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1.
Int J Mol Sci ; 20(18)2019 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-31491880

RESUMO

Vasoactive intestinal peptide receptor 1 (VPAC1) is a member of a secretin-like subfamily of G protein-coupled receptors. Its endogenous neuropeptide (VIP), secreted by neurons and immune cells, modulates various physiological functions such as exocrine and endocrine secretions, immune response, smooth muscles relaxation, vasodilation, and fetal development. As a drug target, VPAC1 has been selected for therapy of inflammatory diseases but drug discovery is still hampered by lack of its crystal structure. In this study we presented the homology model of this receptor constructed with the well-known web service GPCRM. The VPAC1 model is composed of extracellular and transmembrane domains that form a complex with an endogenous hormone VIP. Using the homology model of VPAC1 the mechanism of action of potential drug candidates for VPAC1 was described. Only two series of small-molecule antagonists of confirmed biological activity for VPAC1 have been described thus far. Molecular docking and a series of molecular dynamics simulations were performed to elucidate their binding to VPAC1 and resulting antagonist effect. The presented work provides the basis for the possible binding mode of VPAC1 antagonists and determinants of their molecular recognition in the context of other class B GPCRs. Until the crystal structure of VPAC1 will be released, the presented homology model of VPAC1 can serve as a scaffold for drug discovery studies and is available from the author upon request.


Assuntos
Desenho de Drogas , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Receptores Tipo I de Polipeptídeo Intestinal Vasoativo/química , Sítios de Ligação , Humanos , Ligantes , Estrutura Molecular , Ligação Proteica , Conformação Proteica , Relação Quantitativa Estrutura-Atividade , Receptores Tipo I de Polipeptídeo Intestinal Vasoativo/antagonistas & inibidores
2.
PLoS One ; 14(1): e0211433, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30682157

RESUMO

BACKGROUND: PACAP and VIP are closely related neuropeptides with wide distribution and potent effect in the vasculature. We previously reported vasomotor activity in peripheral vasculature of male wild type (WT) and PACAP-deficient (KO) mice. However, female vascular responses are still unexplored. We hypothesized that PACAP-like activity is maintained in female PACAP KO mice and the mechanism through which it is regulated differs from that of male PACAP KO animals. METHODS: We investigated the vasomotor effects of VIP and PACAP isoforms and their selective blockers in WT and PACAP KO female mice in carotid and femoral arteries. The expression and level of different PACAP receptors in the vessels were measured by RT-PCR and Western blot. RESULTS: In both carotid and femoral arteries of WT mice, PACAP1-38, PACAP1-27 or VIP induced relaxation, without pronounced differences between them. Reduced relaxation was recorded only in the carotid arteries of KO mice as compared to their WT controls. The specific VPAC1R antagonist completely blocked the PACAP/VIP-induced relaxation in both arteries of all mice, while PAC1R antagonist affected relaxation only in their femoral arteries. CONCLUSION: In female WT mice, VPAC1 receptors appear to play a dominant role in PACAP-induced vasorelaxation both in carotid and in femoral arteries. In the PACAP KO group PAC1R activation exerts vasorelaxation in the femoral arteries but in carotid arteries there is no significant effect of the activation of this receptor. In the background of this regional difference, decreased PAC1R and increased VPAC1R availability in the carotid arteries was found.


Assuntos
Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/genética , Receptores Tipo I de Polipeptídeo Intestinal Vasoativo/metabolismo , Vasodilatação , Animais , Artérias Carótidas/efeitos dos fármacos , Artérias Carótidas/fisiologia , Feminino , Artéria Femoral/efeitos dos fármacos , Artéria Femoral/fisiologia , Proteínas de Insetos/farmacologia , Camundongos , Camundongos Knockout , Nitroprussiato/farmacologia , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/deficiência , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/farmacologia , Receptores Tipo I de Polipeptídeo Intestinal Vasoativo/antagonistas & inibidores , Peptídeo Intestinal Vasoativo/farmacologia , Vasodilatação/efeitos dos fármacos
3.
Curr Med Chem ; 26(34): 6261-6281, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-29848264

RESUMO

BACKGROUND: Migraine is one of the most disabling neurological conditions and associated with high socio-economic costs. Though certain aspects of the pathomechanism of migraine are still incompletely understood, the leading hypothesis implicates the role of the activation of the trigeminovascular system. Triptans are considered to be the current gold standard therapy for migraine attacks; however, their use in clinical practice is limited. Prophylactic treatment includes non-specific approaches for migraine prevention. All these support the need for future studies in order to develop innovative anti-migraine drugs. OBJECTIVE: The present study is a review of the current literature regarding new therapeutic lines in migraine research. METHODS: A systematic literature search in the database of PUBMED was conducted concerning therapeutic strategies in a migraine published until July 2017. RESULTS: Ongoing clinical trials with 5-HT1F receptor agonists and glutamate receptor antagonists offer promising new aspects for acute migraine treatment. Monoclonal antibodies against CGRP and the CGRP receptor are revolutionary in preventive treatment; however, further long-term studies are needed to test their tolerability. Preclinical studies show positive results with PACAP- and kynurenic acid-related treatments. Other promising therapeutic strategies (such as those targeting TRPV1, substance P, NOS, or orexin) have failed to show efficacy in clinical trials. CONCLUSION: Due to their side-effects, current therapeutic approaches are not suitable for all migraine patients. Especially frequent episodic and chronic migraine represents a therapeutic challenge for researchers. Clinical and preclinical studies are needed to untangle the pathophysiology of migraine in order to develop new and migraine-specific therapies.


Assuntos
Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Transtornos de Enxaqueca/tratamento farmacológico , Agonistas do Receptor de Serotonina/uso terapêutico , Anti-Inflamatórios não Esteroides/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Peptídeo Relacionado com Gene de Calcitonina/imunologia , Ensaios Clínicos como Assunto , Humanos , Ácido Cinurênico/uso terapêutico , Transtornos de Enxaqueca/diagnóstico , Receptores Tipo I de Polipeptídeo Intestinal Vasoativo/antagonistas & inibidores
4.
Eur J Med Chem ; 155: 84-95, 2018 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-29864700

RESUMO

Radiolabeled heterobivalent peptidic ligands (HBPLs), being able to address different receptors, are highly interesting tumor imaging agents as they can offer multiple advantages over monovalent peptide receptor ligands. However, few examples of radiolabeled HBPLs have been described so far. One promising approach is the combination of gastrin-releasing peptide receptor (GRPR)- and vasoactive intestinal peptide receptor subtype 1 (VPAC1R)-targeting peptides into one single radioligand since gastrinomas, prostate and breast cancer have been shown to concomitantly or complementarily overexpress both receptors. Here we report the design and synthesis of different HBPLs, comprising a GRPR-binding (BBN7-14) and a VPAC1R-targeting (PACAP-27) peptide. The heterodimers were varied with regard to the distance between the peptide binders and the steric rigidity of the systems. We radiolabeled the HBPLs 19-23 as well as their monomeric reference standards 26 and 27 with 68Ga, achieving radiochemical yields and purities of 95-99% and non-optimized molar activities of 25-61 GBq/µmol. We tested the stability of the radioligands and further evaluated them in vitro regarding their uptake in different prostate carcinoma cell lines (PC-3, DU-145 and VCaP cells). We found that the heterobivalent substances [68Ga]19 - [68Ga]23 showed comparable uptakes into the tumor cells to those of the respective monomers [68Ga]26 and [68Ga]27, indicating that both peptides are still able to address their target receptors. Furthermore, the obtained results indicate that in case of overall low receptor densities, heterobivalent peptides surpass peptide monomers in tumor cell uptake. Most importantly, it could be shown by blocking studies that both peptide parts of the HBPL [68Ga]19 contributed to tumor cell uptake in VCaP cells, expressing both receptor types. Thus, we describe here the first examples of HBPLs being able to address the GRPR as well as the VPAC1R and have the potential to - by several mechanisms - improve tumor targeting for several malignancies compared to monospecific peptides.


Assuntos
Desenho de Drogas , Peptídeos/farmacologia , Receptores da Bombesina/antagonistas & inibidores , Receptores Tipo I de Polipeptídeo Intestinal Vasoativo/antagonistas & inibidores , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Humanos , Ligantes , Estrutura Molecular , Peptídeos/síntese química , Peptídeos/química , Receptores da Bombesina/genética , Receptores Tipo I de Polipeptídeo Intestinal Vasoativo/genética , Relação Estrutura-Atividade
5.
J Diabetes Res ; 2016: 9321395, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-28044141

RESUMO

Pituitary adenylate cyclase-activating polypeptide (PACAP) acts on multiple processes of glucose and energy metabolism. PACAP potentiates insulin action in adipocytes and insulin release from pancreatic ß-cells, thereby enhancing glucose tolerance. Contrary to these effects at organ levels, PACAP null mice exhibit hypersensitivity to insulin. However, this apparent discrepancy remains to be solved. We aimed to clarify the mechanism underlying the antidiabetic phenotype of PACAP null mice. Feeding with high-fat diet (HFD) impaired insulin sensitivity and glucose tolerance in wild type mice, whereas these changes were prevented in PACAP null mice. HFD also impaired insulin-induced Akt phosphorylation in the liver in wild type mice, but not in PACAP null mice. Using GeneFishing method, HFD increased the leukocyte common antigen-related (LAR) protein tyrosine phosphatase in the liver in wild type mice. Silencing of LAR restored the insulin signaling in the liver of HFD mice. Moreover, the increased LAR expression by HFD was prevented in PACAP null mice. HFD increased the expression of VPAC1 receptor (VPAC1-R), one of three PACAP receptors, in the liver of wild type mice. These data indicate that PACAP-VPAC1-R signaling induces LAR expression and insulin resistance in the liver of HFD mice. Antagonism of VPAC1-R may prevent progression of HFD-induced insulin resistance in the liver, providing a novel antidiabetic strategy.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Resistência à Insulina , Fígado/metabolismo , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/farmacologia , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/genética , Receptores Tipo I de Polipeptídeo Intestinal Vasoativo/fisiologia , Animais , Expressão Gênica/efeitos dos fármacos , Hipoglicemiantes , Fígado/química , Fígado/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Camundongos Knockout , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/deficiência , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/genética , RNA Mensageiro/análise , Receptores Tipo I de Polipeptídeo Intestinal Vasoativo/antagonistas & inibidores , Receptores Tipo I de Polipeptídeo Intestinal Vasoativo/genética
6.
Artigo em Inglês | MEDLINE | ID: mdl-25438751

RESUMO

Vasoactive intestinal polypeptide (VIP) is an intrinsic 28-amino acid peptide, involved in a wide range of physiologic effects, and therefore considered as a promising drug candidate for the treatment of several diseases. But the clinical application of VIP has been limited for the easy in vivo digestion. Various researches aiming to prolong the VIP half-life, by modifying the VIP structure, have been reported. The first thing to be considered after structural modification is to know it is a VPAC agonist or antagonist. To analyze the structure-activity relationships of VIP derivatives and build classifiers to distinguish newly designed VIPs, here in this work, we collected 46 samples and two classifiers were established respectively for VPAC1 and VPAC2 receptors. The built classifiers are robust and predictive with high sensitivity, specificity and concordance for the prediction set. By analyzing the meanings of the used variables, we found that the electrostatic properties of VIP derivatives are vital in their interactions with VPAC receptors. Finally, these two classifiers were used to predict the bioactivities of novel VIPs, without experimental activities, which were suggested for experimental research groups to test their bioactivities and the possible practical applications in future.


Assuntos
Receptores Tipo II de Peptídeo Intestinal Vasoativo/agonistas , Receptores Tipo II de Peptídeo Intestinal Vasoativo/antagonistas & inibidores , Receptores Tipo I de Polipeptídeo Intestinal Vasoativo/agonistas , Receptores Tipo I de Polipeptídeo Intestinal Vasoativo/antagonistas & inibidores , Peptídeo Intestinal Vasoativo/química , Peptídeo Intestinal Vasoativo/farmacologia , Sequência de Aminoácidos , Simulação por Computador , Descoberta de Drogas , Humanos , Modelos Biológicos , Dados de Sequência Molecular , Relação Estrutura-Atividade
7.
Hippocampus ; 24(11): 1353-63, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24935659

RESUMO

Vasoactive intestinal peptide (VIP), an important modulator of hippocampal synaptic transmission, influences exploration and hippocampal-dependent learning in rodents. Homosynaptic long-term depression (LTD) and depotentiation are two plasticity phenomena implicated in learning of behavior flexibility and spatial novelty detection. In this study, we investigated the influence of endogenous VIP on LTD and depotentiation induced by low-frequency stimulation (1 Hz, 900 pulses) of the hippocampal CA1 area in vitro in juvenile and young adult rats, respectively. LTD and depotentiation were enhanced by the VIP receptor antagonist Ac-Tyr(1) , D-Phe(2) GRF (1-29), and the selective VPAC1 receptor antagonist, PG 97-269, but not the selective VPAC2 receptor antagonist, PG 99-465. This action was mimicked by an anti-VIP antibody, suggesting that VIP, and not pituitary adenylate cyclase-activating polypeptide (PACAP), is the endogenous mediator of these effects. Selective inhibition of PAC1 receptors with PACAP (6-38) enhanced depotentiation, but not LTD. VPAC1 receptor blockade also revealed LTD in young adult rats, an effect abolished by the GABAA antagonist bicuculline, evidencing an involvement of GABAergic transmission. We conclude that inhibition of LTD and depotentiation by endogenous VIP occurs through VPAC1 receptor-mediated mechanisms and suggest that disinhibition of pyramidal cell dendrites is the most likely physiological mechanism underlying this effect. As such, VPAC1 receptor ligands may be considered promising pharmacological targets for treatment of cognitive dysfunction in diseases involving altered GABAergic circuits and pathological saturation of LTP/LTD like Down's syndrome and temporal lobe epilepsy.


Assuntos
Região CA1 Hipocampal/fisiologia , Plasticidade Neuronal/fisiologia , Receptores Tipo I de Polipeptídeo Intestinal Vasoativo/metabolismo , Animais , Região CA1 Hipocampal/efeitos dos fármacos , Região CA1 Hipocampal/crescimento & desenvolvimento , Fármacos do Sistema Nervoso Central/farmacologia , Estimulação Elétrica , Masculino , Plasticidade Neuronal/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/farmacologia , Ratos Wistar , Receptores de Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/metabolismo , Receptores Tipo II de Peptídeo Intestinal Vasoativo/antagonistas & inibidores , Receptores Tipo II de Peptídeo Intestinal Vasoativo/metabolismo , Receptores Tipo I de Polipeptídeo Intestinal Vasoativo/antagonistas & inibidores , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia , Técnicas de Cultura de Tecidos , Peptídeo Intestinal Vasoativo/farmacologia
8.
J Med Chem ; 55(13): 6137-48, 2012 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-22708876

RESUMO

A potent, selective glucagon receptor antagonist 9m, N-[(4-{(1S)-1-[3-(3,5-dichlorophenyl)-5-(6-methoxynaphthalen-2-yl)-1H-pyrazol-1-yl]ethyl}phenyl)carbonyl]-ß-alanine, was discovered by optimization of a previously identified lead. Compound 9m is a reversible and competitive antagonist with high binding affinity (IC(50) of 6.6 nM) and functional cAMP activity (IC(50) of 15.7 nM). It is selective for glucagon receptor relative to other family B GPCRs, showing IC(50) values of 1020 nM for GIPR, 9200 nM for PAC1, and >10000 nM for GLP-1R, VPAC1, and VPAC2. Compound 9m blunted glucagon-induced glucose elevation in hGCGR mice and rhesus monkeys. It also lowered ambient glucose levels in both acute and chronic mouse models: in hGCGR ob/ob mice it reduced glucose (AUC 0-6 h) by 32% and 39% at 3 and 10 mpk single doses, respectively. In hGCGR mice on a high fat diet, compound 9m at 3, and 10 mpk po in feed lowered blood glucose levels by 89% and 94% at day 10, respectively, relative to the difference between the vehicle control and lean hGCGR mice. On the basis of its favorable biological and DMPK properties, compound 9m (MK-0893) was selected for further preclinical and clinical evaluations.


Assuntos
Glicemia/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucagon/metabolismo , Pirazóis/farmacologia , Receptores de Glucagon/antagonistas & inibidores , beta-Alanina/análogos & derivados , Animais , Área Sob a Curva , Células CHO , Cricetinae , Cricetulus , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Cães , Receptor do Peptídeo Semelhante ao Glucagon 1 , Humanos , Concentração Inibidora 50 , Macaca mulatta , Camundongos , Camundongos Obesos , Microssomos Hepáticos/metabolismo , Pirazóis/química , Pirazóis/uso terapêutico , Ratos , Receptores dos Hormônios Gastrointestinais/antagonistas & inibidores , Receptores de Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/antagonistas & inibidores , Receptores Tipo II de Peptídeo Intestinal Vasoativo/antagonistas & inibidores , Receptores Tipo I de Polipeptídeo Intestinal Vasoativo/antagonistas & inibidores , beta-Alanina/química , beta-Alanina/farmacologia , beta-Alanina/uso terapêutico
10.
Am J Physiol Gastrointest Liver Physiol ; 302(3): G352-8, 2012 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-22075777

RESUMO

Glucagon-like peptide-1 (GLP-1) acts at the G protein-coupled receptor, GLP-1R, to stimulate secretion of insulin and to inhibit secretion of glucagon and gastric acid. Involvement in mucosal secretory physiology has received negligible attention. We aimed to study involvement of GLP-1 in mucosal chloride secretion in the small intestine. Ussing chamber methods, in concert with transmural electrical field stimulation (EFS), were used to study actions on neurogenic chloride secretion. ELISA was used to study GLP-1R effects on neural release of acetylcholine (ACh). Intramural localization of GLP-1R was assessed with immunohistochemistry. Application of GLP-1 to serosal or mucosal sides of flat-sheet preparations in Ussing chambers did not change baseline short-circuit current (I(sc)), which served as a marker for chloride secretion. Transmural EFS evoked neurally mediated biphasic increases in I(sc) that had an initial spike-like rising phase followed by a sustained plateau-like phase. Blockade of the EFS-evoked responses by tetrodotoxin indicated that the responses were neurally mediated. Application of GLP-1 reduced the EFS-evoked biphasic responses in a concentration-dependent manner. The GLP-1 receptor antagonist exendin-(9-39) suppressed this action of GLP-1. The GLP-1 inhibitory action on EFS-evoked responses persisted in the presence of nicotinic or vasoactive intestinal peptide receptor antagonists but not in the presence of a muscarinic receptor antagonist. GLP-1 significantly reduced EFS-evoked ACh release. In the submucosal plexus, GLP-1R immunoreactivity (IR) was expressed by choline acetyltransferase-IR neurons, neuropeptide Y-IR neurons, somatostatin-IR neurons, and vasoactive intestinal peptide-IR neurons. Our results suggest that GLP-1R is expressed in guinea pig submucosal neurons and that its activation leads to a decrease in neurally evoked chloride secretion by suppressing release of ACh at neuroepithelial junctions in the enteric neural networks that control secretomotor functions.


Assuntos
Cloretos/metabolismo , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Mucosa Intestinal/inervação , Mucosa Intestinal/metabolismo , Intestino Delgado/metabolismo , Acetilcolina/metabolismo , Animais , Carbacol/farmacologia , Colina O-Acetiltransferase/metabolismo , Citoplasma/metabolismo , Proteínas ELAV/metabolismo , Condutividade Elétrica , Estimulação Elétrica , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Fenômenos Eletrofisiológicos/fisiologia , Peptídeo 1 Semelhante ao Glucagon/antagonistas & inibidores , Receptor do Peptídeo Semelhante ao Glucagon 1 , Cobaias , Hexametônio/farmacologia , Íleo/efeitos dos fármacos , Íleo/inervação , Íleo/metabolismo , Técnicas In Vitro , Mucosa Intestinal/efeitos dos fármacos , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/inervação , Masculino , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neuropeptídeo Y/metabolismo , Fragmentos de Peptídeos/farmacologia , Receptores de Glucagon/metabolismo , Receptores Tipo I de Polipeptídeo Intestinal Vasoativo/antagonistas & inibidores , Escopolamina/farmacologia , Somatostatina/metabolismo , Peptídeo Intestinal Vasoativo/metabolismo , Peptídeo Intestinal Vasoativo/farmacologia
11.
Cephalalgia ; 31(2): 181-9, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20974589

RESUMO

OBJECTIVE: We pharmacologically characterized pituitary adenylate cyclase-activating polypeptides (PACAPs), vasoactive intestinal peptide (VIP) and the VPAC(1), VPAC(2) and PAC(1) receptors in human meningeal (for their role in migraine) and coronary (for potential side effects) arteries. METHODS: Concentration response curves to PACAP38, PACAP27, VIP and the VPAC(1) receptor agonist ([Lys15,Arg16,Leu27]-VIP[1-7]-GRF[8-27]) were constructed in the absence or presence of the PAC(1) receptor antagonist PACAP6-38 or the VPAC(1) receptor antagonist, PG97269. mRNA expression was measured using qPCR. RESULTS: PACAP38 was less potent than VIP in both arteries. Both peptides had lower potency and efficacy in meningeal than in coronary arteries, while mRNA expression of VPAC(1) receptor was more pronounced in meningeal arteries. PACAP6-38 reduced the E(max) of PACAP27, while PG97269 right-shifted the VIP-induced relaxation curve only in the coronary arteries. CONCLUSION: The direct vasodilatory effect of VIP and PACAP might be less relevant than the central effect of this compound in migraine pathogenesis.


Assuntos
Vasos Coronários/fisiologia , Artérias Meníngeas/fisiologia , Transtornos de Enxaqueca/fisiopatologia , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase , Receptores de Peptídeo Intestinal Vasoativo , Adulto , Idoso , Vasos Coronários/efeitos dos fármacos , Feminino , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/fisiologia , Humanos , Masculino , Artérias Meníngeas/efeitos dos fármacos , Pessoa de Meia-Idade , Transtornos de Enxaqueca/tratamento farmacológico , Fragmentos de Peptídeos/farmacologia , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/efeitos adversos , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/antagonistas & inibidores , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/genética , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/farmacologia , RNA Mensageiro/metabolismo , Receptores de Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/agonistas , Receptores de Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/antagonistas & inibidores , Receptores de Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/genética , Receptores de Peptídeo Intestinal Vasoativo/agonistas , Receptores de Peptídeo Intestinal Vasoativo/antagonistas & inibidores , Receptores de Peptídeo Intestinal Vasoativo/genética , Receptores Tipo II de Peptídeo Intestinal Vasoativo/agonistas , Receptores Tipo II de Peptídeo Intestinal Vasoativo/antagonistas & inibidores , Receptores Tipo II de Peptídeo Intestinal Vasoativo/genética , Receptores Tipo I de Polipeptídeo Intestinal Vasoativo/agonistas , Receptores Tipo I de Polipeptídeo Intestinal Vasoativo/antagonistas & inibidores , Receptores Tipo I de Polipeptídeo Intestinal Vasoativo/genética , Peptídeo Intestinal Vasoativo/análogos & derivados , Peptídeo Intestinal Vasoativo/farmacologia , Vasodilatação/efeitos dos fármacos , Vasodilatação/fisiologia , Vasodilatadores/farmacologia
12.
Br J Haematol ; 151(1): 54-61, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20735399

RESUMO

Megakaryocytes and platelets express the stimulatory G protein (Gs)-coupled VPAC1 receptor, for which the pituitary adenylyl cyclase-activating peptide (PACAP) and vasoactive intestinal peptide (VIP) are agonists. The neuropeptide PACAP and VPAC1 were previously found to negatively regulate megakaryopoiesis, and inhibition of their physiological pathway was found to have a thrombopoietic effect in conditions where megakaryopoiesis and thrombopoiesis were impaired, such as chemotherapy-induced thrombocytopenia and congenital thrombocytopenia. The present study explored the thrombopoietic effect of VPAC1 inhibition in a murine model of syngeneic bone marrow transplantation (BMT) and in passive immune thrombocytopenia. Treatment of donor mice with a neutralizing anti-VPAC1 antibody stimulated the initial, most critical recovery of the platelets in irradiated mice. In the passive immune thrombocytopenia model, we observed a thrombopoietic effect, resulting in a less severe platelet drop after induction of their removal in the spleen by an anti-platelet antibody. We concluded that inhibition of the physiological PACAP/VPAC1 pathway could stimulate in vivo megakaryopoiesis. This inhibition can be applied to attenuate thrombocytopenia in conditions where platelets are destroyed as the major pathogenetic mechanism, e.g. immune thrombocytopenia purpura, or need to be produced de novo, e.g. after irradiation and BMT.


Assuntos
Receptores Tipo I de Polipeptídeo Intestinal Vasoativo/antagonistas & inibidores , Trombocitopenia/terapia , Trombopoese/fisiologia , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/uso terapêutico , Transplante de Medula Óssea , Células Cultivadas , Modelos Animais de Doenças , Feminino , Humanos , Megacariócitos/ultraestrutura , Camundongos , Camundongos Endogâmicos C57BL , Contagem de Plaquetas , Púrpura Trombocitopênica Idiopática/fisiopatologia , Púrpura Trombocitopênica Idiopática/terapia , Receptores Tipo I de Polipeptídeo Intestinal Vasoativo/fisiologia , Transdução de Sinais , Trombocitopenia/fisiopatologia , Irradiação Corporal Total
13.
Peptides ; 31(8): 1517-22, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20452385

RESUMO

Recent studies have suggested the potential use of vasoactive intestinal peptide (VIP) in the treatment of pulmonary arterial hypertension (PAH). An understanding of the mechanism of action of VIP is important for the development of new therapies for PAH. The biological effects of VIP are mediated by two type II guanine nucleotide binding protein (G-protein)-coupled receptors VIP/PACAP (pituitary adenylate cyclase activating peptide) receptor type1 (VPAC1) and VIP/PACAP receptor type 2 (VPAC2). In the present study, the distribution and role of these receptors were investigated and compared in cultured smooth muscle cells from rat aorta and pulmonary artery, as well as in fixed tissue sections of the aorta and pulmonary artery. Western blot analysis, RT-PCR and immunohistochemistry showed the expression of both VIP receptors in tissue sections of the aorta and pulmonary artery as well as in cultured smooth muscle cells from these vessels. The application of a specific antagonist of VPAC1 resulted in a small release from VIP induced inhibition of cell proliferation. In contrast (VIP 6-28; 300nM) which is an antagonist against both receptors resulted in a significant restoration of proliferation. The expression of cAMP was reduced in the presence of VIP 6-28 and slightly decreased by VPAC1 antagonist. These findings suggest a dual role for VPAC1 and VPAC2 receptors in mediating the antiproliferative effects of VIP with VPAC2 appearing to play a more dominant role.


Assuntos
Aorta/metabolismo , Proliferação de Células/efeitos dos fármacos , Miócitos de Músculo Liso/fisiologia , Artéria Pulmonar/metabolismo , Receptores Tipo II de Peptídeo Intestinal Vasoativo/fisiologia , Receptores Tipo I de Polipeptídeo Intestinal Vasoativo/fisiologia , Peptídeo Intestinal Vasoativo/fisiologia , Animais , Aorta/citologia , Western Blotting , Células Cultivadas , AMP Cíclico/metabolismo , Expressão Gênica , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/fisiopatologia , Imuno-Histoquímica , Masculino , Fragmentos de Peptídeos/farmacologia , Artéria Pulmonar/citologia , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores Tipo II de Peptídeo Intestinal Vasoativo/antagonistas & inibidores , Receptores Tipo II de Peptídeo Intestinal Vasoativo/genética , Receptores Tipo I de Polipeptídeo Intestinal Vasoativo/antagonistas & inibidores , Receptores Tipo I de Polipeptídeo Intestinal Vasoativo/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa
14.
Am J Physiol Gastrointest Liver Physiol ; 297(4): G716-25, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19661154

RESUMO

We tested the hypothesis that spontaneous release of vasoactive intestinal peptide (VIP) from enteric neurons maintains homeostasis in smooth muscle function in mild inflammatory insults and that infusion of exogenous VIP has therapeutic effects on colonic smooth muscle dysfunction in inflammation. In vitro experiments were performed on human colonic circular smooth muscle tissues and in vivo on rats. The incubation of human colonic circular smooth muscle strips with TNF-alpha suppressed their contractile response to ACh and the expression of the pore-forming alpha(1C) subunit of Ca(v)1.2 channels. VIP reversed both effects by blocking the translocation of NF-kappaB to the nucleus and its binding to the kappaB recognition sites on halpha(1C)1b promoter. The translocation of NF-kappaB was inhibited by blocking the degradation of IkappaBbeta. Induction of inflammation by a subthreshold dose of 17 mg/kg trinitrobenzene sulfonic acid (TNBS) in rats moderately decreased muscularis externa concentration of VIP, and it had little effect on the contractile response of circular smooth muscle strips to ACh. The blockade of VIP and pituitary adenylate cyclase-activating peptide receptors 1/2 during mild inflammatory insult significantly worsened the suppression of contractility and the inflammatory response. The induction of more severe inflammation by 68 mg/kg TNBS induced marked suppression of colonic circular muscle contractility and decrease in serum VIP. Exogenous infusion of VIP by an osmotic pump reversed these effects. We conclude that the spontaneous release of VIP from the enteric motor neurons maintains homeostasis in smooth muscle function in mild inflammation by blocking the activation of NF-kappaB. The infusion of exogenous VIP mitigates colonic inflammatory response and smooth muscle dysfunction.


Assuntos
Colite/metabolismo , Colo/inervação , Sistema Nervoso Entérico/metabolismo , Mediadores da Inflamação/metabolismo , Músculo Liso/inervação , Neuroimunomodulação , Peptídeo Intestinal Vasoativo/metabolismo , Acetilcolina/farmacologia , Transporte Ativo do Núcleo Celular , Animais , Sítios de Ligação , Canais de Cálcio Tipo L/genética , Canais de Cálcio Tipo L/metabolismo , Células Cultivadas , Colite/induzido quimicamente , Colite/imunologia , Colite/fisiopatologia , Colite/prevenção & controle , Colo/efeitos dos fármacos , Colo/imunologia , Colo/fisiopatologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Sistema Nervoso Entérico/efeitos dos fármacos , Sistema Nervoso Entérico/imunologia , Sistema Nervoso Entérico/fisiopatologia , Homeostase , Antagonistas de Hormônios/farmacologia , Humanos , Proteínas I-kappa B/metabolismo , Técnicas In Vitro , Infusões Subcutâneas , Contração Muscular , Músculo Liso/efeitos dos fármacos , Músculo Liso/imunologia , Músculo Liso/fisiopatologia , NF-kappa B/metabolismo , Neuroimunomodulação/efeitos dos fármacos , Regiões Promotoras Genéticas , Ratos , Ratos Sprague-Dawley , Receptores Tipo II de Peptídeo Intestinal Vasoativo/antagonistas & inibidores , Receptores Tipo II de Peptídeo Intestinal Vasoativo/metabolismo , Receptores Tipo I de Polipeptídeo Intestinal Vasoativo/antagonistas & inibidores , Receptores Tipo I de Polipeptídeo Intestinal Vasoativo/metabolismo , Fatores de Tempo , Transfecção , Ácido Trinitrobenzenossulfônico , Fator de Necrose Tumoral alfa/metabolismo , Peptídeo Intestinal Vasoativo/administração & dosagem , Peptídeo Intestinal Vasoativo/farmacologia
15.
Am J Physiol Gastrointest Liver Physiol ; 295(1): G187-G196, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18467505

RESUMO

Recent findings show that the enteric neurotransmitter VIP enhances gene transcription of the alpha1C subunit of Cav1.2 (L-type) Ca2+ channels in the primary cultures of human colonic circular smooth muscle cells and circular smooth muscle strips. In this study, we investigated whether systemic infusion of VIP in intact animals enhances the gene transcription and protein expression of these channels to accelerate colonic transit. We also investigated whether similar systemic infusions of VPAC1/2 receptor antagonist retards colonic transit by repressing the constitutive gene expression of the alpha1C subunit. We found that the systemic infusion of VIP for 7 days by a surgically implanted osmotic pump enhances the gene and protein expression of the alpha1C subunit and circular muscle contractility in the proximal and the middle rat colons, but not in the distal colon. A similar systemic infusion of VPAC1/2 receptor antagonist represses the expression of the alpha1C subunit and circular smooth muscle contractility in the proximal and the middle colons. The VIP infusion accelerates colonic transit and pellet defecation by rats, whereas the infusion of VPAC1/2 receptor antagonist retards colonic transit and pellet defecation. VPAC1 receptors, but not VPAC2 receptors, mediate the above gene transcription-induced promotility effects of VIP. We conclude that VIP and VPAC(1) receptor agonists may serve as potential promotility agents in constipation-like conditions, whereas VPAC receptor antagonists may serve as potential antimotility agents in diarrhea-like conditions produced by enhanced motility function.


Assuntos
Canais de Cálcio Tipo L/genética , Receptores Tipo II de Peptídeo Intestinal Vasoativo/agonistas , Receptores Tipo II de Peptídeo Intestinal Vasoativo/antagonistas & inibidores , Receptores Tipo I de Polipeptídeo Intestinal Vasoativo/agonistas , Receptores Tipo I de Polipeptídeo Intestinal Vasoativo/antagonistas & inibidores , Peptídeo Intestinal Vasoativo/farmacologia , Acetilcolina/metabolismo , Animais , Canais de Cálcio Tipo L/metabolismo , Colo/efeitos dos fármacos , Colo/fisiologia , Motilidade Gastrointestinal/efeitos dos fármacos , Regulação da Expressão Gênica , Terapia Genética , Bombas de Infusão Implantáveis , Masculino , Contração Muscular/efeitos dos fármacos , Contração Muscular/fisiologia , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiologia , Ratos , Ratos Sprague-Dawley , Água/metabolismo
16.
Peptides ; 29(3): 479-86, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17942192

RESUMO

Vasoactive intestinal peptide (VIP) binds to two receptors, VPAC1 and VPAC2. Non-selective VIP antagonists have been shown to inhibit human cancer cell proliferation and reduce tumor growth in mice. Many human cancers over-express VPAC1 but not VPAC2. We show that VPAC1-selective antagonists can inhibit human cancer cell proliferation and identify five positions in the VPAC1-selective antagonist PG 97-269 that may be responsible for VPAC1 selectivity. Position 16 appears to be particularly critical for selectivity, as demonstrated in the replacement of Arg16 of PG 97-269 with the native VIP amino acid; this single change results in greatly reduced VPAC1 binding and selectivity. Finally, we show that site-specific conjugation with a 22kDa polyethylene glycol (PEG) at the C-terminus of VPAC1-selective antagonists further improves VPAC1-selective binding and has minimal effect on antagonistic activity. Our studies have further solidified VPAC1 as a cancer target and offer the possibility of generating highly potent VPAC1-selective antagonists with minimal number of mutations to reduce the risk of immunogenicity and potentially prolonged duration of action to allow more efficient treatment regimen.


Assuntos
Proliferação de Células/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Polietilenoglicóis/química , Receptores Tipo I de Polipeptídeo Intestinal Vasoativo/antagonistas & inibidores , Sequência de Aminoácidos , Animais , Células CHO , Linhagem Celular Tumoral , Cricetinae , Cricetulus , Eletroforese em Gel de Poliacrilamida , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Dados de Sequência Molecular , Fragmentos de Peptídeos/química , Ligação Proteica/efeitos dos fármacos , Radioimunoensaio , Receptores Tipo I de Polipeptídeo Intestinal Vasoativo/genética , Receptores Tipo I de Polipeptídeo Intestinal Vasoativo/metabolismo , Homologia de Sequência de Aminoácidos , Relação Estrutura-Atividade , Peptídeo Intestinal Vasoativo/química , Peptídeo Intestinal Vasoativo/farmacologia
17.
Peptides ; 28(9): 1727-37, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17683829

RESUMO

Several reports have highlighted the potential roles for the VIP-related neuropeptides in regeneration/neuroprotection after brain or nerve injuries. We previously reported that peripheral inflammation worsened ibotenate-induced cystic white matter lesions. Because VIP is also known as an immunomodulator, we wonder if VIP could also limit the deleterious effects of local inflammation. Therefore, we first tested the effects of peripheral IL-1beta on VIP and PACAP central production. Second, we observed that cox-2 activation by IL-1beta was essential to generate changes in ligand/receptor gene expression. We further tested whether the intraperitoneal injection of IL-1beta, known to aggravate the ibotenate-induced lesions, could modify the expression pattern of VIP-related genes. Finally, we concluded using histological analysis that VIP[ala(11,22,28)], a synthetic VPAC(1) agonist completely reversed the aggravating effects of IL-1beta on ibotenate-induced lesions of the periventricular white matter. Conversely, VIP-neurotensin hybrid, a nonselective VIP receptor antagonist, worsened the lesions. All together, our results suggest that an activation of VIP/VPAC(1) signaling cascade in the vicinity of the injury site could circumvent the synergizing degenerative effects of ibotenate and pro-inflammatory cytokines. Therefore, development of therapeutic tools inducing/sustaining the activation of VIP/VPAC(1) signaling cascade may lead to future preventive treatments for inflammatory conditions during pregnancy.


Assuntos
Encéfalo/efeitos dos fármacos , Ácido Ibotênico/farmacologia , Inflamação/fisiopatologia , Receptores de Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/metabolismo , Peptídeo Intestinal Vasoativo/metabolismo , Animais , Animais Recém-Nascidos , Encéfalo/metabolismo , Encéfalo/patologia , Feminino , Expressão Gênica/efeitos dos fármacos , Inflamação/patologia , Interleucina-1beta/farmacologia , Masculino , Fragmentos de Peptídeos/farmacologia , Gravidez , Receptores de Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/genética , Receptores Tipo I de Polipeptídeo Intestinal Vasoativo/agonistas , Receptores Tipo I de Polipeptídeo Intestinal Vasoativo/antagonistas & inibidores , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Tempo , Peptídeo Intestinal Vasoativo/genética
18.
Peptides ; 28(9): 1631-9, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17574305

RESUMO

VIP and PACAP impact strongly on human pathophysiology. Their receptors are very promising targets for developing new drugs in the treatment of inflammatory and neurodegenerative diseases. This article reviews the present knowledge regarding VIP and PACAP receptors, i.e. VPAC1, VPAC2 and PAC1. This includes: (I) a critical review of instrumental peptide agonists and antagonists; (II) a survey of recent data regarding the structure of VPAC1 receptor and the docking of VIP in the receptor binding domain. Structural models for the VPAC2 and PAC1 receptor N-terminal ectodomains are also described; (III) A critical description of the two models of VPAC1 receptor activation in the general context of class II/family B G protein-coupled receptors.


Assuntos
Receptores de Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/química , Receptores Tipo II de Peptídeo Intestinal Vasoativo/química , Receptores Tipo I de Polipeptídeo Intestinal Vasoativo/química , Sequência de Aminoácidos , Animais , Humanos , Modelos Moleculares , Dados de Sequência Molecular , Estrutura Terciária de Proteína , Receptores de Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/agonistas , Receptores de Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/antagonistas & inibidores , Receptores Tipo II de Peptídeo Intestinal Vasoativo/agonistas , Receptores Tipo II de Peptídeo Intestinal Vasoativo/antagonistas & inibidores , Receptores Tipo I de Polipeptídeo Intestinal Vasoativo/agonistas , Receptores Tipo I de Polipeptídeo Intestinal Vasoativo/antagonistas & inibidores , Homologia de Sequência de Aminoácidos
19.
Neuropeptides ; 40(5): 349-55, 2006 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17030371

RESUMO

The present study investigated the potential role of vasoactive intestinal peptide (VIP) receptors, VPAC1 and VPAC2, in VIP-elicited coronary vasodilation of the isolated perfused rat heart. Additional studies determined the role of ATP-sensitive (K(ATP)) and voltage-gated K(+) (K(V)) channels in the VIP-elicited coronary vasodilation. Both the selective VPAC1 agonist, K15,R16,L27VIPl-7GRF8-27, and the selective VPAC2 agonist, RO25-1553, decreased coronary vascular resistance (CVR) in a dose-dependent manner, with EC(50) values of 1.67x10(-9)M and 7.11x10(-9)M, respectively (VPAC1 vs VPAC2 agonist, P<0.05). K15,R16,L27VIP1-7GRF8-27 and RO25-1553 maximally reduced CVR by -42+/-4% and -39+/-6% at 1x10(-8) and 3x10(-8)M, respectively. VIP at 1x10(-10)M decreased CVR by -14+/-2% in the absence (vehicle), by -11+/-3% in the presence of the nonselective VIP receptor antagonist VIP10-28 (1x10(-7)M; P>0.05 vs. vehicle) and by only -4+/-2% in the presence of the selective VPAC2 receptor antagonist PACAP6-38 (1x10(-7)M; P<0.05 vs. vehicle). In additional studies, VIP at 1x10(-10)M decreased CVR by -22+/-1% in the absence (control) and by only -10+/-2% in the presence of the nonselective K(+) channel blocker tetrabutylammonium (3x10(-4)M; P<0.05 vs. control). VIP reduced CVR by -4+/-1% in the presence of the K(ATP) channel blocker glibenclamide (3x10(-6)M; P<0.05 vs control) and by -28+/-2% in the presence of the K(V) channel blocker 4-aminopyridine (3x10(-4)M; P>0.05 vs control). Thus, selective VPAC1 and VPAC2 receptor activation in the coronary circulation produces vasodilation and the VIP-elicited coronary vasodilation involves activation of VPAC2 receptors and K(ATP) but not K(V) channels. In addition, VIP10-28 does not effectively block coronary vascular VIP receptors.


Assuntos
Circulação Coronária/efeitos dos fármacos , Vasos Coronários/efeitos dos fármacos , Coração/efeitos dos fármacos , Peptídeo Intestinal Vasoativo/farmacologia , Vasodilatação/efeitos dos fármacos , Animais , Técnicas In Vitro , Canais KATP , Masculino , Bloqueadores dos Canais de Potássio/farmacologia , Canais de Potássio Corretores do Fluxo de Internalização/efeitos dos fármacos , Canais de Potássio de Abertura Dependente da Tensão da Membrana/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptores Tipo II de Peptídeo Intestinal Vasoativo/agonistas , Receptores Tipo II de Peptídeo Intestinal Vasoativo/antagonistas & inibidores , Receptores Tipo II de Peptídeo Intestinal Vasoativo/genética , Receptores Tipo I de Polipeptídeo Intestinal Vasoativo/agonistas , Receptores Tipo I de Polipeptídeo Intestinal Vasoativo/antagonistas & inibidores , Receptores Tipo I de Polipeptídeo Intestinal Vasoativo/genética
20.
Neuropharmacology ; 51(6): 1086-98, 2006 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16930633

RESUMO

VPAC/PAC receptor activation classically results in cyclic-AMP production, with limited reports evaluating calcium signalling. These studies systematically characterise intracellular cyclic-AMP ([cAMP](i)) and calcium ([Ca(2+)](i)) responses in CHO-cells expressing recombinant human (h) VPAC/PAC receptors (hVPAC(1)R, hVPAC(2)R, hPAC(1)R), using two simple, non-radioactive, HT-amenable assays. The rank order of potency (ROP) of the agonists VIP, PACAP-27 and PACAP-38 was similar in both assays for each individual receptor subtype, although potencies (EC(50)) in the [Ca(2+)](i) assay were approximately 100-fold lower. Importantly, this shift was also evident in SHSY-5Y cells endogenously expressing hPAC(1)R. Furthermore, [Ala(11,22,28)]VIP and maxadilan were selective hVPAC(1)R and hPAC(1)R agonists, respectively, and although R3P65 had no demonstrable hVPAC(2)R selectivity, these compounds exhibited comparable reductions in [Ca(2+)](i) EC(50) values. In contrast, PG97-269 and PG99-465, putatively selective hVPAC(1)R and hVPAC(2)R antagonists, respectively, were marginally less potent in [cAMP](i) studies, whereas M65 was equipotent at hPAC(1)R. Moreover, PG99-465 alone increased [cAMP](i) at all three hVPAC/PAC receptor subtypes, with full hVPAC(1)R and hPAC(1)R agonism. With equivalent agonist ROPs generated in both assays, [Ca(2+)](i) signalling provides an alternative approach to examine hVPAC/PAC receptor pharmacology. However, these studies underscore the paucity of receptor selective compounds, complexities in comparing drug potencies across assays, and the pleiotropic nature of VPAC/PAC-receptor signalling.


Assuntos
Sinalização do Cálcio/efeitos dos fármacos , AMP Cíclico/fisiologia , Receptores Tipo II de Peptídeo Intestinal Vasoativo/efeitos dos fármacos , Receptores Tipo I de Polipeptídeo Intestinal Vasoativo/efeitos dos fármacos , Sequência de Aminoácidos , Animais , Células CHO , Linhagem Celular Tumoral , Células Cultivadas , Cricetinae , Interpretação Estatística de Dados , Ensaio de Imunoadsorção Enzimática , Humanos , Microscopia de Fluorescência , Dados de Sequência Molecular , Fármacos Neuroprotetores/farmacologia , Fragmentos de Peptídeos/farmacologia , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/farmacologia , Receptores Tipo II de Peptídeo Intestinal Vasoativo/agonistas , Receptores Tipo II de Peptídeo Intestinal Vasoativo/antagonistas & inibidores , Receptores Tipo I de Polipeptídeo Intestinal Vasoativo/agonistas , Receptores Tipo I de Polipeptídeo Intestinal Vasoativo/antagonistas & inibidores , Transfecção , Peptídeo Intestinal Vasoativo/análogos & derivados , Peptídeo Intestinal Vasoativo/farmacologia
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