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1.
Prostaglandins Other Lipid Mediat ; 88(3-4): 68-72, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19007903

RESUMO

We found that prostaglandin (PG) D(2), the most abundant PG produced in the central nervous system (CNS), exhibited anxiolytic-like activity at a dose of 10-100pmol/mouse after intracerebroventricular (i.c.v.) administration in the elevated plus-maze test in mice. A DP(1) receptor-selective agonist, BW245C, mimicked the anxiolytic-like activity of PGD(2), while a DP(2) receptor agonist 13,14-dihydro-15-keto-PGD(2) was inactive. The anxiolytic-like activity of PGD(2) was blocked by a DP(1) antagonist, BWA868C, suggesting that PGD(2)-induced anxiolytic-like activity was mediated by the DP(1) receptor. Adenosine A(2A) or GABA(A) receptor antagonists, SCH58261 or bicuculline, respectively, also blocked its anxiolytic-like activity. Taken together, centrally administered PGD(2) may induce anxiolytic-like activity via the A(2A) and GABA(A) receptors, downstream of the DP(1) receptor.


Assuntos
Ansiolíticos/farmacologia , Aprendizagem em Labirinto/efeitos dos fármacos , Prostaglandinas D/farmacologia , Receptores de Prostaglandina/metabolismo , Antagonistas do Receptor A2 de Adenosina , Animais , Bicuculina/farmacologia , Antagonistas de Receptores de GABA-A , Hidantoínas/farmacologia , Masculino , Camundongos , Receptor A2A de Adenosina/metabolismo , Receptores de GABA-A/metabolismo , Receptores de Prostaglandina/antagonistas & inibidores
2.
Trends Mol Med ; 12(4): 148-58, 2006 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-16545607

RESUMO

The lipid mediator prostaglandin D(2) (PGD(2)) has long been implicated in various inflammatory diseases including asthma. PGD(2) elicits biological responses by activating two seven-transmembrane (7TM) G-protein-coupled receptors, the D-prostanoid receptor DP and the chemoattractant receptor homologous-molecule expressed on T-helper-type-2 cells (CRTH2), which are linked to different signaling pathways. Understanding how immune cells integrate and coordinate signals that are triggered by the same ligand is crucial for the development of novel anti-inflammatory therapies. Here, we examine the roles of DP and CRTH2 in the orchestration of complex inflammatory processes, and discuss their importance as emerging targets for the treatment of asthma and inflammatory diseases.


Assuntos
Inflamação/fisiopatologia , Receptores Imunológicos/fisiologia , Receptores de Prostaglandina/fisiologia , Animais , Movimento Celular/efeitos dos fármacos , Humanos , Hipersensibilidade/fisiopatologia , Modelos Biológicos , Prostaglandinas D/farmacologia , Prostaglandinas D/fisiologia , Receptores Acoplados a Proteínas G/fisiologia , Células Th2/citologia , Células Th2/efeitos dos fármacos , Células Th2/fisiologia
3.
J Pharmacol Exp Ther ; 314(1): 244-51, 2005 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15798001

RESUMO

Prostaglandin (PG) D2, a major cyclooxygenase metabolite generated from immunologically stimulated mast cells, is known to induce activation and chemotaxis in eosinophils, basophils, and T helper 2 (Th2) lymphocytes via a newly identified PGD2 receptor, chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2). CRTH2 is hypothesized to play an important role in the outcome of allergic responses. However, the absence of selective CRTH2 antagonists has prevented the elucidation of the role of CRTH2 in pathogenesis of allergic diseases. We now report compounds discovered as selective CRTH2 antagonists, (2R*,4S*)-N-(1-benzoyl-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)-N-phenylisobutyramide (K117) and (2R*,4S*)-N-(1-benzoyl-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)-N-phenylcyclopropanecarboxamide (K604). K117 and K604 have inhibitory effects on human CRTH2 with Ki values of 5.5 and 11 nM, respectively. The effect of these compounds is CRTH2-specific with no cross-reactivity against 15 other receptors and four arachidonic acid-metabolizing enzymes. K117 and K604 has no effect on the basal Ca2+ level and inhibited the Ca2+ response induced by PGD2 in 293EBNA cells expressing human CRTH2. Also, K117 and K604 inhibit PGD2-induced human eosinophil chemotaxis with IC50 values of 7.8 and 42.2 nM, respectively, but they do not inhibit the CC-chemokine receptor 3 agonist eotaxin-induced chemotaxis. These results indicate that K117 and K604 are highly potent and selective antagonists for human CRTH2. These compounds have possibilities to become useful tools to explore CRTH2 functions in allergic diseases.


Assuntos
Movimento Celular/efeitos dos fármacos , Eosinófilos/efeitos dos fármacos , Prostaglandinas D/farmacologia , Quinolinas/farmacologia , Receptores Imunológicos/antagonistas & inibidores , Receptores de Prostaglandina/antagonistas & inibidores , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Cálcio/metabolismo , Carbazóis/farmacologia , Linhagem Celular , Quimiotaxia de Leucócito/efeitos dos fármacos , Inibidores de Ciclo-Oxigenase/farmacologia , Vetores Genéticos , Humanos , Indometacina/farmacologia , Ligantes , Inibidores da Agregação Plaquetária/farmacologia , Receptores Imunológicos/agonistas , Receptores Imunológicos/genética , Receptores de Prostaglandina/agonistas , Receptores de Prostaglandina/genética , Receptores de Tromboxanos/antagonistas & inibidores , Sulfonamidas/farmacologia
4.
J Pharmacol Exp Ther ; 293(2): 321-8, 2000 May.
Artigo em Inglês | MEDLINE | ID: mdl-10772998

RESUMO

The prostanoid receptor-subtype binding affinities, selectivities, potencies, and intrinsic activities of four natural prostanoids and six synthetic DP class prostanoids were determined using binding and functional assays with endogenous receptors. SQ27986 exhibited the highest affinity for the human platelet DP receptor and the best DP receptor selectivity profile. Prostaglandin (PG)D(2) was the least DP receptor-selective. The rank order of compound affinities at the DP receptor was SQ27986 (K(i) = 10 +/- 2 nM) > RS93520 = ZK110841 = BW245C (K(i) = 23-26 nM) > ZK118182 (K(i) = 50 +/- 9 nM) > PGD(2) (K(i) = 80 +/- 5 nM). DP receptor agonists produced cAMP in embryonic bovine tracheal fibroblasts with different potencies (EC(50) values in nM): ZK118182 (18 +/- 6), RS93520 (28 +/- 6), SQ27986 (29 +/- 7), ZK110841 (31 +/- 7), BW245C (53 +/- 16), and PGD(2) (98 +/- 10). BW245C was more efficacious and RS93520 was less efficacious than PGD(2). ZK110841 and ZK118182 exhibited a relatively high potency at the adenylyl cyclase-coupled EP(2) receptor in human nonpigmented ciliary epithelial cells but were partial agonists. None of the DP class agonists showed any EP(4) receptor functional activity in Chinese hamster ovary cells. The DP receptor antagonist BWA868C competitively antagonized the PGD(2)-induced cAMP accumulation in embryonic bovine tracheal fibroblast cells (pA(2) = 7.83 +/- 0.08). The dissociation constants for BWA868C antagonizing PGD(2)-, BW245C-, and ZK118182-induced cAMP production were quite similar (apparent -log K(b) = 7.9-8.2, n = 5-9). The pharmacological properties of some natural and numerous DP class synthetic prostanoids have been determined using endogenous receptors.


Assuntos
Prostaglandinas D/metabolismo , Prostaglandinas Sintéticas/farmacologia , Prostaglandinas/farmacologia , Receptores de Prostaglandina/efeitos dos fármacos , Células 3T3 , Adenilil Ciclases/metabolismo , Alprostadil/análogos & derivados , Alprostadil/metabolismo , Animais , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Células CHO , Linhagem Celular , Cricetinae , Epoprostenol/metabolismo , Humanos , Técnicas In Vitro , Camundongos , Fosfatidilinositóis/metabolismo , Prostaglandina D2/metabolismo , Prostaglandinas/metabolismo , Prostaglandinas D/farmacologia , Prostaglandinas F/metabolismo , Prostaglandinas Sintéticas/metabolismo
6.
Prostaglandins ; 50(2): 57-63, 1995 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-8588073

RESUMO

The chemistry and biology of novel TXA2(TP)-receptor agonists based on the prostanoid skeleton is described and structure-activity-relationships are discussed. One compound,(5Z,13E), (9R,15R)-9-fluoro-15-hydroxy-16-phenoxy-17,18,19,20-tetranor- 5,13-prostadienoic acid (33), was identified which is 10 times more potent than the standard TP-receptor against U 46619.


Assuntos
Prostaglandinas D/farmacologia , Tromboxano A2/agonistas , Plaquetas/metabolismo , Membrana Celular/metabolismo , Humanos , Agregação Plaquetária/efeitos dos fármacos , Prostaglandinas D/síntese química , Receptores de Tromboxanos/metabolismo
7.
J Allergy Clin Immunol ; 93(5): 817-24, 1994 May.
Artigo em Inglês | MEDLINE | ID: mdl-8182221

RESUMO

The symptoms and hemodynamic alterations that accompany episodes of systemic mast cell activation have been largely attributed to excessive prostaglandin (PG)D2 release. Quantification of the major urinary metabolite of PGD2 has been invaluable in elucidating a role for PGD2 in these clinical entities and in the biochemical evaluation of systemic mastocytosis. With the use of a modified mass spectrometric assay for the major urinary metabolite of PGD2, this metabolite was detected in plasma from 10 normal volunteers (3.5 +/- 1.4 pg/ml). Ingestion of niacin, which induces endogenous release of PGD2, increased plasma levels of this metabolite 6.3 to 33 times above the upper limit of normal by 2 hours. Thereafter, levels declined gradually but remained elevated for up to 6 to 8 hours. In contrast, circulating levels of 9 alpha, 11 beta-PGF2, the initial metabolite of PGD2, peaked by 30 minutes and returned to baseline by 2 hours. The clinical utility of measuring the major urinary metabolite in the circulation was demonstrated by detection of markedly increased levels in plasma and serum from patients with systemic mastocytosis and a patient with a severe type I allergic reaction. Thus in the biochemical evaluation of episodes of systemic mast cell activation and endeavors to further elucidate the role of PGD2 in human disease, there are kinetic advantages of measuring the major urinary metabolite of PGD2 in the circulation. One particular advantage is the evaluation of clinical events, which only in retrospect are suspected to be associated with excessive release of PGD2, yet plasma or serum was obtained proximate to the event.


Assuntos
Mastocitose/sangue , Prostaglandina D2/urina , Prostaglandinas D/sangue , Anafilaxia/sangue , Anafilaxia/urina , Dinoprosta/sangue , Estabilidade de Medicamentos , Armazenamento de Medicamentos , Feminino , Humanos , Cinética , Masculino , Mastocitose/urina , Niacina , Prostaglandinas D/farmacologia , Prostaglandinas D/urina , Fatores de Tempo , Urticaria Pigmentosa/sangue , Urticaria Pigmentosa/urina
8.
J Physiol ; 448: 307-20, 1992 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-1593469

RESUMO

1. We investigated the effect of intraperitoneal (I.P.) injections of the immune cytokines, interleukin-1 beta (IL-1 beta) and tumour necrosis factor (TNF) on cardiovascular responses in free-moving rats, using a biotelemetry system. 2. The I.P. injection of a small dose of IL-1 beta (1 microgram/kg) induced a monophasic increase in the heart rate, and that of a large dose (10 micrograms/kg) induced biphasic increases in the blood pressure and heart rate. However, the I.P. injection of any of several doses of TNF (1, 10 and 50 micrograms/kg) had no effect on cardiovascular responses in rats. 3. Pre-treatment with I.P. injection of indomethacin (10 mg/kg), an inhibitor of cyclo-oxygenase, significantly suppressed the cardiovascular responses and the increase in the plasma noradrenaline (NA) concentration induced by I.P. injection of IL-1 beta. 4. Microinjection of IL-1 beta (1 and 10 ng) into the preoptic and anterior hypothalamic (PO-AH) region induced dose-dependent increases in the blood pressure and heart rate in rats. These responses were also suppressed by pretreatment with I.P. indomethacin (10 mg/kg). In addition, microinjection of prostaglandin E2 (20 and 100 ng) into the PO-AH region increased blood pressure and heart rate, but that of prostaglandin D2 (100 ng) had no effect. 5. The present results suggest that IL-1 beta stimulates the release of prostaglandins, presumably E series, near regions of the hypothalamus, which act on the hypothalamus to induce activation of the sympathetic nervous system. Subsequently, the blood pressure, heart rate and the plasma level of NA increase.


Assuntos
Pressão Sanguínea/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Interleucina-1/farmacologia , Fator de Necrose Tumoral alfa/farmacologia , Animais , Dinoprostona/farmacologia , Relação Dose-Resposta a Droga , Indometacina/farmacologia , Masculino , Norepinefrina/sangue , Prostaglandinas D/farmacologia , Ratos , Ratos Endogâmicos , Fatores de Tempo
9.
Mol Cell Biochem ; 102(1): 35-47, 1991 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-1646955

RESUMO

Incubation of rocker-cultured neonatal rat heart cells with 3 mM L(+)-lactate led to a sharp increase in the sensitivity of cardiomyocytes to the beta-adrenergic agonist isoprenaline, as measured by their chronotropic response. This effect was accompanied by a reduction in the arachidonic acid content of the total phospholipids. The phospholipase A2-activator melittin as well as free arachidonic acid induced this supersensitivity to the same degree. On the other hand, the L(+)-lactate-evoked supersensitivity could be blocked by the phospholipase A2 inhibitors mepacrine and n-bromophenacyl-bromide, suggesting an involvement of phospholipase A2 in the process of beta-adrenergic sensitization. The sensitizing action of arachidonic acid was blocked by the lipoxygenase inhibitors esculetin and nordihydroguaiaretic acid, but not by the cyclo-oxygenase inhibitor indomethacin. Supersensitivity was likewise evoked by 15-S-hydroxyeicosatetraenoic acid (15-S-HETE), but not by 5-S-HPETE or 5-S-HETE. These findings suggest that the phospholipase A2-15-lipoxygenase pathway plays a role in the induction of beta-adrenergic supersensitivity in the cultured cardiomyocytes and point to a new physiological role of the lipoxygenase product 15-S-HETE.


Assuntos
Ácidos Araquidônicos/farmacologia , Coração/efeitos dos fármacos , Isoproterenol/farmacologia , Fosfolipases A/metabolismo , Prostaglandinas D/farmacologia , Receptores Adrenérgicos beta/efeitos dos fármacos , Acetofenonas/farmacologia , Animais , Ácido Araquidônico , Ácidos Araquidônicos/metabolismo , Células Cultivadas/efeitos dos fármacos , Fenômenos Cronobiológicos , Relação Dose-Resposta a Droga , Ativação Enzimática/efeitos dos fármacos , Coração/fisiologia , Ácidos Hidroxieicosatetraenoicos/farmacologia , Lactatos/farmacologia , Leucotrienos/farmacologia , Meliteno/farmacologia , Fosfolipases A/antagonistas & inibidores , Fosfolipases A2 , Quinacrina/farmacologia , Ratos , Ratos Endogâmicos
10.
Graefes Arch Clin Exp Ophthalmol ; 227(5): 476-81, 1989.
Artigo em Inglês | MEDLINE | ID: mdl-2478423

RESUMO

Effects of topically applied prostaglandin (PG) D2 on the aqueous outflow facility, uveoscleral flow, and aqueous flow rate were studied in rabbits to reveal its intraocular pressure (IOP)-reducing mechanism. The outflow facility after PGD2 application (50 micrograms) as measured by 2-min tonography was 0.19 microliters/min/mm Hg and did not differ from that before the application (0.22) or from that of the control contralateral eye (0.21). Direct measurement of the uveoscleral flow by perfusion of the anterior chamber for 30 min with fluorescein isothiocyanate-labeled dextran solution showed the flow rate to be about 0.15 microliters/min in indomethacin-treated (10 mg/kg, i.p.) rabbits. In these animals, PGD2 (50 micrograms) was ineffective in changing the flow rate, while PGF2 alpha (50 micrograms) significantly increased the flow by about 35%. Indirect assessment of the effects of PGs on this flow system was made using the uveoscleral flow-antagonizing ability of topical pilocarpine (1.5 mg). IOP reduction by PGD2 (50 micrograms) was only slightly inhibited by pilocarpine, while that by PGF2 alpha (10 micrograms) was markedly reduced. Aqueous flow rate measured fluorophotometrically was about 3.5 microliters/min in normal eyes. After PGD2 (50 micrograms) the flow rate was significantly reduced to 3.0 microliters/min. The magnitude of this reduction was estimated to be enough to account for the IOP reduction after application of 50 micrograms of PGD2. These results indicate that IOP reduction caused by topical PGD2 application is due mostly to the inhibition of aqueous flow rate.


Assuntos
Humor Aquoso/efeitos dos fármacos , Fluoresceína-5-Isotiocianato/análogos & derivados , Pressão Intraocular/efeitos dos fármacos , Prostaglandinas D/farmacologia , Administração Tópica , Animais , Humor Aquoso/metabolismo , Corpo Ciliar/efeitos dos fármacos , Corpo Ciliar/metabolismo , Dextranos , Dinoprosta/farmacologia , Fluoresceínas , Fluorometria , Masculino , Pilocarpina/farmacologia , Prostaglandinas D/administração & dosagem , Coelhos , Esclera/efeitos dos fármacos , Esclera/metabolismo , Tonometria Ocular , Úvea/efeitos dos fármacos , Úvea/metabolismo
11.
Gynecol Oncol ; 32(1): 60-4, 1989 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-2521212

RESUMO

Direct inhibitory effects of neuroendocrine hormones on human ovarian cancer cell proliferation in vitro were examined. Except for melatonin, all neuroendocrine hormones used in this study inhibited proliferation of KF cells derived from human serous cystadenocarcinoma of the ovary in a dose-dependent manner. The degree of inhibition of prostaglandin D2 was most marked being comparable to that of 5-fluorouracil and followed by beta-endorphin, alpha-endorphin, and Met-enkephalin. More than 200 microM melatonin stimulated the cell proliferation. The inhibitory effects by endorphins were partially reversible by 20 microM naloxone. From analyses of uptakes of radiolabeled precursors by the KF cell, endorphins were considered to inhibit protein and RNA syntheses but not DNA synthesis. These results suggest that neuroendocrine hormones may play an important role in regulation of tumor growth.


Assuntos
Cistadenocarcinoma/patologia , Endorfinas/farmacologia , Melatonina/farmacologia , Neoplasias Ovarianas/patologia , Prostaglandinas D/farmacologia , Divisão Celular/efeitos dos fármacos , DNA de Neoplasias/biossíntese , Relação Dose-Resposta a Droga , Endorfinas/antagonistas & inibidores , Encefalina Metionina/antagonistas & inibidores , Encefalina Metionina/farmacologia , Feminino , Fluoruracila/farmacologia , Humanos , Técnicas In Vitro , Naloxona/farmacologia , Prostaglandinas D/antagonistas & inibidores , Precursores de Proteínas/biossíntese , RNA Neoplásico/biossíntese , Células Tumorais Cultivadas/efeitos dos fármacos , beta-Endorfina/antagonistas & inibidores , beta-Endorfina/farmacologia
12.
J Pharmacol Exp Ther ; 246(1): 47-53, 1988 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-2839671

RESUMO

Functional interactions between several contractile agonists were examined in the guinea pig isolated trachea. Cumulative concentration-response effects of agonist A were obtained in the absence and presence of steady-state contractions induced by agonist B. The agonists examined included histamine, prostaglandin D2, platelet activating factor, leukotrienes E4 and D4 and carbamylcholine. We found that none of the agonists studied caused a leftward shift in the concentration-response curve of a second agonist, nor did any agonist decrease the concentration of a second agonist required to evoke a maximum response. In general the functional interactions fit the predictions based on the early models of functional additivity. However, the interactions deviated categorically from this model in that there was less than predicted additivity at concentrations of the interactants that alone induced greater than a 50% response. The degree to which this deviation occurred was agonist dependent. The results suggest that in the guinea pig trachea a contractile agonist does not uncover or increase a reserve in the receptor-subeffect-response chain of a second contractile agonist. The findings that the quantitative nature of the interactions were somewhat agonist dependent supports the hypothesis that more than one biochemical mechanism is involved in the receptor-mediated contraction of airway smooth muscle.


Assuntos
Contração Muscular/efeitos dos fármacos , Traqueia/efeitos dos fármacos , Algoritmos , Animais , Carbacol/farmacologia , Relação Dose-Resposta a Droga , Cobaias , Histamina/farmacologia , Leucotrieno E4 , Masculino , Prostaglandina D2 , Prostaglandinas D/farmacologia , SRS-A/análogos & derivados , SRS-A/farmacologia
13.
Eur J Biochem ; 175(1): 45-50, 1988 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-3165341

RESUMO

In isolated rat liver perfused at constant pressure perivascular nerve stimulation caused an increase of glucose and lactate output and a reduction of perfusion flow. The metabolic and hemodynamic nerve effects could be inhibited by inhibitors of prostanoid synthesis, which led to the suggestion that the effects of nerve stimulation were, at least partially, mediated by prostanoids [Iwai, M. & Jungermann, K. (1987) FEBS Lett. 221, 155-160]. This suggestion is corroborated by the present study. 1. Prostaglandin D2, E2 and F2 alpha as well as the thromboxane A2 analogue U46619 enhanced glucose and lactate release and lowered perfusion flow similar to nerve stimulation. 2. The extents, the kinetics and the concentration dependencies of the metabolic and hemodynamic actions of the various prostanoids were different. Prostaglandin F2 alpha and D2 caused relatively stronger changes of metabolism, while prostaglandin E2 and U46619 had stronger effects on hemodynamics. Prostaglandin F2 alpha elicited greater maximal alterations than D2 with similar half-maximally effective concentrations. Prostaglandin F2 alpha mimicked the nerve actions on both metabolism and hemodynamics best with respect to the relative extents and the kinetics of the alterations. 3. The hemodynamic effects of prostaglandin F2 alpha could be prevented completely by the calcium antagonist nifedipine without impairing the metabolic actions of the prostanoid. Apparently, prostaglandin F2 alpha influenced metabolism directly rather than indirectly via hemodynamic changes. The present results, together with the previously described effects of prostanoid synthesis inhibitors, suggest that prostanoids, probably prostaglandin F2 alpha and/or D2, could be involved in the actions of sympathetic hepatic nerves on liver carbohydrate metabolism. Since prostanoids are synthesized only in non-parenchymal cells, nervous control of metabolism appears to depend on complex intra-organ cell-cell interactions between the nerve, non-parenchymal and parenchymal cells.


Assuntos
Fígado/inervação , Prostaglandinas D/farmacologia , Prostaglandinas E/farmacologia , Prostaglandinas F/farmacologia , Sistema Nervoso Simpático/fisiologia , Tromboxano A2/farmacologia , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico , Animais , Dinoprosta , Dinoprostona , Estimulação Elétrica , Glucose/metabolismo , Hemodinâmica/efeitos dos fármacos , Lactatos/metabolismo , Ácido Láctico , Masculino , Norepinefrina/metabolismo , Perfusão , Prostaglandina D2 , Endoperóxidos Sintéticos de Prostaglandinas/farmacologia , Ratos , Ratos Endogâmicos , Sistema Nervoso Simpático/efeitos dos fármacos
14.
Proc Natl Acad Sci U S A ; 85(11): 4082-6, 1988 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-3163802

RESUMO

The sleep-inducing effect of prostaglandin D2 (PGD2) was studied in five conscious male rhesus monkeys (Macaca mulatta) maintained in a 12-hr light/dark cycle. PGD2 was infused into the lateral or the third ventricle of the cerebrum slowly and continuously for 6 hr in the light period. Infusion of PGD2 into the lateral ventricle at 15-2250 pmol/min induced natural sleep as identified by electroencephalogram, electromyogram, electrooculogram, body temperature, heart rate, and animal behavior. Although sensitivity to PGD2 was slightly different among individual animals, the amount of total sleep time increased maximally up to 3- to 4-fold over the control level. PGD2 infused into the third ventricle induced effects similar to those observed for the lateral ventricular route, but infusion into the third ventricle was about 1000 times more effective than infusion into the lateral ventricle. In three monkeys, PGD2 increased the amount of sleep in a dose-dependent manner. Bell-shaped dose-response curves were observed for the other two monkeys. Infusion of prostaglandin E2 or F2 alpha into the lateral ventricle caused sedation but slightly reduced the amount of slow-wave sleep and produced increases in heart rate and body temperature. These findings suggest that endogenous PGD2 may be involved in the regulation of sleep by acting on the brain structures surrounding the third ventricle in the rhesus monkey.


Assuntos
Encéfalo/fisiologia , Prostaglandinas D/farmacologia , Sono/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Temperatura Corporal/efeitos dos fármacos , Dinoprosta , Dinoprostona , Relação Dose-Resposta a Droga , Frequência Cardíaca/efeitos dos fármacos , Injeções Intraventriculares , Macaca mulatta , Prostaglandina D2 , Prostaglandinas E/farmacologia , Prostaglandinas F/farmacologia
15.
Inflammation ; 12(3): 213-21, 1988 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-2843463

RESUMO

Neutrophils from atopic and nonatopic donors were treated with prostaglandins D2 and E2 before stimulation of the respiratory burst. Both agents inhibited neutrophil response to formyl-methionyl-leucyl-phenylalanine, but superoxide production was inhibited much more profoundly by D2 than by E2. Inhibition was similar in atopics and nonatopics. Phorbol myristate acetate stimulation of superoxide production was not significantly altered by prostaglandins. These findings suggest that minor alterations in pathways of prostaglandin synthesis may have major effects on modulation of neutrophil function, and exploration of the mechanism of stimulus-specific inhibition may further elucidate the role of neutrophils in the inflammatory response.


Assuntos
Hipersensibilidade Imediata/metabolismo , Neutrófilos/metabolismo , Prostaglandinas D/farmacologia , Prostaglandinas E/farmacologia , Dinoprostona , Humanos , Peróxido de Hidrogênio/metabolismo , Técnicas In Vitro , Neutrófilos/efeitos dos fármacos , Consumo de Oxigênio , Prostaglandina D2 , Superóxidos/antagonistas & inibidores
16.
Biochem J ; 252(2): 601-5, 1988 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-3166374

RESUMO

The possible role of Kupffer and endothelial liver cells in the regulation of parenchymal-liver-cell function was assessed by studying the influence of conditioned media of isolated Kupffer and endothelial cells on protein phosphorylation in isolated parenchymal cells. The phosphorylation state of three proteins was selectively influenced by the conditioned media. The phosphorylation state of an Mr-63,000 protein was decreased and the phosphorylation state of an Mr-47,000 and an Mr-97,000 protein was enhanced by these media. These effects could be mimicked by adding either prostaglandin E1, E2 or D2. Both conditioned media and prostaglandins stimulated the phosphorylase activity in parenchymal liver cells, suggesting that the Mr-97,000 phosphoprotein might be phosphorylase. Parenchymal liver cells secrete a phosphoprotein of Mr-63,000 and pI 5.0-5.5. The phosphorylation of this protein is inhibited by Kupffer- and endothelial-liver-cell media, and prostaglandins E1, E2 and D2 had a similar effect. The data indicate that Kupffer and endothelial liver cells secrete factors which influence the protein phosphorylation in parenchymal liver cells. This forms further evidence that products from non-parenchymal liver cells, in particular prostaglandin D2, might regulate glucose homoeostasis and/or other specific metabolic processes inside parenchymal cells. This stresses the concept of cellular communication inside the liver as a way by which the liver can rapidly respond to extrahepatic signals.


Assuntos
Células de Kupffer/metabolismo , Fígado/metabolismo , Prostaglandinas/farmacologia , Proteínas/metabolismo , Animais , Eletroforese , Endotélio/citologia , Endotélio/metabolismo , Técnicas In Vitro , Fígado/citologia , Fígado/efeitos dos fármacos , Masculino , Fosfatos/análise , Fosfoproteínas/metabolismo , Fosforilase a/metabolismo , Fosforilação , Prostaglandina D2 , Prostaglandinas D/farmacologia , Prostaglandinas E/farmacologia , Ratos , Ratos Endogâmicos
17.
Prostaglandins ; 35(6): 959-68, 1988 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-3187057

RESUMO

An alteration in smooth muscle sensitivity may be one of the mechanisms of the airway hyperresponsiveness observed in asthma. Indomethacin inhibits experimentally induced airway hyperresponsiveness. We thus examined the effects of the cyclooxygenase products PGD2, PGF2 alpha and a thromboxane A2 analogue U46619 on contractile responses of rabbit airway smooth muscle to histamine, carbachol and electrical field stimulation (EFS). PGD2 did not potentiate any contractile responses. When PGF2 alpha (1 microM) was administered 30 min before cumulative concentration-response curves to histamine and carbachol, no potentiation was observed. However, PGF2 alpha (1 microM) added immediately before EFS and bolus doses of histamine potentiated the contractile responses. U46619 increased the cumulative concentration-responses to both histamine and carbachol. The fact that we could alter smooth muscle sensitivity in vitro with PGF2 alpha and a thromboxane analogue suggests that these mediators may be involved in the airway hyperresponsiveness observed in asthma.


Assuntos
Brônquios/efeitos dos fármacos , Dinoprosta/farmacologia , Músculo Liso/efeitos dos fármacos , Endoperóxidos Sintéticos de Prostaglandinas/farmacologia , Prostaglandinas D/farmacologia , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico , Animais , Carbacol/farmacologia , Estimulação Elétrica , Histamina/farmacologia , Técnicas In Vitro , Contração Muscular/efeitos dos fármacos , Coelhos
18.
Br J Ophthalmol ; 72(6): 461-4, 1988 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-3164634

RESUMO

When PGD2 was topically applied to the rabbit eye a reduction of intraocular pressure (IOP) was observed within 30 min. The IOP reduction lasted throughout the observation period of 7 hours. No increase of IOP was observed during the period. The effect of PGD2 was dose-dependent (0.4 microgram to 250 micrograms), and the minimum effective dose was estimated to be 2.0 micrograms. The application of PGD2 did not affect the pupil diameter. No sign of inflammatory response was observed by PGD2 application, that is, no hyperaemia, no flare, no irritation, and no increase of protein content in the aqueous humour. These results suggest that PGD2 or its analogues may be useful for treating glaucoma.


Assuntos
Pressão Intraocular/efeitos dos fármacos , Prostaglandinas D/farmacologia , Animais , Dinoprosta , Dinoprostona , Relação Dose-Resposta a Droga , Prostaglandina D2 , Prostaglandinas E/farmacologia , Prostaglandinas F/farmacologia , Coelhos
19.
Invest Ophthalmol Vis Sci ; 29(6): 882-91, 1988 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-3131263

RESUMO

In teleosts, retinomotor movements of photoreceptors and retinal pigment epithelium are regulated both by light and by an endogenous circadian rhythm. Light induces cones to contract, rods to elongate and RPE cells to disperse their pigment granules into their long apical projections; darkness induces opposite movements. When fish are maintained in prolonged constant darkness, appropriate movements nonetheless occur at subjective dusk and dawn. To explore the mechanisms of this light and circadian regulation, we have been investigating effects of several extracellular messengers known to be present in retina on retinomotor movements in the green sunfish (Lepomis cyanellus). Here we report that prostaglandin E1 (PGE1) can induce movements characteristic of dark onset (or night) in both cones and RPE in isolated light-adapted retinas in the light; ie, PGE1 induces cone elongation and RPE pigment granule aggregation. The extent of PGE1-induced cone and RPE movements were dose-dependent with maximal movement occurring at 250-500 nM; higher concentrations were not as effective. Incubations with PGE2 and PGD2 also induced dark-adaptive cone and RPE retinomotor movements, but PGF2 alpha did not. Further observations suggest that prostaglandins may play a role in mediating the induction of cone and RPE movements by dark onset: dark-induced movements were inhibited by pretreating light-adapted isolated retinas before dark culture with agents which inhibit endogenous prostaglandin synthesis. Both indomethicin (50 microM) and acetylsalicylic acid (50 microM), two inhibitors of the cyclooxygenase component of specific prostaglandin synthase, inhibited dark-induced cone elongation and pigment aggregation in cultured sunfish retinas. Another cyclooxygenase inhibitor, ibuprofen (50 microM) had no effect. Together the effectiveness of PGE1 inducing dark-adaptive movement and the inhibition of dark adaptive movement by cyclooxygenase inhibitors suggest that prostaglandins may play a role in vivo in mediating the induction of dark-adapted RPE and cone retinomotor movements by dark onset.


Assuntos
Alprostadil/farmacologia , Adaptação à Escuridão , Células Fotorreceptoras/fisiologia , Epitélio Pigmentado Ocular/fisiologia , Prostaglandinas D/farmacologia , Prostaglandinas E/farmacologia , Animais , Movimento Celular/efeitos dos fármacos , Cobalto/farmacologia , Inibidores de Ciclo-Oxigenase , Dinoprostona , Perciformes , Inibidores de Fosfodiesterase/farmacologia , Epitélio Pigmentado Ocular/citologia , Segmento Externo da Célula Bastonete/efeitos dos fármacos
20.
Cancer Res ; 48(10): 2813-8, 1988 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-3162825

RESUMO

The effect of prostaglandin A2 (PGA2) on c-myc expression was investigated in a human promyelocytic leukemia cell line, HL-60, which responded to PGA2 with a dose-dependent growth inhibition. Northern blot analysis indicated that treatment with PGA2 at 0.5 to 5.0 micrograms/ml remarkably reduced the steady state level of c-myc mRNA within 3 h, and then it gradually recovered according to the order of concentration of the drug. In contrast to c-myc, the level of class I HLA mRNA, as an internal control, was not diminished by PGA2 treatment. Further, this reduction of c-myc was not disturbed by cycloheximide, suggesting that this PGA2 action on c-myc expression is independent of de novo protein synthesis. Cytofluorometric analysis revealed that the exposure of HL-60 cells to PGA2 at 0.5 or 5.0 micrograms/ml arrested the cells in the G0-G1 phase of the cell cycle. This accumulation of the cells in G0-G1 phase continues until 24 or 36 h at 0.5 or 5.0 micrograms/ml, respectively. The G0-G1 arrest of the cell cycle was also recovered as the inhibition of c-myc was released. This recovery may be due to the loss of activity of PGA2 in culture medium. This study clearly showed that PGA2 treatment arrested HL-60 cells in the G0-G1 phase of the cell cycle and was associated with the reduction of c-myc mRNA.


Assuntos
Leucemia Mieloide Aguda/genética , Prostaglandinas A/farmacologia , Proto-Oncogenes , Ciclo Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Cicloeximida/farmacologia , Citometria de Fluxo , Antígenos HLA/genética , Humanos , Leucemia Mieloide Aguda/patologia , Prostaglandina D2 , Prostaglandinas D/farmacologia , RNA Mensageiro/análise , Células Tumorais Cultivadas
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