RESUMO
Intracellular Ca(2+) signaling is important for stem cell differentiation and there is evidence it may coordinate the process. Arginine vasopressin (AVP) is a neuropeptide hormone secreted mostly from the posterior pituitary gland and increases Ca(2+) signals mainly via V1 receptors. However, the role of AVP in adipogenesis of human adipose-derived stem cells (hASCs) is unknown. In this study, we identified the V1a receptor gene in hASCs and demonstrated that AVP stimulation increased intracellular Ca(2+) concentration during adipogenesis. This effect was mediated via V1a receptors, Gq-proteins and the PLC-IP3 pathway. These Ca(2+) signals were due to endoplasmic reticulum release and influx from the extracellular space. Furthermore, AVP supplementation to the adipogenic medium decreased the number of adipocytes and adipocyte marker genes during differentiation. The effect of AVP on adipocyte formation was reversed by the V1a receptor blocker V2255. These findings suggested that AVP may function to inhibit adipocyte differentiation.
Assuntos
Adipogenia/efeitos dos fármacos , Tecido Adiposo/citologia , Arginina Vasopressina/farmacologia , Células-Tronco/citologia , Adipócitos/citologia , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Adulto , Idoso , Antagonistas dos Receptores de Hormônios Antidiuréticos/farmacologia , Arginina Vasopressina/análogos & derivados , Cálcio/metabolismo , Diferenciação Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Feminino , Humanos , Inositol 1,4,5-Trifosfato/metabolismo , Espaço Intracelular/metabolismo , Masculino , Pessoa de Meia-Idade , Receptores de Vasopressinas/genética , Receptores de Vasopressinas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Células-Tronco/efeitos dos fármacos , Células-Tronco/metabolismo , Fosfolipases Tipo C/metabolismoRESUMO
We recently reviewed the status of peptide and nonpeptide agonists and antagonists for the V(1a), V(1b) and V(2) receptors for arginine vasopressin (AVP) and the oxytocin receptor for oxytocin (OT). In the present review, we update the status of peptides and nonpeptides as: (i) research tools and (ii) therapeutic agents. We also present our recent findings on the design of fluorescent ligands for V(1b) receptor localisation and for OT receptor dimerisation. We note the exciting discoveries regarding two novel naturally occurring analogues of OT. Recent reports of a selective VP V(1a) agonist and a selective OT agonist point to the continued therapeutic potential of peptides in this field. To date, only two nonpeptides, the V(2) /V(1a) antagonist, conivaptan and the V(2) antagonist tolvaptan have received Food and Drug Administration approval for clinical use. The development of nonpeptide AVP V(1a), V(1b) and V(2) antagonists and OT agonists and antagonists has recently been abandoned by Merck, Sanofi and Pfizer. A promising OT antagonist, Retosiban, developed at Glaxo SmithKline is currently in a Phase II clinical trial for the prevention of premature labour. A number of the nonpeptide ligands that were not successful in clinical trials are proving to be valuable as research tools. Peptide agonists and antagonists continue to be very widely used as research tools in this field. In this regard, we present receptor data on some of the most widely used peptide and nonpeptide ligands, as a guide for their use, especially with regard to receptor selectivity and species differences.
Assuntos
Arginina Vasopressina/análogos & derivados , Arginina Vasopressina/uso terapêutico , Ocitocina/análogos & derivados , Ocitocina/uso terapêutico , Animais , Antagonistas dos Receptores de Hormônios Antidiuréticos , Arginina Vasopressina/agonistas , Arginina Vasopressina/antagonistas & inibidores , Ensaios Clínicos como Assunto , Avaliação Pré-Clínica de Medicamentos/métodos , Avaliação Pré-Clínica de Medicamentos/estatística & dados numéricos , Humanos , Ocitocina/agonistas , Ocitocina/antagonistas & inibidores , Receptores de Ocitocina/agonistas , Receptores de Ocitocina/antagonistas & inibidores , Receptores de Vasopressinas/agonistas , Relação Estrutura-AtividadeRESUMO
BACKGROUND: The objective of this study was to determine the pharmacological basis of the medicinal use of psyllium husk (Ispaghula) in gastrointestinal motility disorders. METHODS: In-vivo studies were conducted on mice, and isolated rabbit jejunum and guinea-pig ileum were used in in-vitro experiments. RESULTS: The crude extract of Ispaghula (Po.Cr) had a laxative effect in mice at 100 and 300 mg/kg, which was partially sensitive to atropine or SB203186 (5-HT(4) antagonist). At higher doses (500 and 1,000 mg/kg), Po.Cr had antisecretory and antidiarrheal activity. In guinea-pig ileum, Po.Cr (1-10 mg/ml) had a stimulatory effect, which was partially sensitive to atropine or SB203186. In rabbit jejunum, Po.Cr had a partially atropine-sensitive stimulatory effect followed by relaxation at 10 mg/ml. The relaxation was inhibited by the presence of L-NAME, a nitric oxide (NO) synthase inhibitor, or methylene blue, a guanylyl cyclase inhibitor. Similarly, the relaxant effect of Po.Cr on K(+) (80 mM)-induced contractions, was attenuated in the presence of L-NAME or methylene blue. Activity-directed fractionation of Po.Cr revealed that the gut stimulatory and inhibitory constituents were widely distributed in the aqueous and organic fractions. CONCLUSION: This study demonstrates that Ispaghula has a gut-stimulatory effect, mediated partially by muscarinic and 5-HT(4) receptor activation, which may complement the laxative effect of its fiber content, and a gut-inhibitory activity possibly mediated by blockade of Ca(2+) channels and activation of NO-cyclic guanosine monophosphate pathways. This may explain its medicinal use in diarrhea. It is, perhaps, also intended by nature to offset an excessive stimulant effect.
Assuntos
Constipação Intestinal/tratamento farmacológico , Diarreia/tratamento farmacológico , Psyllium/farmacologia , Animais , Arginina Vasopressina/análogos & derivados , Arginina Vasopressina/efeitos dos fármacos , Feminino , Cobaias , Jejuno/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Coelhos , Verapamil/farmacologiaRESUMO
We previously reported that vasopressin deficient Brattleboro (BRAT) rats exhibit deficits in prepulse inhibition (PPI) of the startle reflex that are consistent with PPI deficits exhibited by patients with schizophrenia and other neuropsychiatric disorders. Preliminary evidence indicates that this may be the basis of a predictive model for antipsychotic drug efficacy. Here we report the effects of acute and chronic administration of established and putative antipsychotics on these PPI deficits. BRAT rats, compared to their derivative strain, Long Evans rats, exhibited significantly decreased PPI and startle habituation consistent with patients with schizophrenia and other neuropsychiatric disorders. The second generation antipsychotics, risperidone and clozapine as well as a neurotensin agonist (PD149163) increased BRAT rat PPI, whereas saline, the typical antipsychotic, haloperidol, and a vasopressin analog (1-desamino-D-arginine vasopressin) did not. Similar to their effects in humans, chronic administration of antipsychotic drugs produced stronger effects than acute administration. These results further support the BRAT rat as a model of sensorimotor gating deficits with predictive validity for antipsychotics. The model appears to be able to differentiate first generation from second generation antipsychotics, identify putative antipsychotics with novel mechanisms (i.e., peptides) and reasonably model the therapeutic time course of antipsychotic drugs in humans.
Assuntos
Antipsicóticos/farmacologia , Arginina Vasopressina/fisiologia , Inibição Neural/efeitos dos fármacos , Reflexo de Sobressalto/efeitos dos fármacos , Esquizofrenia/tratamento farmacológico , Análise de Variância , Animais , Arginina Vasopressina/análogos & derivados , Arginina Vasopressina/deficiência , Arginina Vasopressina/genética , Clozapina/farmacologia , Desamino Arginina Vasopressina/farmacologia , Modelos Animais de Doenças , Esquema de Medicação , Avaliação Pré-Clínica de Medicamentos/métodos , Habituação Psicofisiológica/efeitos dos fármacos , Haloperidol/farmacologia , Neurotensina/análogos & derivados , Neurotensina/farmacologia , Ratos , Ratos Brattleboro , Ratos Long-Evans , Ratos Mutantes , Risperidona/farmacologia , Esquizofrenia/fisiopatologia , Estatísticas não ParamétricasRESUMO
We speculated that the influence of lateral preoptic area (LPO) in sodium balance, involves arginine8-vasopressin (AVP) and angiotensin (ANG II) on Na+ uptake in LPO. Therefore, the present study investigated the effects of central administration of specific AVP and ANG II antagonists (d(CH2)5-Tyr (Me)-AVP (AAVP) and [Adamanteanacetyl1, 0-ET-d-Tyr2, Val4, Aminobutyryl6, Arg(8,9)]-AVP (ATAVP) antagonists of V1 and V2 receptors of AVP. Also the effects of losartan and CGP42112A (selective ligands of the AT1 and AT2 angiotensin receptors, respectively), was investigated on Na+ uptake and renal fluid and electrolyte excretion. After an acclimatization period of 7 days, the animals were maintained under tribromoethanol (200 mg/kg body weight, intraperitonial) anesthesia and placed in a Kopf stereotaxic instrument. Stainless guide cannula was implanted into the LPO. AAVP and ATAVP injected into the LPO prior to AVP produced a reduction in the NaCl intake. Both the AT1 and AT2 ligands administered into the LPO elicited a decrease in the NaCl intake induced by AVP injected into the LPO. AVP injection into the LPO increased sodium renal excretion, but this was reduced by prior AAVP administration. The ATAVP produced a decreased in the natriuretic effect of AVP. The losartan injected into LPO previous to AVP decreased the sodium excretion and the CGP 421122A also decreased the natriuretic effect of AVP. The AVP produced an antidiuresis effect that was inhibited by prior administration into LPO of the ATAVP. The AAVP produced no change in the antidiuretic effect of AVP. These results suggest that LPO are implicated in sodium balance that is mediated by V1, V2, AT1 and AT2 receptors.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Antagonistas de Receptores de Angiotensina , Arginina Vasopressina/antagonistas & inibidores , Receptores de Vasopressinas/administração & dosagem , Sódio/metabolismo , Angiotensina II/antagonistas & inibidores , Animais , Arginina Vasopressina/análogos & derivados , Arginina Vasopressina/farmacologia , Arginina Vasopressina/fisiologia , Pressão Sanguínea , Relação Dose-Resposta a Droga , Hipotálamo/metabolismo , Injeções Intraventriculares , Losartan/farmacologia , Masculino , Oligopeptídeos/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de Angiotensina/fisiologiaRESUMO
Syrian hamsters are photoperiodic and become sexually quiescent when exposed to short "winter-like" photoperiods. In short photoperiods, male hamsters display significantly higher levels of aggression than males housed in long photoperiods. Arginine-vasopressin (AVP) within the anterior hypothalamus (AH) has been reported to modulate aggression in hamsters housed in long photoperiods. Previous studies have shown that AVP can facilitate aggression and its effects appear to be mediated by AVP V(1a) receptors (V(1a)R). In the present study, we investigated whether the increased levels of aggression observed after exposure to short photoperiod were the result of an increased responsiveness to AVP within the AH. Injections of AVP into the AH significantly increased aggression in hamsters housed in a long photoperiod, but had no effect in hamsters housed in a short photoperiod. In addition, injection of a V(1a)R antagonist into the AH significantly inhibited aggression in hamsters housed in long photoperiod, but had no effect in hamsters housed in a short photoperiod. These findings indicate that AVP within the AH increases aggression in hamsters housed in long photoperiods, but not in hamsters housed in short photoperiods.
Assuntos
Agressão/fisiologia , Arginina Vasopressina/análogos & derivados , Arginina Vasopressina/fisiologia , Hipotálamo/fisiologia , Fotoperíodo , Animais , Antagonistas dos Receptores de Hormônios Antidiuréticos , Arginina Vasopressina/administração & dosagem , Cricetinae , Antagonistas de Hormônios/farmacologia , Hipotálamo/efeitos dos fármacos , Masculino , Mesocricetus , MicroinjeçõesRESUMO
Subcutaneous or intracerebroventricular injection of either arginine8-vasopressin or desglycinamide9-arginine8-vasopressin has been shown to facilitate memory, reduce or reverse the effects of amnesic drugs, and maintain tolerance to some effects of ethanol. These actions of vasopressin (and, by inference, of desglycinamide9-arginine8-vasopressin) are mediated by vasopressin V1 receptors in brain, via a c-fos-dependent mechanism, but the receptors at which the desglycinamide analog acts have not been identified. The precise central sites are also not known, but evidence of several types suggested the anterior hypothalamus and septum as probable loci of vasopressin action. In the present work, this question was studied by immunocytochemistry, using antibodies against Fos and Fos-like proteins. The numbers of Fos-immunoreactive nuclei were counted in several related brain regions and structures, after administration of arginine8-vasopressin, des-Gly9-[Arg8]-vasopressin or saline. A subcutaneous injection of vasopressin, but not of saline, enhanced Fos expression in the paraventricular, supraoptic and suprachiasmatic nuclei of the hypothalamus, but the desglycinamide analog stimulated Fos expression only in the suprachiasmatic nucleus. Vasopressin injection significantly increased the number of Fos-immunoreactive cells in the intermediate lateral septum, medial septum, and dorsal and ventral divisions of the lateral septum. In contrast, the desglycinamide analog increased the numbers of Fos-immunoreactive cells in the dorsal and intermediate portions of the lateral septum, but caused no change in the medial septum, and a decrease in the ventral portion of the lateral septum. Increased Fos expression was also found in the subfornical organ after subcutaneous injection of either vasopressin or the desglycinamide analog. Double labeling with antibodies against Fos protein and against vasopressin revealed that most of the vasopressin-induced Fos-immunoreactive cells in the supraoptic, paraventricular and suprachiasmatic hypothalamic nuclei are also vasopressin immunoreactive, i.e. they are vasopressin-producing neurons. These findings suggest that a circuit involving V1 receptors in the subfornical organ, connecting fibres to the suprachiasmatic nucleus, and vasopressinergic projections from the suprachiasmatic nucleus to the lateral septum, may play a central role in mediating the actions of both vasopressin and its desglycinamide analog in the maintenance of ethanol tolerance.
Assuntos
Arginina Vasopressina/análogos & derivados , Arginina Vasopressina/farmacologia , Hipotálamo/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Septo Pelúcido/metabolismo , Animais , Imuno-Histoquímica , Masculino , Ratos , Ratos Sprague-Dawley , Órgão Subfornical/metabolismoRESUMO
1. Microinjection of the cholinergic agonist carbachol (3.3, 5.5 and 13.2 nmol) into the posterior hypothalamic nucleus of conscious rats evokes a dose-dependent increase in blood pressure. The pressor response evoked by the lower doses of carbachol was attenuated by pretreatment with the ganglionic nicotinic receptor antagonist pentolinium (10 mg kg(-1), i.v.) while blockade of V1-vasopressin receptors with [d(CH2)5Tyr(Me)]AVP (20 microg kg(-1), i.v.) reduced the pressor response evoked by the highest dose. 2. The combination of pentolinium and the muscarinic receptor antagonist methylatropine (2 mg kg(-1), i.v.) completely blocked the response evoked by the lower doses while the addition of [d(CH2)5Tyr(Me)]AVP to these two antagonists was required for further inhibition of the pressor response to the highest dose of carbachol. Bilateral adrenal demedullation did not affect the pressor response evoked by 5.5 or 13.2 nmol of carbachol. 3. Treatment of intact and adrenal demedullated rats with pentolinium after the pressor response to 13.2 nmol of carbachol was underway reversed the pressor response, but not to the same degree as that provided by the combination of pentolinium and methylatropine, or pentolinium and [d(CH2)5Tyr(Me)]AVP. 4. Methylatropine or [d(CH2)5Tyr(Me)]AVP caused a slight reversal of the carbachol-induced pressor response once it was underway in intact rats. Methylatropine given before or after pentolinium worked with the pentolinium to completely reverse the response. Methylatropine given alone reversed the bradycardia evoked by carbachol to a tachycardia which itself was antagonized by subsequent treatment with pentolinium. 5. These results suggest that the pressor response evoked by carbachol microinjection into the posterior hypothalamic nucleus of conscious rats involves sympathoexcitation and vasopressin release. The sympathoexcitation involves nicotinic and muscarinic receptors in autonomic ganglia.
Assuntos
Carbacol/farmacologia , Hipotálamo/efeitos dos fármacos , Agonistas Muscarínicos/farmacologia , Agonistas Nicotínicos/farmacologia , Medula Suprarrenal/cirurgia , Animais , Antagonistas dos Receptores de Hormônios Antidiuréticos , Arginina Vasopressina/análogos & derivados , Arginina Vasopressina/farmacologia , Derivados da Atropina/farmacologia , Carbacol/administração & dosagem , Bloqueadores Ganglionares/farmacologia , Hipotálamo/metabolismo , Masculino , Microinjeções , Agonistas Muscarínicos/administração & dosagem , Agonistas Nicotínicos/administração & dosagem , Parassimpatolíticos/farmacologia , Tartarato de Pentolínio/farmacologia , Ratos , Ratos Sprague-DawleyRESUMO
In situ hybridization and Northern blot assay were used to evaluate the effects of exogenous AVP(4-8) on the transcription of mRNAs for nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophin 3 (NT-3) in the adult rat brain. NGF and BDNF expression was found to be significantly enhanced by AVP(4-8) administration in the cerebral cortex and hippocampus, but NT-3 expression was not changed. In the same conditions, behavior-active arginine-vasopressin (AVP) showed a small effect and its behavior-inactive homologue, oxytocin did not. Our results suggest that selective regulation of neurotrophin gene expression by the peptides may be responsible for its memory-enhancing function.
Assuntos
Arginina Vasopressina/análogos & derivados , Fator Neurotrófico Derivado do Encéfalo/biossíntese , Encéfalo/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Fatores de Crescimento Neural/biossíntese , Fragmentos de Peptídeos/farmacologia , Animais , Arginina Vasopressina/farmacologia , Northern Blotting , Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/genética , DNA Complementar/genética , Hibridização In Situ , Masculino , Fatores de Crescimento Neural/genética , Neurotrofina 3 , Ácido Pirrolidonocarboxílico/análogos & derivados , RNA Antissenso/genética , RNA Mensageiro/biossíntese , Ratos , Ratos Wistar , Transcrição GênicaRESUMO
Increased plasma osmolality results in increased central as well as peripheral release of vasopressin. Experiments were carried out to determine whether, in this circumstance, vasopressin can act centrally to modulate its peripheral release. Prior to the start of a thirty-min i.v. infusion of 2.5 M or 0.15 M NaCl, the rats were given an intracerebroventricular (i.c.v.) injection of a peptide V1/V2 vasopressin antagonist (2 micrograms), OPC-31260 (60 micrograms), a non-peptide V2 antagonist, or 1-desamino-8-D-arginine vasopressin (dDAVP, 5 ng), a V2 agonist. Experiments with the peptide antagonist were carried out in male and non-estrous female rats. Since there were no differences between males and females in the measured responses, experiments with the other two drugs were carried out only in males. Pretreatment with either the V1/V2 antagonist or the V2 antagonist enhanced the increase in plasma vasopressin levels in response to the hypertonic saline infusion by about 50% at the end of 30 min. dDAVP, on the other hand, had no effect. None of the i.c.v. drugs had an affect on either the pressor or bradycardic responses to hypertonic saline infusion. These observations suggest that vasopressin can act centrally in a negative feedback fashion to attenuate its own release into the peripheral circulation in response to increased plasma osmolality.
Assuntos
Antagonistas dos Receptores de Hormônios Antidiuréticos , Benzazepinas/farmacologia , Desamino Arginina Vasopressina/farmacologia , Caracteres Sexuais , Vasopressinas/metabolismo , Animais , Arginina Vasopressina/análogos & derivados , Arginina Vasopressina/farmacologia , Avaliação Pré-Clínica de Medicamentos , Retroalimentação , Feminino , Antagonistas de Hormônios/farmacologia , Injeções Intraventriculares , Masculino , Concentração Osmolar , Ratos , Ratos Sprague-Dawley , Receptores de Vasopressinas/agonistas , Cloreto de Sódio/farmacologiaRESUMO
We have investigated the effects of mono-substitutions with the conformationally restricted amino acid, 1,2,3,4 tetrahydroisoquinoline-3-carboxylic acid (Tic) at position 3 in arginine vasopressin (AVP), at positions 2, 3 and 7 in potent non-selective cyclic AVP V2/V1a antagonists, in potent and selective cyclic and linear AVP V1a antagonists, in a potent and selective oxytocin antagonist and in a new potent linear oxytocin antagonist Phaa-D-Tyr(Me)-Ile-Val-Asn-Orn-Pro-Orn-NH2 (10). We report here the solid-phase synthesis of peptide 10 together with the following Tic-substituted peptides: 1. [Tic3]AVP: 2. dICH2)5[D-TIc2]VAVP: 3, d(CH2)5[D-Tyr(Et)2Tic3]VAVP: 4, d(CH2)5[Tic2Ala-NH2(9)]AVP: 5. d(CH2)5[Tyr]Me)2.Tic3,Ala-NH2(9)]AVP: 6. d(CH2)5 [Tyr(Me)2,Tic7]AVP: 7, Phaa-D-Tyr(Me)-Phe-Gln-Asn-Lys-Tic-Arg-NH2: 8, desGly-NH2,d[CH2]5[Tic2,Thr4]OVT: 9. desGly-NH2d(CH2)5[Tyr(Me)2Thr4, Tic7[OVT; 11, Phaa-D-Tic-Ile-Val-Asn-Orn-Pro-Orn-NH2, using previously described methods. The protected precursors were synthesized by the solid-phase method, cleaved, purified and deblocked with sodium in liquid ammonia to give the free peptides 1-11 which were purified by methods previously described. Peptides 1-11 were examined for agonistic and antagonistic potency in oxytocic (in vitro, without Mg2+) and AVP antidiuretic (V2-receptor) and vasopressor (V1a-receptor) assays. Tic3 substitution in AVP led to drastic losses of V2, V1a and oxytocic agonistic activities in peptide 1, L- and D-Tic2 substitutions led to drastic losses of anti-V2/anti-V1a and anti-oxytocic potencies in peptides 2, 4, 8 and 11 (peptide 2 retained substantial anti-oxytocic potency; pA2 = 7.25 +/- 0.025). Whereas Tic3 substitution in the selective V1a antagonist d(CH2)5[Tyr(Me)2,Ala-NH2(9)]AVP(C) led to a drastic reduction in anti-V1a potency (from anti-V1a pA2 8.75 to 6.37 for peptide 5, remarkably, Tic3 substitution in the V2/V1a antagonist d(CH2)5(D-Tyr(Et)2]VAVP(B) led to full retention of anti-V2 potency and a 95% reduction in anti-V1a potency. With an anti-V2 pA2 = 7.69 +/- 0.05 and anti-V1a pA2 = 6.95 +/- 0.03. d(CH2)5[D-Tyr(Et)2, Tic3]VAVP exhibits a 13-fold gain in anti-V2/anti-V1a selectivity compared to (B). Tic7 substitutions are very well tolerated in peptides 6, 7 and 9 with excellent retention of the characteristic potencies of the parent peptides. The findings on the effects of Tic3 substitutions reported here may provide promising leads to the design of more selective and possibly orally active V2 antagonists for use as pharmacological tools and as therapeutic clinical agents for the treatment of the syndrome of the inappropriate secretion of antidiuretic hormone (SIADH).
Assuntos
Arginina Vasopressina/análogos & derivados , Arginina Vasopressina/antagonistas & inibidores , Isoquinolinas/química , Ocitocina/análogos & derivados , Ocitocina/antagonistas & inibidores , Tetra-Hidroisoquinolinas , Vasopressinas/antagonistas & inibidores , Vasopressinas/síntese química , Sequência de Aminoácidos , Animais , Arginina Vasopressina/síntese química , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Técnicas In Vitro , Métodos , Estrutura Molecular , Ocitocina/síntese química , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Vasopressinas/químicaRESUMO
Arginine-vasopressin (AVP) is regarded as a potent stimulator of pituitary adrenocorticotropin (ACTH) secretion and participates therefore in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis function in concert with the physiological activator of the axis, hypothalamic corticotropin-releasing hormone (CRH). We examined the effects of AVP and/or three synthetic V1b receptor antagonists on the activity of the HPA axis in vivo and in vitro in the rat. AVP was injected intravenously to Sprague-Dawley rats (1 microgram/rat) through an indwelling jugular catheter. AVP stimulated ACTH release, with maximal effect 10 min after injection. Intravenous injection of three V1b antagonists, [1-(beta-mercapto-beta,beta-cyclopentamethylenepropionic acid), 2-O-ethyltyrosine, 4-valine] arginine vasopressin (d(CH2)5[Tyr(Et2)]VAVP (WK 1-1), 9-desglycine[1-(beta-mercapto-beta,beta- cyclopentamethylenepropionic acid), 2-O-ethyltyrosine, 4-valine] arginine vasopressin desGly9d(CH2)5 [Tyr(Et2)]-VAVP (WK 3-6), and 9-desglycine [1-(beta-mercapto-beta,beta- cyclopentamethylenepropionic acid),2-D-(O-ethyl)tyrosine, 4-valine ] arginine vasopressin des Gly9d(CH2)5[D-Tyr(Et2)]VAVP (AO 3-21), prevented AVP-stimulated ACTH secretion. Explanted rat hypothalami incubated in vitro with graded concentrations of AVP (10(-14)-10(-5) M) secreted immunoreactive CRH (iCRH) in a concentration-dependent fashion. Maximal stimulatory effect occurred at the concentration of 10(-6) M. Incubation of hypothalami with WK 1-1, WK3-6, or AO 3-21 (10(-6) M) prevented AVP-stimulated iCRH secretion. Results suggest that AVP plays a relevant, multiple role in the activation of the HPA axis in the rat.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Glândulas Suprarrenais/efeitos dos fármacos , Antagonistas dos Receptores de Hormônios Antidiuréticos , Hipotálamo/efeitos dos fármacos , Hipófise/efeitos dos fármacos , Glândulas Suprarrenais/fisiologia , Hormônio Adrenocorticotrópico/metabolismo , Animais , Arginina Vasopressina/análogos & derivados , Arginina Vasopressina/farmacologia , Hormônio Liberador da Corticotropina/metabolismo , Hipotálamo/fisiologia , Técnicas In Vitro , Injeções Intravenosas , Cinética , Masculino , Hipófise/fisiologia , Ratos , Ratos Sprague-DawleyRESUMO
Vasopressin and its fragment peptides such as [pGlu4, Cyt6]AVP(4-9) (AVP(4-9) represent putative neuromodulators within central nervous homeostatic, memory and behavioural circuits. To localize their central receptor systems, the previously characterized monoclonal anti-idiotypic antibody mAb 237 was employed in immunocytological investigations of rat brain tissue sections. This antibody was raised to the monoclonal idiotypic anti-AVP antibody mAb 113 which preferentially binds to the acyclic C-terminal portion of the AVP molecule and is therefore also capable of binding the naturally occurring AVP(4-9) fragment. Immunoreactive magnocellular neurones were detected in the AVP-synthesizing supraoptic but not paraventricular nuclei. Dense staining was observed within circumventricular organs lacking a blood-brain barrier (BBB). These structures include the subfornical organ, the organum vasculosum laminae terminalis, the internal layer of the median eminence, the body of the pineal gland, the choroid plexus and the area postrema, where immunoreactivity was found on capillaries, neurones and fibres. Further staining was found in the nucleus of the solitari tract and the arcuate nucleus, endowed with a leaky BBB. Distinct cell patches in the ependymal lining of the third ventricle as well as dendritic processes of juxtaependymal neurones were labelled by the anti-idiotypic antibody mAb 237. The observed staining pattern did not parallel that obtained in autoradiographic studies performed using either radiolabelled AVP or a V1-receptor antagonist, but that found with the [35S]-labelled AVP(4-9) fragment. Using [35S]-labelled AVP(4-9) fragment, specific high density binding sites could be localized autoradiographically in structures within and outside the BBB, in complete agreement with the anti-idiotypic immunoreactivity. Since the anti-idiotypic methodology is based on transfer of complementary structures, and the epitope recognized by the corresponding idiotypic antibody resembles the sequence of AVP(4-9), the anti-idiotypic antibodies might recognize the AVP(4-9) receptor with high affinity.
Assuntos
Arginina Vasopressina/análogos & derivados , Arginina Vasopressina/metabolismo , Química Encefálica/fisiologia , Encéfalo/anatomia & histologia , Fragmentos de Peptídeos/metabolismo , Receptores de Vasopressinas/metabolismo , Vasopressinas/metabolismo , Animais , Anticorpos Monoclonais , Autorradiografia , Ensaio de Imunoadsorção Enzimática , Epitopos , Feminino , Imuno-Histoquímica , Masculino , Ácido Pirrolidonocarboxílico/análogos & derivados , Ratos , Ratos Wistar , Radioisótopos de EnxofreRESUMO
1. In spontaneously breathing rats anaesthetized with Saffan, we have investigated the role of vasopressin in the cardiovascular responses evoked by systemic hypoxia (breathing 8 or 6% O2 for 5 min). 2. Breathing 8% O2 evoked an increase in respiratory frequency and tidal volume; arterial O2 pressure (Pa,O2) fell to 37 mmHg and arterial CO2 pressure (Pa,CO2) fell to 30 mmHg. Concomitantly, there was a fall in arterial pressure, tachycardia and increases in femoral and renal vascular conductances indicating net vasodilatation in skeletal muscle and kidney. The vasopressin V1-receptor antagonist, d(CH2)5Tyr(Me)-arginine vasopressin (20 micrograms kg-1 i.v.), had no significant effect on the baseline values of any recorded variables, nor on the respiratory or blood gas changes evoked by 8% O2. However, it accentuated the fall in arterial pressure and the increase in femoral vascular conductance (+22 vs. +77% at the 5th minute) produced by 8% O2, but had no significant effect on the increase in renal vascular conductance. 3. Breathing 6% O2 evoked qualitatively similar responses as 8% O2 but Pa,O2 fell to 33 mmHg and Pa,CO2 fell to 28 mmHg and the respiratory and cardiovascular changes tended to be larger than those evoked by 8% O2. Again the V1-receptor antagonist accentuated the hypoxia-induced fall in arterial pressure and increase in femoral vascular conductance (+5 vs. +76% at the 5th minute). 4. Infusion of vasopressin (1.5 ng min-1 kg-1 i.v.) for 5 min with the aim of producing a plasma concentration comparable to that reached during 8% O2, induced a rise in arterial pressure (9%), bradycardia (-5%) and a decrease in femoral (-11%) and renal vascular conductance (-4%). 5. These results suggest that vasopressin released during hypocapnic hypoxia helps to limit the evoked fall in arterial pressure by exerting a vasoconstrictor influence on skeletal muscle.
Assuntos
Hemodinâmica/fisiologia , Hipóxia/fisiopatologia , Vasopressinas/fisiologia , Anestesia , Animais , Antagonistas dos Receptores de Hormônios Antidiuréticos , Arginina Vasopressina/análogos & derivados , Arginina Vasopressina/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Coração/efeitos dos fármacos , Coração/fisiopatologia , Hemodinâmica/efeitos dos fármacos , Hipotálamo/fisiologia , Masculino , Ratos , Ratos Wistar , Fluxo Sanguíneo Regional/fisiologia , Respiração/efeitos dos fármacos , Vasopressinas/antagonistas & inibidores , Vasopressinas/efeitos dos fármacosRESUMO
We sought to determine whether arginine vasopressin (AVP) modulates arterial pressure (AP) by a receptor-mediated action in the nucleus reticularis rostroventrolateralis (nRVL). Immunocytochemical labeling with an antiserum against a synthetic AVP conjugate revealed a discrete although modest presumptive neuropeptidergic innervation of the nRVL. Electron microscopic analysis of vasopressinergic processes in the nRVL revealed that AVP-like immunoreactivity (AVP-LI) was primarily in axons and axon terminals. Immunoreactive terminals contained numerous small clear vesicles and large dense core vesicles and formed synapses with unlabeled dendrites. In the nRVL, retrograde transport-immunofluorescence data demonstrated close appositions between vasopressinergic beaded processes and a compact subambigual column of reticulospinal neurons labeled by deposits of cholera toxin beta-subunit into the thoracic spinal cord. Similar methods were used to define the origins of the AVP-afferent projection to nRVL. These retrograde transport-immunofluorescence studies demonstrated numerous retrogradely labeled neurons in the hypothalamus, including the paraventricular nucleus (PVN), after injections of a retrograde tracer, Fluoro-Gold into the ventrolateral medulla. However, double-labeled neurons were rare and confirmed a diffuse AVP afferent innervation of the sympathoexcitatory area. Microinjection of AVP into the nRVL in anesthetized rats produced a large dose-related increase in AP different from control at a dose of 1 pmol or higher. AVP injected intravenously elevated AP only at significantly higher doses. Microinjections of AVP into the nucleus tractus solitarii (NTS) had a smaller effect whereas into the caudal ventrolateral medulla exerted no effect on AP. Bilateral microinjections of an AVP antagonist, d(CH2)5[Tyr(Me)2]AVP into the nRVL produced no change in AP but blocked the increase produced by subsequent injections of AVP. An acute hemorrhage produced by withdrawal of 2 ml of blood from the femoral vein did not alter AP. However, bilateral microinjections of the AVP antagonist into the nRVL 5 min after hemorrhage decreased AP. In contrast, the AVP-antagonist injected intravenously after hemorrhage had no effect on AP. Our data suggest that under conditions demanding increased sympathetic drive to maintain AP, such as hemorrhage, a functional AVP receptor mechanism via terminals in the nRVL may be activated to restore normal levels of AP.
Assuntos
Arginina Vasopressina/análise , Pressão Sanguínea , Encéfalo/fisiologia , Bulbo/fisiologia , Neurônios/fisiologia , Animais , Arginina Vasopressina/administração & dosagem , Arginina Vasopressina/análogos & derivados , Arginina Vasopressina/farmacologia , Arginina Vasopressina/fisiologia , Transporte Axonal , Axônios/fisiologia , Axônios/ultraestrutura , Pressão Sanguínea/efeitos dos fármacos , Imunofluorescência , Hemorragia/fisiopatologia , Masculino , Bulbo/citologia , Bulbo/ultraestrutura , Microinjeções , Neurônios/citologia , Neurônios/ultraestrutura , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Sinapses/fisiologia , Sinapses/ultraestruturaRESUMO
Social transmission of information was tested in a procedure in which a rat (Observer) could demonstrate preference for a flavored tea as drinking solution that a con-specific (Demonstrator) had consumed just prior to a period of social interaction between the two animals. The cue in this procedure, probably olfactory in nature, was remembered for a relatively short period of time. It was prolonged when the Observers were treated with dresglycinamide[Arg8]-vasopressin (DGAVP) or oxytocin immediately after the encounter with the Demonstrator. DGAVP was effective after the injection of 15 micrograms.kg-1 but not of 1.5 ng.kg-1. Oxytocin induced the effect in doses ranging from 1.5 ng.kg-1 to 15 micrograms.kg-1. A dose of 0.15 ng.kg-1 was inactive. The influence of the peptides was cue specific. It is concluded that DGAVP and oxytocin facilitate social transmission of information, as previously found for social recognition.
Assuntos
Arginina Vasopressina/análogos & derivados , Comportamento de Ingestão de Líquido , Relações Interpessoais , Ocitocina/farmacologia , Chá , Animais , Arginina Vasopressina/farmacologia , Arginina Vasopressina/fisiologia , Bebidas , Aromatizantes , Masculino , Memória/efeitos dos fármacos , Ratos , Olfato/fisiologiaRESUMO
It has been demonstrated in animal model of somatic pain that hypothalamic paraventricular nucleus (PVN) participates in acupuncture analgesia, probably by mediation of vasopressin release. The role of PVN in acupuncture analgesia for experimental visceral pain in rats was further investigated in the present study. Experimental results demonstrated that electroacupuncture could inhibit the writhing response, produced by intraperitoneal injection of antimonium potassium tartrate and this inhibitory effect could be enhanced by electrical stimulation of PVN, but decreased by electrolytical lesion of PVN, intracerebroventricular injection of vasopressin antiserum (14 microliters) or the vasopressin antagonist, d(CH2)5Tyr(Me)-AVP (500 ng/5 microliters). Intraperitoneal administration of the latter drug (10 micrograms/kg), however, was ineffective. The above experimental results suggest that vasopressinergic neurons in PVN also participate in the inhibition of visceral pain by electroacupuncture.
Assuntos
Eletroacupuntura , Nociceptores/fisiologia , Núcleo Hipotalâmico Paraventricular/fisiologia , Receptores de Vasopressinas/fisiologia , Analgesia por Acupuntura , Animais , Arginina Vasopressina/análogos & derivados , Arginina Vasopressina/antagonistas & inibidores , Arginina Vasopressina/imunologia , Feminino , Soros Imunes , Masculino , Limiar da Dor , Ratos , Ratos Wistar , Vasopressinas/antagonistas & inibidores , Vasopressinas/imunologiaRESUMO
Experiments were carried out in urethane anaesthetized, ventilated rats to determine if brain arginine-vasopressin (AVP) plays a physiological role in cerebral blood flow autoregulation. Autoregulation was tested by determining local hypothalamic blood flow in the mediobasal hypothalamic area (HBF; H2-gas clearance technique) during consecutive stepwise lowering of systemic mean arterial pressure to 80, 60 and 40 mm Hg, by hemorrhage. Endogenous AVP was blocked by transecting the rostral, lateral and dorsal neuronal connections of the hypothalamus (including the median eminence) from all major brain areas, by bilateral transection of the vasopressin-containing fibres in the hypothalamo-hypophyseal tract to the median eminence at the level of the lateral retrochiasmatic area (RCAL), and finally by intracerebroventricular (i.c.v.) administration of an AVP antagonist, d(CH2)5Tyr(Me)AVP (AAVP). Significant increases of daily water intake indicated impaired vasopressin release following both types of surgical transection. Resting HBF was significantly elevated both after surgical isolation of the hypothalamus and after 10 ng AAVP administration compared to controls. Blood flow autoregulation in the hypothalamic region was seriously impaired following surgical isolation of the hypothalamus. However, HBF autoregulation remained just as effective as that of the control rats following either selective bilateral transection of the vasopressin pathways or following AAVP treatment. The present data indicate that AVP may play a role in the control of resting hypothalamic blood flow, but does not support a role of AVP in HBF autoregulatory mechanisms.
Assuntos
Arginina Vasopressina/análogos & derivados , Arginina Vasopressina/fisiologia , Pressão Sanguínea/efeitos dos fármacos , Encéfalo/fisiologia , Ventrículos Cerebrais/fisiologia , Hipotálamo/irrigação sanguínea , Animais , Arginina Vasopressina/administração & dosagem , Arginina Vasopressina/antagonistas & inibidores , Arginina Vasopressina/farmacologia , Encéfalo/efeitos dos fármacos , Ventrículos Cerebrais/efeitos dos fármacos , Homeostase , Injeções Intraventriculares , Masculino , Eminência Mediana/fisiologia , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Ratos , Ratos Endogâmicos , Fluxo Sanguíneo Regional/efeitos dos fármacos , Resistência Vascular/efeitos dos fármacosRESUMO
In the experiments on mice there were analysed the effects of arginine-vasopressin (AVP) and its analogue des-glycine-arginine-vasopressin (DG-AVP) on the extinction of the conditioned reaction of passive avoidance and the reproduction of memory trace in amnesia caused by detaining the animal in the dangerous section of the unit after electrocutaneous stimulation. An increase of resistance of the conditioned reaction to a sharp extinction at systemic administration of AVP and DG-AVP was shown.
Assuntos
Amnésia/tratamento farmacológico , Arginina Vasopressina/análogos & derivados , Arginina Vasopressina/farmacologia , Condicionamento Clássico/efeitos dos fármacos , Extinção Psicológica/efeitos dos fármacos , Amnésia/etiologia , Animais , Arginina Vasopressina/uso terapêutico , Aprendizagem da Esquiva/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Estimulação Elétrica , Masculino , Memória/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB CRESUMO
Sites which bind oxytocin and vasopressin with high affinity were detected in the brain and upper spinal cord of 12 human subjects, using in vitro light microscopic autoradiography. Tissue sections were incubated with tritiated vasopressin, tritiated oxytocin or an iodinated oxytocin antagonist. The ligand specificity of binding was assessed with unlabelled vasopressin or oxytocin in excess, as well as in competition experiments using synthetic structural analogues. The distribution of vasopressin binding sites differed markedly from that of oxytocin binding sites in the forebrain, while there was overlap in the brainstem. Vasopressin binding sites were detected in the dorsal part of the lateral septal nucleus, in midline nuclei and adjacent intralaminar nuclei of the thalamus, in the hilus of the dentate gyrus, the dorsolateral part of the basal amygdaloid nucleus and the brainstem. The distribution of oxytocin binding sites in the brainstem has been recently reported (Loup et al., 1989). Oxytocin binding sites were also observed in the basal nucleus of Meynert, the nucleus of the vertical limb of the diagonal band of Broca, the ventral part of the lateral septal nucleus, the preoptic/anterior hypothalamic area, the posterior hypothalamic area, and variably in the globus pallidus and ventral pallidum. The presence of oxytocin and vasopressin binding sites in limbic and autonomic areas suggests a neurotransmitter or neuromodulator role for these peptides in the human central nervous system. They may also affect cholinergic transmission in the basal forebrain and consequently play a role in Alzheimer's disease.