mediated by distinct striatal dopamine projection pathways. PMID:23946394

  9. Serotonin 2A receptors differentially contribute to abuse-related effects of cocaine and cocaine-induced nigrostriatal and mesolimbic dopamine overflow in nonhuman primates.

    PubMed

    Murnane, Kevin S; Winschel, Jake; Schmidt, Karl T; Stewart, LaShaya M; Rose, Samuel J; Cheng, Kejun; Rice, Kenner C; Howell, Leonard L

    2013-08-14

    Two of the most commonly used procedures to study the abuse-related effects of drugs in laboratory animals are intravenous drug self-administration and reinstatement of extinguished behavior previously maintained by drug delivery. Intravenous self-administration is widely accepted to model ongoing drug-taking behavior, whereas reinstatement procedures are accepted to model relapse to drug taking following abstinence. Previous studies indicate that 5-HT2A receptor antagonists attenuate the reinstatement of cocaine-maintained behavior but not cocaine self-administration in rodents. Although the abuse-related effects of cocaine have been closely linked to brain dopamine systems, no previous study has determined whether this dissociation is related to differential regulation of dopamine neurotransmission. To elucidate the neuropharmacological and neuroanatomical mechanisms underlying this phenomenon, we evaluated the effects of the selective 5-HT2A receptor antagonist M100907 on intravenous cocaine self-administration and drug- and cue-primed reinstatement in rhesus macaques (Macaca mulatta). In separate subjects, we evaluated the role of 5-HT2A receptors in cocaine-induced dopamine overflow in the nucleus accumbens (n = 4) and the caudate nucleus (n = 5) using in vivo microdialysis. Consistent with previous studies, M100907 (0.3 mg/kg, i.m.) significantly attenuated drug- and cue-induced reinstatement but had no significant effects on cocaine self-administration across a range of maintenance doses. Importantly, M100907 (0.3 mg/kg, i.m.) attenuated cocaine-induced (1.0 mg/kg, i.v.) dopamine overflow in the caudate nucleus but not in the nucleus accumbens. These data suggest that important abuse-related effects of cocaine are mediated by distinct striatal dopamine projection pathways. PMID:23946394

  10. Beta-blockers for treatment of hypertension.

    PubMed

    Basile, Jan N; Cohen, Jerome D

    2003-12-01

    Beta-blockers are an established class in the management of hypertension, and numerous randomized, controlled trials have shown that these drugs can prevent cardiovascular events in this population. However, beta-blockers are underutilized in managing the general hypertensive population. This phenomenon may stem in part from concerns about side effects. On the contrary, beta-blockers demonstrate comparable efficacy, safety, and tolerability compared with other classes of antihypertensive drugs. Because beta-blockers offer unique cardiovascular protection, they should be considered an integral part of the treatment regimen for patients with hypertension who are at risk for cardiovascular events.

  11. The antidepressant activity of inositol in the forced swim test involves 5-HT(2) receptors.

    PubMed

    Einat, H; Clenet, F; Shaldubina, A; Belmaker, R H; Bourin, M

    2001-01-01

    The effect of inositol as an antidepressant was previously demonstrated in both animal models of depression-like behavior and in clinical trials. Unlike most antidepressant drugs, inositol does not have a clear target in the synapse and was not demonstrated to alter monoamine levels in the brain. The present study attempted to draw a psychopharmacological profile of inositol's behavioral effects by exploring the interactions between the drug and specific receptor agonists and antagonists in the forced swim test. Rats received inositol treatment (or control) in combination with the serotonergic metabolism inhibitor PCPA or with the noradrenergic neurotoxin DSP-4. Results indicated that PCPA but not DSP-4 abolished the ability of inositol to cause a reduction in immobility time in the forced swim test. In mice, the specific 5-HT(2A)/5-HT(2C) antagonist ritanserin, but not the 5-HT(1A)/5-HT(1B)/beta adrenergic antagonist pindolol, abolished inositol's effect in the forced swim test. The 5-HT(2A)/5-HT(2C) agonist DOI and the 5-HT(1A) agonist 8-OH-DPAT did not have any significant effects on inositol's activity. The present data indicates that the antidepressant effect of inositol may involve 5-HT(2) receptors. It is thus possible that the effects of reuptake antidepressant drugs and the effects of inositol may have a common final pathway.

  12. The effect of the sigma-1 receptor selective compound LS-1-137 on the DOI-induced head twitch response in mice.

    PubMed

    Malik, Maninder; Rangel-Barajas, Claudia; Mach, Robert H; Luedtke, Robert R

    2016-09-01

    Several receptor mediated pathways have been shown to modulate the murine head twitch response (HTR). However, the role of sigma receptors in the murine (±)-2,5-dimethoxy-4-iodoamphetamine (DOI)-induced HTR has not been previously investigated. We examined the ability of LS-1-137, a novel sigma-1 vs. sigma-2 receptor selective phenylacetamide, to modulate the DOI-induced HTR in DBA/2J mice. We also assessed the in vivo efficacy of reference sigma-1 receptor antagonists and agonists PRE-084 and PPCC. The effect of the sigma-2 receptor selective antagonist RHM-1-86 was also examined. Rotarod analysis was performed to monitor motor coordination after LS-1-137 administration. Radioligand binding techniques were used to determine the affinity of LS-1-137 at 5-HT2A and 5-HT2C receptors. LS-1-137 and the sigma-1 receptor antagonists haloperidol and BD 1047 were able to attenuate a DOI-induced HTR, indicating that LS-1-137 was acting in vivo as a sigma-1 receptor antagonist. LS-1-137 did not compromise rotarod performance within a dose range capable of attenuating the effects of DOI. Radioligand binding studies indicate that LS-1-137 exhibits low affinity binding at both 5-HT2A and 5-HT2C receptors. Based upon the results from these and our previous studies, LS-1-137 is a neuroprotective agent that attenuates the murine DOI-induced HTR independent of activity at 5-HT2 receptor subtypes, D2-like dopamine receptors, sigma-2 receptors and NMDA receptors. LS-1-137 appears to act as a sigma-1 receptor antagonist to inhibit the DOI-induced HTR. Therefore, the DOI-induced HTR can be used to assess the in vivo efficacy of sigma-1 receptor selective compounds. PMID:27397487

  13. The effect of the sigma-1 receptor selective compound LS-1-137 on the DOI-induced head twitch response in mice.

    PubMed

    Malik, Maninder; Rangel-Barajas, Claudia; Mach, Robert H; Luedtke, Robert R

    2016-09-01

    Several receptor mediated pathways have been shown to modulate the murine head twitch response (HTR). However, the role of sigma receptors in the murine (±)-2,5-dimethoxy-4-iodoamphetamine (DOI)-induced HTR has not been previously investigated. We examined the ability of LS-1-137, a novel sigma-1 vs. sigma-2 receptor selective phenylacetamide, to modulate the DOI-induced HTR in DBA/2J mice. We also assessed the in vivo efficacy of reference sigma-1 receptor antagonists and agonists PRE-084 and PPCC. The effect of the sigma-2 receptor selective antagonist RHM-1-86 was also examined. Rotarod analysis was performed to monitor motor coordination after LS-1-137 administration. Radioligand binding techniques were used to determine the affinity of LS-1-137 at 5-HT2A and 5-HT2C receptors. LS-1-137 and the sigma-1 receptor antagonists haloperidol and BD 1047 were able to attenuate a DOI-induced HTR, indicating that LS-1-137 was acting in vivo as a sigma-1 receptor antagonist. LS-1-137 did not compromise rotarod performance within a dose range capable of attenuating the effects of DOI. Radioligand binding studies indicate that LS-1-137 exhibits low affinity binding at both 5-HT2A and 5-HT2C receptors. Based upon the results from these and our previous studies, LS-1-137 is a neuroprotective agent that attenuates the murine DOI-induced HTR independent of activity at 5-HT2 receptor subtypes, D2-like dopamine receptors, sigma-2 receptors and NMDA receptors. LS-1-137 appears to act as a sigma-1 receptor antagonist to inhibit the DOI-induced HTR. Therefore, the DOI-induced HTR can be used to assess the in vivo efficacy of sigma-1 receptor selective compounds.

  14. The therapeutic advantage of combination antihypertensive drug therapy using amlodipine and irbesartan in hypertensive patients: Analysis of the post-marketing survey data from PARTNER (Practical combination therapy of Amlodin and angiotensin II Receptor blocker; safety and efficacy in patients with hypertension) study.

    PubMed

    Ishimitsu, Toshihiko; Fukuda, Hirofumi; Uchida, Masako; Ishibashi, Kazushi; Sato, Fusako; Nukui, Kazuhiko; Nagao, Munehiko

    2015-01-01

    Two-thirds of hypertensive patients need a combination antihypertensive therapy to achieve the target blood pressure (BP). The PARTNER (Practical combination therapy of Amlodin and angiotensin II Receptor blocker; Safety and efficacy in paTieNts with hypERtension) study is a prospective specific clinical use survey examining the efficacy and safety of 12-week treatment with amlodipine (AML) and Angiotensin II Receptor Blocker (ARB) in 5900 hypertensive patients. The current analysis was performed as to the BP control, adverse reactions, and the effects on laboratory data in patients treated with the combination of AML and irbesartan (IRB), namely the patients added AML to already taking IRB (AML add-on group, n = 1202) and the patients added IRB to AML (IRB add-on group, n = 1050). Both study groups showed distinct decreases in office BP at 4 week (p < 0.001) and the antihypertensive effects were sustained to 12 week (p < 0.001). The percentage of patients achieving BP < 140/90 mmHg was ∼70% in either group. Proteinuria and estimated glomerular filtration rate (eGFR) were significantly improved in hypertensive patients with baseline eGFR <60 ml/min/1.73 m(2). Serum uric acid was reduced either by adding AML or IRB, and the reductions were prominent in patients with serum uric acid >7 mg/dl. The incidence of adverse reactions was as few as 1.11% and there were no severe adverse reactions which hampered the continuation of combination therapy. In conclusion, combination antihypertensive therapy with AML and IRB effectively lowers BP without particular safety problems, reduces serum uric acid especially in patients with hyperuricemia and exhibits renoprotective effects in patients with chronic kidney disease.

  15. Increased numbers of motor activity peaks during light cycle are associated with reductions in adrenergic alpha(2)-receptor levels in a transgenic Huntington's disease rat model.

    PubMed

    Bode, Felix J; Stephan, Michael; Wiehager, Sara; Nguyen, Huu Phuc; Björkqvist, Maria; von Hörsten, Stephan; Bauer, Andreas; Petersén, Asa

    2009-12-14

    Huntington's disease (HD) is a neurodegenerative disorder caused by a CAG repeat expansion in the HD gene. Besides psychiatric, motor and cognitive symptoms, HD patients suffer from sleep disturbances. In order to screen a rat model transgenic for HD (tgHD rats) for sleep-wake cycle dysregulation, we monitored their circadian activity peaks in the present study. TgHD rats of both sexes showed hyperactivity during the dark cycle and more frequent light cycle activity peaks indicative for a disturbed sleep-wake cycle. Focusing on males at the age of 4 and 14 months, analyses of receptor levels in the hypothalamus and the basal forebrain revealed that 5-HT(2A)- and adrenergic alpha(2)-receptor densities in these regions were significantly altered in tgHD rats compared to their wild-type littermates. Adrenergic receptor densities correlated negatively with the light cycle hyperactivity peaks at later stages of the disease in male tgHD rats. Furthermore, reduced leptin levels, a feature associated with circadian misalignment, were present. Our study demonstrates that the male tgHD rat is a suitable model to investigate HD associated sleep alterations. Further studies are warranted to elucidate the role of adrenergic- and 5-HT(2A)-receptors as therapeutic targets for dysregulation of the circadian activity in HD.

  16. Vasospastic angina and Ca channel blockers.

    PubMed

    Minatoguchi, Shinya

    2013-08-01

    Coronary artery spasm is one of the causes of angina pectoris,acute myocardial infarction and ventricular fibrillation-related sudden death. It has been established that Ca channel blockers are protective against vasospastic angina (VSA) and treatment with Ca channel blockers provides a better prognosis of VSA. However, it is not still clarified what kinds of Ca channel blockers shows the best prognosis of VSA. We performed a meta-analysis in which 4Ca channel blockers amlodipine, nifedipine, benidipine and diltiazem were used for the treatment of VSA patients and found that among 4 Ca channel blockers, benidipine showed a statistically significant better prognostic effect on MACE than amlodipine, nifedipine or diltiazem.

  17. Serotonin1A receptors in the pathophysiology of schizophrenia: development of novel cognition-enhancing therapeutics.

    PubMed

    Sumiyoshi, Tomiki; Bubenikova-Valesova, Vera; Horacek, Jiri; Bert, Bettina

    2008-10-01

    Serotonin (5-HT) receptors have been suggested to play key roles in psychosis, cognition, and mood via influence on neurotransmitters, synaptic integrity, and neural plasticity. Specifically, genetic evidence indicates that 5-HT(1A), 5-HT(2A), and 5-HT(2C) receptor single-nucleotide polymorphisms (SNPs) are related to psychotic symptoms, cognitive disturbances, and treatment response in schizophrenia. Data from animal research suggest the role of 5-HT in cognition via its influence on dopaminergic, cholinergic, glutamatergic, and GABAergic function. This article provides up-to-date findings on the role of 5-HT receptors in endophenotypic variations in schizophrenia and the development of newer cognition-enhancing medications, based on basic science and clinical evidence. Imaging genetics studies on associations of polymorphisms of several 5-HT receptor subtypes with brain structure, function, and metabolism suggest a role for the prefrontal cortex and the parahippocampal gyrus in cognitive impairments of schizophrenia. Data from animal experiments to determine the effect of agonists/antagonists at 5-HT(1A), 5-HT(2A), and 5-HT(2C) receptors on behavioral performance in animal models of schizophrenia based on the glutamatergic hypothesis provide useful information. For this purpose, standard as well as novel cognitive tasks provide a measure of memory/information processing and social interaction. In order to scrutinize mixed evidence for the ability of 5-HT(1A) agonists/antagonists to improve cognition, behavioral data in various paradigms from transgenic mice overexpressing 5-HT(1A) receptors provide valuable insights. Clinical trials reporting the advantage of 5-HT(1A) partial agonists add to efforts to shape pharmacologic perspectives concerning cognitive enhancement in schizophrenia by developing novel compounds acting on 5-HT receptors. Overall, these lines of evidence from translational research will facilitate the development of newer pharmacologic strategies

  18. Nebivolol: a novel beta-blocker with nitric oxide-induced vasodilatation.

    PubMed

    Weiss, Robert

    2006-01-01

    Nebivolol is a novel beta1-blocker with a greater degree of selectivity for beta1-adrenergic receptors than other agents in this class and a nitric oxide (NO)-potentiating, vasodilatory effect that is unique among beta-blockers currently available to clinicians (nebivolol is approved in Europe and is currently under review in the US). A NO-potentiating agent such as nebivolol may have an important role in hypertensive populations with reduced endothelial function such as diabetics, African-Americans and those with vascular disease. Nebivolol is a racemic mixture with beta-blocker activity residing in the d-isomer; in contrast, l-nebivolol is far more potent in facilitating NO release. Nebivolol is unique among beta-blockers in that, at doses < 10 mg, it does not inhibit the increase in heart rate normally seen with exercise. The efficacy ofnebivolol has been tested successfully in clinical trials against other agents including other beta-blockers, angiotensin-converting enzyme-inhibitors and calcium channel antagonists in patients with hypertension, angina, and congestive heart failure. The tolerability of nebivolol has been shown to be superior to that of atenolol and metoprolol. In controlled clinical trials, nebivolol has a side effect profile that is similar to placebo, in particular as it relates to fatigue and sexual dysfunction. This article will review published clinical data regarding this cardioselective beta-blocker. PMID:17326335

  19. A meta-analysis of the effects of β-adrenergic blockers in chronic heart failure

    PubMed Central

    Zhang, Xiaojian; Shen, Chengwu; Zhai, Shujun; Liu, Yukun; Yue, Wen-Wei; Han, Li

    2016-01-01

    Adrenergic β-blockers are drugs that bind to, but do not activate β-adrenergic receptors. Instead they block the actions of β-adrenergic agonists and are used for the treatment of various diseases such as cardiac arrhythmias, angina pectoris, myocardial infarction, hypertension, headache, migraines, stress, anxiety, prostate cancer, and heart failure. Several meta-analysis studies have shown that β-blockers improve the heart function and reduce the risks of cardiovascular events, rate of mortality, and sudden death through chronic heart failure (CHF) of patients. The present study identified results from recent meta-analyses of β-adrenergic blockers and their usefulness in CHF. Databases including Medline/Embase/Cochrane Central Register of Controlled Trials (CENTRAL), and PubMed were searched for the periods May, 1985 to March, 2011 and June, 2013 to August, 2015, and a number of studies identified. Results of those studies showed that use of β-blockers was associated with decreased sudden cardiac death in patients with heart failure. However, contradictory results have also been reported. The present meta-analysis aimed to determine the efficacy of β-blockers on mortality and morbidity in patients with heart failure. The results showed that mortality was significantly reduced by β-blocker treatment prior to the surgery of heart failure patients. The results from the meta-analysis studies showed that β-blocker treatment in heart failure patients correlated with a significant decrease in long-term mortality, even in patients that meet one or more exclusion criteria of the MERIT-HF study. In summary, the findings of the current meta-analysis revealed beneficial effects different β-blockers have on patients with heart failure or related heart disease. PMID:27703506

  20. Misperceptions About β-Blockers and Diuretics

    PubMed Central

    Ubel, Peter A; Jepson, Christopher; Asch, David A

    2003-01-01

    BACKGROUND Based on a series of clinical trials showing no difference in the effectiveness or tolerability of most major classes of antihypertensive medications, the Joint National Commission on High Blood Pressure Treatment recommends that physicians prescribe β-blockers or diuretics as initial hypertensive therapy unless there are compelling indications for another type of medication. Nevertheless, many physicians continue to favor more expensive medications like angiotensin-converting enzyme (ACE) inhibitors and calcium channel blockers as first line agents. The persistent use of these agents raises questions as to whether physicians perceive ACE inhibitors and calcium channel blockers to be better than β-blockers and diuretics. METHODS We surveyed 1,200 primary care physicians in 1997, and another 500 primary care physicians in 2000, and asked them to estimate the relative effectiveness and side effects of 4 classes of medication in treating a hypothetical patient with uncomplicated hypertension: ACE inhibitors, β-blockers, calcium channel blockers, and diuretics. In addition, we asked them to indicate whether they ever provided free samples of hypertension medications to their patients. RESULTS Perceptions of the relative effectiveness and side effects of the 4 classes of hypertension medications did not significantly change over the 3 years, nor did prescription recommendations. Physicians perceive that diuretics are less effective at lowering blood pressure than the other 3 classes (P < .001). They also perceive that β-blockers are less tolerated than the other 3 classes (P < .001). In a multivariate model, perceptions of effectiveness and tolerability displayed significant associations with prescription preference independent of background variables. The only other variable to contribute significantly to the model was provision of free medication samples to patients. CONCLUSIONS Despite numerous clinical trials showing no difference in the effectiveness

  1. A systematic investigation of the differential roles for ventral tegmentum serotonin 1- and 2-type receptors on food intake in the rat.

    PubMed

    Pratt, Wayne E; Clissold, Kara A; Lin, Peagan; Cain, Amanda E; Ciesinski, Alexa F; Hopkins, Thomas R; Ilesanmi, Adeolu O; Kelly, Erin A; Pierce-Messick, Zachary; Powell, Daniel S; Rosner, Ian A

    2016-10-01

    Central serotonin (5-HT) pathways are known to influence feeding and other ingestive behaviors. Although the ventral tegmentum is important for promoting the seeking and consumption of food and drugs of abuse, the roles of 5-HT receptor subtypes in this region on food intake have yet to be comprehensively examined. In these experiments, food restricted rats were given 2-h access to rat chow; separate groups of non-restricted animals had similar access to a sweetened fat diet. Feeding and locomotor activity were monitored following ventral tegmentum stimulation or blockade of 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2B, or 5-HT2C receptors. 5-HT1A receptor stimulation transiently inhibited rearing behavior and chow intake in food-restricted rats, and had a biphasic effect on non-restricted rats offered the palatable diet. 5-HT1B receptor agonism transiently inhibited feeding in restricted animals, but did not affect intake of non-restricted rats. In contrast, 5-HT1B receptor antagonism decreased palatable feeding. Although stimulation of ventral tegmental 5-HT2B receptors with BW723C86 did not affect hunger-driven food intake, it significantly affected palatable feeding, with a trend for an increasing intake at 2.0µg/side but not at 5.0µg/side. Antagonism of the same receptor modestly but significantly inhibited feeding of the palatable diet at 5.0µg/side ketanserin. Neither stimulation nor blockade of 5-HT2A or 5-HT2C receptors caused prolonged effects on intake or locomotion. These data suggest that serotonin's effects on feeding within the ventral tegmentum depend upon the specific receptor targeted, as well as whether intake is motivated by food restriction or the palatable nature of the offered diet. PMID:27431937

  2. A systematic investigation of the differential roles for ventral tegmentum serotonin 1- and 2-type receptors on food intake in the rat.

    PubMed

    Pratt, Wayne E; Clissold, Kara A; Lin, Peagan; Cain, Amanda E; Ciesinski, Alexa F; Hopkins, Thomas R; Ilesanmi, Adeolu O; Kelly, Erin A; Pierce-Messick, Zachary; Powell, Daniel S; Rosner, Ian A

    2016-10-01

    Central serotonin (5-HT) pathways are known to influence feeding and other ingestive behaviors. Although the ventral tegmentum is important for promoting the seeking and consumption of food and drugs of abuse, the roles of 5-HT receptor subtypes in this region on food intake have yet to be comprehensively examined. In these experiments, food restricted rats were given 2-h access to rat chow; separate groups of non-restricted animals had similar access to a sweetened fat diet. Feeding and locomotor activity were monitored following ventral tegmentum stimulation or blockade of 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2B, or 5-HT2C receptors. 5-HT1A receptor stimulation transiently inhibited rearing behavior and chow intake in food-restricted rats, and had a biphasic effect on non-restricted rats offered the palatable diet. 5-HT1B receptor agonism transiently inhibited feeding in restricted animals, but did not affect intake of non-restricted rats. In contrast, 5-HT1B receptor antagonism decreased palatable feeding. Although stimulation of ventral tegmental 5-HT2B receptors with BW723C86 did not affect hunger-driven food intake, it significantly affected palatable feeding, with a trend for an increasing intake at 2.0µg/side but not at 5.0µg/side. Antagonism of the same receptor modestly but significantly inhibited feeding of the palatable diet at 5.0µg/side ketanserin. Neither stimulation nor blockade of 5-HT2A or 5-HT2C receptors caused prolonged effects on intake or locomotion. These data suggest that serotonin's effects on feeding within the ventral tegmentum depend upon the specific receptor targeted, as well as whether intake is motivated by food restriction or the palatable nature of the offered diet.

  3. How Do Beta Blocker Drugs Affect Exercise?

    MedlinePlus

    ... American Heart area Search by State SELECT YOUR LANGUAGE Español (Spanish) 简体中文 (Traditional Chinese) 繁体中文 (Simplified Chinese) ... used because beta blockers affect everyone differently. The second way to monitor your intensity is simpler: making ...

  4. 5-Hydroxytryptamine Receptor Subtypes and their Modulators with Therapeutic Potentials

    PubMed Central

    Pithadia, Anand B.; Jain, Sunita M.

    2009-01-01

    5-hydroxytryptamine (5-HT) has become one of the most investigated and complex biogenic amines. The main receptors and their subtypes, e.g., 5-HTI (5-HT1A, 5-HT1B, 5-HTID, 5-HTIE and 5-HT1F), 5-HT2 (5-HT2A, 5-HT2B and 5-HT2C), 5-HT3, 5-HT4, 5-HT5 (5-HT5A, 5-HT5B), 5-HT6 and 5-HT7 have been identified. Specific drugs which are capable of either selectively stimulating or inhibiting these receptor subtypes are being designed. This has generated therapeutic potentials of 5-HT receptor modulators in a variety of disease conditions. Conditions where 5-HT receptor modulators have established their use with distinct efficacy and advantages include migraine, anxiety, psychosis, obesity and cancer therapy-induced vomiting by cytotoxic drugs and radiation. Discovery of 5-HT, its biosynthesis, metabolism, physiological role and the potential of 5-HT receptor modulators in various nervous, cardiovascular and gastrointestinal tract disorders, bone growth and micturition have been discussed in this article. Keywords 5-hydroxytryptamine (5-HT) receptors; Modulators; Biogenic amines PMID:22505971

  5. Discriminative stimulus properties of 1.25mg/kg clozapine in rats: Mediation by serotonin 5-HT2 and dopamine D4 receptors.

    PubMed

    Prus, Adam J; Wise, Laura E; Pehrson, Alan L; Philibin, Scott D; Bang-Andersen, Benny; Arnt, Jørn; Porter, Joseph H

    2016-10-01

    The atypical antipsychotic drug clozapine remains one of most effective treatments for schizophrenia, given a lack of extrapyramidal side effects, improvements in negative symptoms, cognitive impairment, and in symptoms in treatment-resistant schizophrenia. The adverse effects of clozapine, including agranulocytosis, make finding a safe clozapine-like a drug a goal for drug developers. The drug discrimination paradigm is a model of interoceptive stimulus that has been used in an effort to screen experimental drugs for clozapine-like atypical antipsychotic effects. The present study was conducted to elucidate the receptor-mediated stimulus properties that form this clozapine discriminative cue by testing selective receptor ligands in rats trained to discriminate a 1.25mg/kg dose of clozapine from vehicle in a two choice drug discrimination task. Full substitution occurred with the 5-HT2A inverse agonist M100907 and the two preferential D4/5-HT2/α1 receptor antagonists Lu 37-114 ((S)-1-(3-(2-(4-(1H-indol-5-yl)piperazin-1-yl)ethyl)indolin-1-yl)ethan-1-one) and Lu 37-254 (1-(3-(4-(1H-indol-5-yl)piperazin-1-yl)propyl)-3,4-dihydroquinolin-2(1H)-one). Partial substitution occurred with the D4 receptor antagonist Lu 38-012 and the α1 adrenoceptor antagonist prazosin. Drugs selective for 5-HT2C, 5-HT6 muscarinic, histamine H1, and benzodiazepine receptors did not substitute for clozapine. The present findings suggest that 5-HT2A inverse agonism and D4 receptor antagonism mediate the discriminative stimulus properties of 1.25mg/kg clozapine in rats, and further confirm that clozapine produces a complex compound discriminative stimulus. PMID:27502027

  6. Human Serotonin 5-HT2C G Protein-Coupled Receptor Homology Model from the β2 Adrenoceptor Structure: Ligand Docking and Mutagenesis Studies

    PubMed Central

    RDOVA-SINTJAGO, TANIA CÓ; VILLA, NANCY; CANAL, CLINTON; BOOTH, RAYMOND

    2013-01-01

    Activation of the serotonin (5-hydroxytryptamine, 5-HT) 5HT2C G protein-coupled receptor (GPCR) is proposed as novel pharmacotherapy for obesity and neuropsychiatric disorders. In contrast, activation of the 5-HT2A and 5-HT2B GPCRs is associated with untoward hallucinogenic and cardiopulmonary effects, respectively. There is no crystal structure available to guide design of 5-HT2C receptor-specific ligands. For this reason, a homology model of the 5-HT2C receptor was built based on the crystal structure of the human β2 adrenoceptor GPCR to delineate molecular determinants of ligand–receptor interactions for drug design purposes. Computational and experimental studies were carried out to validate the model. Binding of N(CH3)2-PAT [(1R, 3S)-(−)-trans-1-phenyl-3-N,N-dimethylamino-1,2,3,4-tetrahydronaphthalene], a novel 5-HT2C agonist/5-HT2A/2B inverse agonist, and its secondary [NH(CH3)-PAT] and primary (NH2-PAT) amine analogs were studied at the 5-HT2C wild type (WT) and D3.32A, S3.36A, and Y7.43A 5-HT2C point-mutated receptors. Reference ligands included the tertiary amines lisuride and mesulergine and the primary amine 5-HT. Modeling results indicated that 5-HT2C residues D3.32, S3.36, and Y7.43 play a role in ligand binding. Experimental ligand binding results with WT and point-mutated receptors confirmed the impact of D3.32, S3.36, and Y7.43 on ligand affinity. PMID:24244046

  7. A Randomized Controlled Trial of the Efficacy and Safety of CCX282-B, an Orally-Administered Blocker of Chemokine Receptor CCR9, for Patients with Crohn’s Disease

    PubMed Central

    Keshav, Satish; Vaňásek, Tomáš; Niv, Yaron; Petryka, Robert; Howaldt, Stephanie; Bafutto, Mauro; Rácz, István; Hetzel, David; Nielsen, Ole Haagen; Vermeire, Séverine; Reinisch, Walter; Karlén, Per; Schreiber, Stefan; Schall, Thomas J.; Bekker, Pirow

    2013-01-01

    CCX282-B, also called vercirnon, is a specific, orally-administered chemokine receptor CCR9 antagonist that regulates migration and activation of inflammatory cells in the intestine. This randomized, placebo-controlled trial was conducted to evaluate the safety and efficacy of CCX282-B in 436 patients with Crohn’s disease. Crohn’s Disease Activity Index (CDAI) scores were 250–450 and C-reactive protein >7.5 mg/L at study entry. In addition to stable concomitant Crohn’s medication (85% of subjects), subjects received placebo or CCX282-B (250 mg once daily, 250 mg twice daily, or 500 mg once daily) for 12 weeks. They then received 250 mg CCX282-B twice daily, open-label, through week 16. Subjects who had a clinical response (a ≥70 point drop in CDAI) at week 16 were randomly assigned to groups given placebo or CCX282-B (250 mg, twice daily) for 36 weeks. Primary endpoints were clinical response at Week 8 and sustained clinical response at Week 52. During the 12-week Induction period, the clinical response was highest in the group given 500 mg CCX282-B once daily. Response rates at week 8 were 49% in the placebo group, 52% in the group given CCX282-B 250 mg once daily (odds ratio [OR] = 1.12; p = .667 vs placebo), 48% in the group given CCX282-B 250 mg twice daily (OR = 0.95; p = .833), and 60% in the group given CCX282-B 500 mg once daily (OR = 1.53; p = .111). At week 12, response rates were 47%, 56% (OR = 1.44; p = .168), 49% (OR = 1.07; p = .792), and 61% (OR = 1.74; p = .039), respectively. At the end of the Maintenance period (week 52), 47% of subjects on CCX282-B were in remission, compared to 31% on placebo (OR = 2.01; p = .012); 46% showed sustained clinical responses, compared to 42% on placebo (OR = 1.14; p = .629). CCX282-B was well tolerated. Encouraging results from this clinical trial led to initiation of Phase 3 clinical trials in Crohn’s disease. Trial Registration Clinical

  8. Serotonin aggravates exercise-induced cardiac ischemia in the dog: effect of serotonin receptor antagonists.

    PubMed

    Guilbert, Frédérique; Lainée, Pierre; Dubreuil, Brigitte; McCort, Gary; O'Connor, Stephen E; Janiak, Philip; Herbert, Jean-Marc

    2004-08-16

    We investigated the effects of serotonin (5-HT), SL65.0472 (7-fluoro-2-oxo-4-[2-[4-thieno[3,2-c]pyridine-4-yl)piperazin-1-yl]ethyl]-1,2-dihydroquinoline-1-acetamide, a 5-HT(1B)/5-HT(2A) receptor antagonist) and ketanserin (a 5-HT(2A) receptor antagonist) during exercise-induced cardiac ischemia in conscious dogs. Dogs were administered a hypercholesterolemic diet and an inhibitor of nitric oxide synthetase to produce chronic endothelial dysfunction. Myocardial ischemia was induced by a treadmill exercise test associated with limitation of left anterior descending coronary blood flow. Infusion of serotonin during exercise produced dose-related cardiovascular changes (after 10 microg/kg/min; heart rate +27+/-6 bpm, systolic blood pressure +18+/-3 mm Hg, left circumflex coronary blood flow +64+/-8 ml/min, myocardial segment length shortening in the ischemic zone -5.9+/-1.9%, P<0.05). SL65.0472 blocked serotonin-induced increases in blood pressure, rate pressure product and circumflex coronary artery flow (100 microg/kg i.v., P<0.05) and reduced serotonin-induced ischemic myocardial segment length shortening (300 microg/kg i.v., P<0.05). Ketanserin (30-300 microg/kg i.v.) had no significant effect on any serotonin-induced changes during exercise. Thus, SL65.0472 opposes serotonin-induced myocardial dysfunction in a dog model of exercise-induced ischemia.

  9. Antagonism of lateral saphenous vein serotonin receptors from steers grazing endophyte-free, wild-type, or novel endophyte-infected tall fescue.

    PubMed

    Klotz, J L; Aiken, G E; Johnson, J M; Brown, K R; Bush, L P; Strickland, J R

    2013-09-01

    Pharmacologic profiling of serotonin (5HT) receptors of bovine lateral saphenous vein has shown that cattle grazing endophyte-infected (Neotyphodium coenophialum) tall fescue (Lolium arundinaceum) have altered responses to ergovaline, 5HT, 5HT2A, and 5HT7 agonists. To determine if 5HT receptor activity of tall fescue alkaloids is affected by grazing endophyte-free (EF), wild-type [Kentucky-31 (KY31)], novel endophyte AR542-infected (MAXQ), or novel endophyte AR584-infected (AR584) tall fescue, contractile responses of lateral saphenous veins biopsied from cattle grazing these different fescue-endophyte combinations were evaluated in presence or absence of antagonists for 5HT2A (ketanserin) or 5HT7 (SB-269970) receptors. Biopsies were conducted over 2 yr on 35 mixed-breed steers (361.5 ± 6.3 kg) grazing EF (n = 12), KY31 (n = 12), MAXQ (n = 6), or AR584 (n = 5) pasture treatments (3 ha) between 84 and 98 d (Yr 1) or 108 to 124 d (Yr 2). Segments (2 to 3 cm) of vein were surgically biopsied, sliced into 2- to 3-mm cross-sections, and suspended in a myograph chamber containing 5 mL of oxygenated Krebs-Henseleit buffer (95% O2/5% CO2; pH = 7.4; 37°C). Veins were exposed to increasing concentrations of 5HT, ergovaline, and ergovaline + 1 × 10(-5) M ketanserin or + 1 × 10(-6) M SB-269970 in Yr 1. In Yr 2, ergotamine and ergocornine were evaluated in presence or absence of 1 × 10(-5) M ketanserin. Contractile response data were normalized to a reference addition of 1 × 10(-4) M norepinephrine. In Yr 1, contractile response to 5HT and ergovaline were least (P < 0.05) in KY31 pastures and the presence of ketanserin greatly reduced (P < 0.05) the response to ergovaline in all pastures. However, presence of SB-269970 did not (P = 0.91) alter contractile response to ergovaline. In Yr 2, there was no difference in contractile response to ergotamine (P = 0.13) or ergocornine (P = 0.99) across pasture treatments, but ketanserin reduced (P < 0.05) the contractile response to

  10. Translational neurophysiological markers for activity of the metabotropic glutamate receptor (mGluR2) modulator JNJ-40411813: Sleep EEG correlates in rodents and healthy men.

    PubMed

    Ahnaou, A; de Boer, P; Lavreysen, H; Huysmans, H; Sinha, V; Raeymaekers, L; Van De Casteele, T; Cid, J M; Van Nueten, L; Macdonald, G J; Kemp, J A; Drinkenburg, W H I M

    2016-04-01

    Alterations in rapid eye movement sleep (REM) have been suggested as valid translational efficacy markers: activation of the metabotropic glutamate receptor 2 (mGluR2) was shown to increase REM latency and to decrease REM duration. The present paper addresses the effects on vigilance states of the mGluR2 positive allosteric modulator (PAM) JNJ-40411813 at different circadian times in rats and after afternoon dosing in humans. Due to its dual mGluR2 PAM/serotonin 2A (5-HT2A) receptor antagonism in rodents, mGlu2R specificity of effects was studied in wild-type (WT) and mGluR2 (-/-) mice. 5-HT2A receptor occupancy was determined in humans using positron emission tomography (PET). Tolerance development was examined in rats after chronic dosing. EEG oscillations and network connectivity were assessed using multi-channel EEG. In rats, JNJ-40411813 increased deep sleep time and latency of REM onset but reduced REM time when administered 2 h after 'lights on' (CT2): this was sustained after chronic dosing. At CT5 similar effects were elicited, at CT10 only deep sleep was enhanced. Withdrawal resulted in baseline values, while re-administration reinstated drug effects. Parieto-occipital cortical slow theta and gamma oscillations were correlated with low locomotion. The specificity of functional response was confirmed in WT but not mGluR2 (-/-) mice. A double-blind, placebo-controlled polysomnographic study in healthy, elderly subjects showed that 500 mg of JNJ-40411813 consistently increased deep sleep time, but had no effect on REM parameters. This deep sleep effect was not explained by 5-HT2A receptor binding, as in the PET study even 700 mg only marginally displaced the tracer. JNJ-40411813 elicited comparable functional responses in rodents and men if circadian time of dosing was taken into account. These findings underscore the translational potential of sleep mechanisms in evaluating mGluR2 therapeutics when administered at the appropriate circadian time.

  11. Combined unilateral blockade of cholinergic, peptidergic, and serotonergic receptors in the ventral respiratory column does not affect breathing in awake or sleeping goats

    PubMed Central

    Muere, Clarissa; Neumueller, Suzanne; Olesiak, Samantha; Miller, Justin; Langer, Thomas; Hodges, Matthew R.; Pan, Lawrence

    2015-01-01

    Previous work in intact awake and sleeping goats has found that unilateral blockade of excitatory inputs in the ventral respiratory column (VRC) elicits changes in the concentrations of multiple neurochemicals, including serotonin (5-HT), substance P, glycine, and GABA, while increasing or having no effect on breathing. These findings are consistent with the concept of interdependence between neuromodulators, whereby attenuation of one modulator elicits compensatory changes in other modulators to maintain breathing. Because there is a large degree of redundancy and multiplicity of excitatory inputs to the VRC, we herein tested the hypothesis that combined unilateral blockade of muscarinic acetylcholine (mACh), neurokinin-1 (NK1, the receptor for substance P), and 5-HT2A receptors would elicit changes in multiple neurochemicals, but would not change breathing. We unilaterally reverse-dialyzed a cocktail of antagonists targeting these receptors into the VRC of intact adult goats. Breathing was continuously monitored while effluent fluid from dialysis was collected for quantification of neurochemicals. We found that neither double blockade of mACh and NK1 receptors, nor triple blockade of mACh, NK1, and 5-HT2A receptors significantly affected breathing (P ≥ 0.05) in goats that were awake or in non-rapid eye movement (NREM) sleep. However, both double and triple blockade increased the effluent concentration of substance P (P < 0.001) and decreased GABA concentrations. These findings support our hypothesis and, together with past data, suggest that both in wakefulness and NREM sleep, multiple neurom