RESUMO
BACKGROUND: During two decades of migraine provocation studies with naturally occurring signalling molecules, vasodilators such as prostaglandin E(2), prostaglandin I(2) (prostacyclin) and prostaglandin D(2) were shown to be able to induce headache in man. To elucidate the role of inflammation and vasodilatation in the generation of headache, we investigated whether the pro-inflammatory and vasoconstricting prostanoid prostaglandin F(2α) (PGF(2α)) would cause headache in a human model of headache. METHODS: Twelve healthy volunteers were randomly allocated to receive 3.5 µg/kg/min PGF(2α) or placebo over 20 min in a two-way crossover study. We recorded headache intensity on a verbal rating scale, middle cerebral artery blood flow velocity (V(MCA)) and the diameters of the superficial temporal artery (STA) and radial artery (RA). RESULTS: We found no difference in the area under the curve (AUC) for immediate headache (0-90 min) between PGF(2α) and placebo (p = 0.144). The McNemar's test showed no difference in the incidence of immediate and delayed headache between verum and placebo (p = 0.500 and p = 1.000, respectively). There was no difference in V(MCA) (p = 0.776) and in the diameter of the STA (p = 0.460) or RA (p = 0.780) between PGF(2α) and placebo. CONCLUSION: The present study shows that PGF(2α), unlike vasodilating prostaglandins, does not provoke headache. We suggest that the vasodilating abilities of prostaglandins are important for the induction of experimental headache in healthy volunteers.
Assuntos
Artérias/efeitos dos fármacos , Artérias/fisiopatologia , Dinoprosta/toxicidade , Cefaleia/induzido quimicamente , Cefaleia/fisiopatologia , Adulto , Estudos Cross-Over , Feminino , Humanos , Mediadores da Inflamação/toxicidade , Masculino , Vasoconstritores/toxicidade , Adulto JovemRESUMO
BACKGROUND: Delayed cerebral vasospasm (dCVS) following aneurysmal subarachnoid hemorrhage (aSAH) is (next to possible aneurysm rebleeding, cortical spreading depression and early brain injury) one of the main factors contributing to poor overall patient outcome. Since decades, intensive research has been ongoing with the goal of improving our understanding of the pathophysiological principles underlying dCVS. Endothelin-1 (ET-1) and prostaglandin F2 alpha (PGF2a) seem to play a major role during dCVS. The synthesis of ET-1 is enhanced after subarachnoid hemorrhage (SAH) to mediate a long-lasting vasoconstriction, and PGF2a contributes to cerebral inflammation and vasoconstriction. Under physiological conditions, levosimendan (LS) demonstrates an antagonistic effect on PGF2a-induced cerebral vasoconstriction. Thus, the intention of the present study was to analyze potentially beneficial interactions in a pathophysiological situation. METHODS: A modified double hemorrhage model was used. Functional interactions between the calcium-sensitizing action of LS and the vasoconstrictive properties of PGF2a were investigated. RESULTS: After pre-incubation with LS, followed by application of PGF2a, a significant decrease in maximum contraction (Emax) for sham-operated animals was found (Emax 28% with LS, Emax 56% without LS). Using the same setting after SAH, the vessel segments did not reach a statistically significant contraction (but similar like the sham-operated vessels), neither for Emax nor pD2 (-log10EC50) nor EC50 (i.e., the concentration at which half of the maximal effect occurs). LS series in sham animals were performed by pre-incubation with PGF2a. The resultant Emax showed a statistically strong significance concerning a higher vasorelaxation compared with a solvent control group. Vessel segment relaxation was significantly stronger in the same experimental setup after SAH. CONCLUSION: Under physiological and pathophysiological circumstances, LS reduced and dosedependently reversed PGF2a-induced vasoconstriction. These results can be applied to further developing methods to antagonize dCVS after aSAH.
Assuntos
Dinoprosta/toxicidade , Simendana/uso terapêutico , Hemorragia Subaracnóidea/tratamento farmacológico , Vasoconstrição/efeitos dos fármacos , Vasodilatadores/uso terapêutico , Animais , Relação Dose-Resposta a Droga , Masculino , Técnicas de Cultura de Órgãos , Ratos , Ratos Sprague-Dawley , Simendana/farmacologia , Hemorragia Subaracnóidea/fisiopatologia , Vasoconstrição/fisiologia , Vasodilatadores/farmacologiaRESUMO
Purpose: We evaluate the ocular tissue distribution and retinal toxicity of unoprostone (UNO) during 12 months, after transscleral sustained-UNO administration using a drug delivery device in monkey eyes. Methods: The device consisted of a reservoir, controlled-release cover, and a drug formulation of photopolymerized polyethylene glycol dimethacrylate. Six mg UNO was loaded into the device (length, 17 mm; width, 4.4 mm; height, 1 mm). The concentrations of M1, a primary metabolite of UNO, in the retina, choroid, vitreous, lens, aqueous humor, iris, ciliary body, and plasma were determined by liquid chromatography-tandem mass spectrometry at 3, 6, and 12 months after implantation. Retinal toxicity was evaluated by electroretinography (ERG), optical coherence tomography (OCT), and IOP at preimplantation, and at 6, 9, and 12 months after implantation. Focal ERGs were performed at 9 and 12 months after implantation. Results: M1 was detected in the choroid and retina with maximum peaks of 243.2 and 8.41 ng/g at 6 months, respectively. M1 in the ciliary body and iris was detected with maximum peaks of 7.66 and 10.4 ng/g at 6 and 12 months, respectively. Less than 1 ng/mL or ng/g of M1 was detected in the aqueous humor, vitreous, and lens. No changes were observed in retinal function as assessed by ERG, IOP, or macula thickness and retinal histology by OCT examinations during the 12-month period. No differences in focal ERG amplitudes, especially in the macula, were observed. Conclusions: The device provided intraocular sustained delivery of UNO for 12 months without producing severe retinal toxicity.
Assuntos
Anti-Hipertensivos/farmacocinética , Dinoprosta/análogos & derivados , Sistemas de Liberação de Medicamentos , Animais , Anti-Hipertensivos/toxicidade , Cromatografia Líquida , Preparações de Ação Retardada , Dinoprosta/farmacocinética , Dinoprosta/toxicidade , Avaliação Pré-Clínica de Medicamentos , Eletrorretinografia , Pressão Intraocular/efeitos dos fármacos , Macaca , Macaca fascicularis , Metacrilatos/química , Polietilenoglicóis/química , Retina/efeitos dos fármacos , Retina/fisiologia , Esclera/metabolismo , Espectrometria de Massas em Tandem , Distribuição Tecidual , Tomografia de Coerência ÓpticaRESUMO
Oxidative stress-induced antioxidant adaptive response would be particularly important to cells in high reactive oxygen species (ROS) environments. We aimed to determine the dynamic adaptive response of antioxidant enzymatic systems in sheep corpus luteum (CL) during PGF2alpha-induced luteal cell death. Activities of superoxide dismutase (SOD1 and SOD2), catalase (CAT), glutathione peroxidase (GPX) and glutathione reductase (GSR), and in situ DNA fragmentation were determined in CL at day 10 of the estrous cycle (0 h) and at 12, 24 or 48 h after PGF2alpha injection. A decrease in plasma progesterone concentration was first observed at 6 h after treatment (P < 0.05). Apoptotic cells were rarely observed in the CL at 0 h (less than 0.7%), and their incidence increased (P < 0.01) by 12 h post-PGF2alpha (11.7%) and remained thereafter elevated through 48 h. Activities of SOD1, SOD2, GPX and GSR were not changed at any time points after PGF2alpha treatment. CAT activity increased at 12 h (P < 0.01) and at 24 h (P < 0.05) after PGF2alpha treatment as compared to that at 0 h. These findings demonstrate that PGF2alpha induce luteal cell death without depressing the activity of antioxidant enzymes. It is suggested that transient increase in CAT activity is an adaptive response of the CL to oxidative stress induced by PGF2alpha.
Assuntos
Antioxidantes/metabolismo , Apoptose , Catalase/metabolismo , Dinoprosta/toxicidade , Células Lúteas/efeitos dos fármacos , Estresse Oxidativo , Adaptação Fisiológica , Animais , Dinoprosta/antagonistas & inibidores , Feminino , Células Lúteas/citologia , Células Lúteas/enzimologia , Oxirredutases/metabolismo , Ovinos , Regulação para CimaRESUMO
The effect of prostaglandin (PG) F2 alpha-isopropyl ester (IE), PGA2, or PGA2-IE on intraocular pressure (IOP) was tested in eight cynomolgus monkey eyes with argon laser-induced glaucoma. Dose-response testing and baseline IOP measurements were done. For multiple dose testing, 5 micrograms in 25 microliters (0.02%) of each PG was topically applied twice daily for 5 days. The IOP was measured at 30- or 60-minute intervals for 6 hours after the morning dose each day. A significant (P less than 0.05) reduction of IOP peaked at 5-9 mm Hg below baseline values on the 5th day of treatment for each PG. The ocular hypotensive effect of these PGs progressively became more pronounced during the course of twice-daily dosing, with a significant reduction maintained at least 17 hours after some doses. No more than trace aqueous flare and no cells were observed in any eye during the course of treatment. These findings demonstrate that PGs other than F2 alpha are potent ocular hypotensive agents in primates.
Assuntos
Dinoprosta/análogos & derivados , Glaucoma/tratamento farmacológico , Prostaglandinas A/uso terapêutico , Administração Tópica , Animais , Dinoprosta/uso terapêutico , Dinoprosta/toxicidade , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Pressão Intraocular/efeitos dos fármacos , Macaca fascicularis , Prostaglandinas A/toxicidadeRESUMO
1. We analysed the pulmonary hypertensive effects of the F2-isoprostane derivative, 8-iso-prostaglandin F2alpha (8-iso-PGF2alpha), in comparison with those of the high efficacy thromboxane A2/prostanoid (TP) receptor agonist, U-46619, in pentobarbitone-anaesthetized, open-chest rats (n=4-15 per group). 2. 8-iso-PGF2alpha produced dose-dependent increases in mean pulmonary arterial pressure, with an ED50 of 39.0 (31.4-50.6) microg kg(-1), i.v. (geometric mean with 95% confidence limits in parentheses) compared to 1.4 (1.1-2.3) microg kg(-1), i.v., for U-46619. The maximum responses evoked by U-46619 and 8-iso-PGF2alpha were not statistically significantly different (21.0+/-1.0 and 25.8+/-1.9 mmHg at 10 microg kg(-1) of U-46619 and 630 microg kg(-1) of 8-iso-PGF2alpha, respectively). 3. The TP receptor antagonist, SQ 29,548 (0.63 mg kg(-1), i.v. + 0.63 mg kg(-1) h(-1)) fully antagonised both U-46619 and 8-iso-PGF2alpha-induced pulmonary hypertensive responses. 4. Further experiments were carried out to determine whether 8-iso-PGF2alpha antagonized the pulmonary hypertensive responses evoked by U-46619, or those induced by itself, as would be predicted for a partial agonist. However, ED10 or ED25 doses of 8-iso-PGF2alpha (10 or 20 microg kg(-1), i.v.) failed to reduce the pulmonary hypertensive responses induced either by U-46619 or by itself. 5. The data suggest that in the pulmonary vascular bed of the rat, 8-iso-PGF2alpha acts as an agonist of high intrinsic activity at SQ 29,548-sensitive (probably TP) receptors.
Assuntos
Dinoprosta/análogos & derivados , Hipertensão Pulmonar/induzido quimicamente , Receptores de Tromboxanos/fisiologia , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/administração & dosagem , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/toxicidade , Animais , Pressão Sanguínea/efeitos dos fármacos , Compostos Bicíclicos Heterocíclicos com Pontes , Dinoprosta/administração & dosagem , Dinoprosta/toxicidade , Relação Dose-Resposta a Droga , F2-Isoprostanos , Ácidos Graxos Insaturados , Hidrazinas/administração & dosagem , Hidrazinas/farmacologia , Hipertensão Pulmonar/fisiopatologia , Infusões Intravenosas , Masculino , Ratos , Ratos Sprague-Dawley , Receptores de Tromboxanos/agonistas , Receptores de Tromboxanos/antagonistas & inibidores , Vasoconstritores/administração & dosagem , Vasoconstritores/toxicidadeRESUMO
In 5 conscious piglets with electrodes implanted on the antrum pylori, duodenum, jejunum and ileum, the effect of intravenous infusion of PGF2 alpha, 1 and 10 micrograms/kg/min during 2 h, on gastrointestinal electrical activity was studied. The influence of the PG, 10(-8) to 10(-4) M, on longitudinal tissue strips from the same segments was also examined. The in vitro results demonstrate that PGF2 alpha has only a weak contractile effect on duodenal and jejunal strips. This effect was enhanced in the presence of atropine and indomethacin. In the in vivo part of the study PGF2 alpha induced an inhibition of antral electrical activity as evidenced by a prolongation of the inhibitory phases and a reduction of the frequency of the fast oscillations. In the small intestine only ileal activity was changed significantly. PGF2 alpha provoked an increase in the phase II or irregular spiking activity and an increase in the interval of the migrating myoelectrical complexes in this segment.
Assuntos
Dinoprosta/farmacologia , Motilidade Gastrointestinal/efeitos dos fármacos , Intestino Delgado/fisiopatologia , Complexo Mioelétrico Migratório/efeitos dos fármacos , Antro Pilórico/fisiopatologia , Animais , Atropina/farmacologia , Estado de Consciência , Depressão Química , Dinoprosta/toxicidade , Eletromiografia , Feminino , Motilidade Gastrointestinal/fisiologia , Indometacina/farmacologia , Infusões Intravenosas , Complexo Mioelétrico Migratório/fisiologia , Suínos/fisiologiaRESUMO
We investigated the effects of intraperitoneal administration of adrenoceptor antagonists to the hyperthermia and hyperglycemia induced by prostaglandin F2 alpha (50 micrograms) injected into the third cerebral ventricle in anesthetized rats. Phentolamine inhibited the hyperthermia and hyperglycemia induced by prostaglandin F2 alpha. Prazosin inhibited the hyperthermia induced by prostaglandin F2 alpha, while enhancing the hyperglycemia. Yohimbine inhibited the prostaglandin F2 alpha-induced hyperglycemia without an effect on the hyperthermia. Propranolol had no effect on either prostaglandin F2 alpha-induced hyperglycemia or hyperthermia. These observations suggest that the hyperglycemia induced by prostaglandin F2 alpha is regulated by alpha 2-adrenoceptor systems while the hyperthermia is regulated by alpha 1-adrenoceptor systems in rats.
Assuntos
Antagonistas Adrenérgicos alfa/uso terapêutico , Dinoprosta/toxicidade , Febre/tratamento farmacológico , Hiperglicemia/tratamento farmacológico , Antagonistas Adrenérgicos alfa/administração & dosagem , Antagonistas Adrenérgicos alfa/farmacologia , Animais , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Temperatura Corporal/efeitos dos fármacos , Dinoprosta/administração & dosagem , Febre/induzido quimicamente , Hiperglicemia/induzido quimicamente , Injeções Intraperitoneais , Injeções Intraventriculares , Masculino , Fentolamina/administração & dosagem , Fentolamina/farmacologia , Fentolamina/uso terapêutico , Prazosina/administração & dosagem , Prazosina/farmacologia , Prazosina/uso terapêutico , Propranolol/administração & dosagem , Propranolol/farmacologia , Propranolol/uso terapêutico , Ratos , Ratos Wistar , Ioimbina/administração & dosagem , Ioimbina/farmacologia , Ioimbina/uso terapêuticoRESUMO
The enhancement of carcinogen-induced malignant transformation of C3H/M2 mouse fibroblasts by the tumor promoters 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and 12-O-tetradecanoylphorbol-13-acetate (TPA) is associated with the induction of cyclooxygenase expression and the stimulation of prostaglandin (PG) formation. Therefore, the potential of PGs, i.e., PGF(2alpha) and PGE(2), for tumor promotion was studied in the two-step C3H/M2 cell transformation assay, a model of the multi-step process of carcinogenesis. The transformation of fibroblasts was clearly enhanced by the addition of PGF(2alpha) in the promotion phase after pretreatment with a subthreshold dose of a carcinogen (3-methylcholanthrene or N-methyl-N'-nitro-N-nitrosoguanidine). No enhancement of cell transformation was observed in cells without carcinogen-pretreatment, i.e., PGF(2alpha) had no tumor initiating potential. The promotional effect was dose-dependent with a maximum at 16 nM PGF(2alpha). PGE(2) had no significant effect in this assay. Furthermore, PGF(2alpha) (but not PGE(2)) clearly reduced the inhibition of TPA-induced promotion by NS-398, an isozyme-specific inhibitor of cyclooxygenase-2. The inhibition of TPA- or TCDD-induced promotion by the non-specific cyclooxygenase inhibitor indomethacin was not affected by co-treatment with PGF(2alpha) and PGE(2). Our data suggest that PGF(2alpha) acts as an endogenous promoter of cell transformation implying that it may also be critically involved in tumor promoter-induced signalling transfer cascades ultimately triggering the process of carcinogenesis.
Assuntos
Transformação Celular Neoplásica/induzido quimicamente , Dinoprosta/toxicidade , Animais , Carcinógenos/toxicidade , Inibidores de Ciclo-Oxigenase/farmacologia , Dinoprostona/toxicidade , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Fibroblastos/efeitos dos fármacos , Metilcolantreno/toxicidade , Metilnitronitrosoguanidina/toxicidade , Camundongos , Camundongos Endogâmicos C3H , Nitrobenzenos/farmacologia , Dibenzodioxinas Policloradas/antagonistas & inibidores , Dibenzodioxinas Policloradas/metabolismo , Dibenzodioxinas Policloradas/toxicidade , Sulfonamidas/farmacologia , Acetato de Tetradecanoilforbol/antagonistas & inibidores , Acetato de Tetradecanoilforbol/toxicidadeRESUMO
INTRODUCTION: Prostaglandins, especially PG-F2 alpha, have recently been introduced as a new local glaucoma medication. The modulation of cell proliferation and collagen synthesis in various tissues are the major effects of these agents. However, it is unknown whether PG-F2 alpha also modulates the proliferation of the corneal endothelium. METHODS: Bovine corneal endothelial cells (BCEC) were cultured according to established protocols. Experiments were performed after the 1st passage under serum-reduced conditions. A total of 10(4) cells/well were seeded and the cells were then incubated with different (5 x 10(-6) bis 5 x 10(-4) mg/ml) concentrations of PG-F2 (Sigma). The number of cells was determined every 24 h until day 5. Toxicity tests were performed by means of the trypan blue exclusion assay. RESULTS: PG-F2 alpha induced a significant stimulation of BCEC proliferation with all concentrations tested. At the highest concentration of PG-F2 alpha, a 2-fold increase in cell number was found after 5 days only compared to unsupplemented control cultures. No signs of cellular toxicity or morphological alterations could be detected in PG-F2 alpha-supplemented cells. DISCUSSION: For the first time, the present study demonstrates a stimulatory effect of PG-F2 alpha on the corneal endothelium. It appears that this effect is also induced by the PG-F2 alpha concentration determined in the aqueous humour of patients after topical latanoprost application. However, due to the strong contact inhibition of endothelial cells in situ, these results cannot be directly extrapolated to the situation in patients with topical latanoprost treatment.
Assuntos
Divisão Celular/efeitos dos fármacos , Dinoprosta/farmacologia , Endotélio Corneano/efeitos dos fármacos , Animais , Bovinos , Contagem de Células , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Dinoprosta/toxicidade , Relação Dose-Resposta a Droga , Técnicas In VitroRESUMO
Effects of baicalein on release of slow reacting substance of anaphylaxis (SRS-A) or leukotriene (LT) from the sensitized guinea pig lung after antigen challenge and tonus of guinea pig tracheal muscles were studied. Baicalein inhibited release of SRS-A from sensitized guinea pig lung after antigen challenge. High-performance liquid chromatography (HPLC) analysis revealed that released SRS-A consisted to LTC4 and D4. Baicalein also reduced release of LTC4 and D4 from the sensitized lung after antigen challenge. Baicalein relaxed the isolated guinea pig tracheal smooth muscle contracted by LTD4, carbachol or histamine. However, this compound produced a contraction when the tracheal muscle was contracted by prostaglandin F2 alpha(PGF2 alpha). This contraction by baicalein was abolished by pretreatment with indomethacin, a cyclooxygenase inhibitor. Baicalein elicited a relaxation in the normal non-sensitized preparation but a contraction in the tissue isolated from actively sensitized guinea pig in 4 among 7 cases. Baicalein also produced a contraction in the trachea pretreated with phorbol dibutyrate and contracted by carbachol, which was eliminated after treatment with indomethacin. The results suggest that baicalein exerts action via, at least, two different mechanisms, the inhibition of releasing SRS-A (LTs) and direct relaxing effects on the trachea. Besides, baicalein seems to produce contraction under certain conditions, which may involve stimulation of the cyclooxygenase pathway.
Assuntos
Inibidores Enzimáticos/farmacologia , Flavanonas , Flavonoides/farmacologia , Pulmão/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , SRS-A/metabolismo , Animais , Bioensaio , Cromatografia Líquida de Alta Pressão , Inibidores de Ciclo-Oxigenase/toxicidade , Dinoprosta/toxicidade , Relação Dose-Resposta a Droga , Ativação Enzimática/efeitos dos fármacos , Cobaias , Íleo/efeitos dos fármacos , Indometacina/toxicidade , Pulmão/metabolismo , Masculino , Contração Muscular/efeitos dos fármacos , Ovalbumina/administração & dosagem , Ovalbumina/imunologia , Ovalbumina/toxicidade , Ocitócicos/toxicidade , Proteína Quinase C/metabolismo , Traqueia/efeitos dos fármacos , Traqueia/metabolismoRESUMO
The effect of nitric oxide synthase inhibition on prostaglandin F2 alpha (PGF2 alpha)-induced ocular hyperemia in the rabbit has been studied. PGF2 alpha was administered topically as the isopropyl ester (PGF2 alpha-IE) unilaterally, with the other eye serving as a control. The regional blood flow in the eye was determined with radioactively-labelled microspheres in conscious animals. Synthesis of nitric oxide (NO) was blocked by L-NMMA (200 mg kg-1 b.w., i.v.). PGF2 alpha-IE induced marked hyperemia of the surface structures of the eye (conjunctiva, eye lids, nictitating membrane, anterior sclera), as well as increased blood flow of the anterior uvea. L-NMMA blocked the hyperemia of the surface structures but not completely the increase in blood flow of the anterior uvea. PhXA41 (13,14-dihydro-17-phenyl-18,19,20-trinor-PGF2 alpha-isopropyl ester), a selective prostaglandin FP-receptor agonist, had no significant effect on the ocular blood flow. These results indicate that PGF2 alpha causes surface hyperemia of the eye by activating nitric oxide synthase, but this mechanism seems to be only partly involved in the increase in blood flow of the ciliary processes and the iris. The PGF2 alpha-induced ocular hyperemia is unlikely to be mediated by FP receptors.