RESUMEN
Alibertia edulis leaf extract is commonly used in folk medicine, with rutin caffeic and vanillic acids being its major compounds. The Alibertia edulis leaf extract was investigated for its pharmacological effects via platelet aggregation, calcium mobilization, cyclic nucleotides levels, vasodilator-stimulated phosphoprotein Ser157 and Ser239 and protein kinase Cß2 phosphorylation, thromboxane B2, cyclooxygenases 1 and 2, docking and molecular dynamics. Alibertia edulis leaf extract significantly inhibited (100-1000 µg mL-1) platelet aggregation induced by different agonists. Arachidonic acid increased levels of calcium and thromboxane B2, phosphorylation of vasodilator-stimulated phosphoprotein Ser157 and Ser239, and protein kinase Cß, which were significantly reduced by Alibertia edulis leaf extract, rutin, and caffeic acid as well mixtures of rutin/caffeic acid. Cyclooxygenase 1 activity was inhibited for Alibertia edulis leaf extract, rutin and caffeic acid. These inhibitions were firsrtly explored by specific stabilization of rutin and caffeic acid compared to diclofenac at the catalytic site from docking score and free-energy dissociation profiles. Then, simulations detailed the rutin interactions close to the heme group and Tyr385, responsible for catalyzing the conversion of arachidonic acid to its products. Our results reveal the antiplatelet aggregation properties of Alibertia edulis leaf extract, rutin and caffeic acid providing pharmacological information about its origin from cyclooxygenase 1 inhibition and its downstream pathway.
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Regulación de la Expresión Génica/efectos de los fármacos , Extractos Vegetales/farmacología , Agregación Plaquetaria/efectos de los fármacos , Prostaglandina-Endoperóxido Sintasas/metabolismo , Rubiaceae/química , Tromboxanos/antagonistas & inhibidores , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/administración & dosificación , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/farmacología , Adenosina Difosfato/administración & dosificación , Adenosina Difosfato/farmacología , Animales , Ácido Araquidónico/administración & dosificación , Ácido Araquidónico/farmacología , Calcio/metabolismo , Colágeno/administración & dosificación , Colágeno/farmacología , Inhibidores de la Ciclooxigenasa , Humanos , Extractos Vegetales/química , Hojas de la Planta/química , Tromboxanos/genética , Tromboxanos/metabolismo , Pez CebraRESUMEN
OBJECTIVES: To test the feasibility, safety, and efficacy of intratracheal delivery of nitric oxide (NO) generated from air by pulsed electrical discharge via a Scoop catheter. STUDY DESIGN: We studied healthy 3- to 4-month-old lambs weighing 34 ± 4 kg (mean ± SD, n = 6). A transtracheal Scoop catheter was inserted through a cuffed tracheostomy tube. U46619 was infused to increase mean pulmonary arterial pressure (mPAP) from 16 ± 1 to 32 ± 3 mmHg (mean ± SD). Electrically generated NO was delivered via the Scoop catheter to awake lambs. A sampling line, to monitor NO and nitrogen dioxide (NO2) levels, was placed in the distal trachea of the lambs. The effect of varying doses of electrically generated NO, produced continuously, on pulmonary hypertension was assessed. RESULTS: In awake lambs with acute pulmonary hypertension, NO was continuously delivered via the Scoop catheter at 400 ml/min. NO induced pulmonary vasodilation. NO2 levels, measured in the trachea, were below 0.5 ppm at intratracheal NO doses of 10-80 ppm. No changes were detected in the levels of methemoglobin in blood samples before and after 5 min of NO breathing. CONCLUSIONS: Continuously delivering electrically generated NO through a Scoop catheter produces vasodilation of the pulmonary vasculature of awake lambs with pulmonary hypertension. Transtracheal NO delivery may provide a long-term treatment for patients with chronic pulmonary hypertension as an outpatient without requiring a mask or tracheal intubation.
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Hipertensión Pulmonar/tratamiento farmacológico , Óxido Nítrico/farmacología , Vigilia/efectos de los fármacos , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/administración & dosificación , Administración por Inhalación , Aire , Animales , Electricidad , Hipertensión Pulmonar/inducido químicamente , Infusiones Intravenosas , Óxido Nítrico/administración & dosificación , Óxido Nítrico/análisis , Ovinos , Tráquea/química , Vasodilatación/efectos de los fármacosRESUMEN
OBJECTIVE: To determine if continuous infusion of taurocholic acid into the fetoplacental and intervillous circulation of a placental cotyledon affects the fetal arterial pressure response after injection of the thromboxane mimetic U44619. Taurine conjugated bile acid is one bile acid putatively mediating intrahepatic cholestasis of pregnancy (ICP). STUDY DESIGN: We selected 5 placentas from normal, unlabored patients. Two cotyledons from each placenta were isolated and dually perfused. Taurocholic acid was continuously infused into the fetoplacental and intervillous circulation of the test cotyledon. After 30 minutes U44619 was injected into both the test and control cotyledon vascular circuits. Pressure excursions were measured and compared to baseline pressures using a paired Student's t test. RESULTS: There was significant attenuation of the pressure excursion in the cotyledons perfused with taurocholic acid as compared to controls after injection of U44619. The difference from baseline in the taurocholic cotyledon compared with controls was 44.2 mmHg vs. 71.8 mmHg (p = 0.009). CONCLUSION: The perfusion of taurocholic acid attenuated the pressure response to thromboxane mimetic U44619 in the fetoplacental arterial circulation of a placental cotyledon as compared to control. This finding in our ex-vivo model may represent changes that occur in the placental vasculature with intrahepatic cholestasis of pregnancy. These placentas may have dysregulated vascular tone, which could contribute to the adverse fetal effects observed in ICP.
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Presión Sanguínea/efectos de los fármacos , Colagogos y Coleréticos/administración & dosificación , Feto/irrigación sanguínea , Placenta/efectos de los fármacos , Ácido Taurocólico/administración & dosificación , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/administración & dosificación , Colestasis Intrahepática/tratamiento farmacológico , Femenino , Humanos , Inyecciones , Perfusión , Placenta/irrigación sanguínea , Embarazo , Complicaciones del Embarazo/tratamiento farmacológico , Vasoconstrictores/administración & dosificaciónRESUMEN
This chapter describes the use of bilateral vagotomy as a tool for determining autonomic regulation of airway responses to the exogenous bronchoconstrictor thromboxane mimetic U46619 in an acute model of asthma in the mouse. Mice receive a sensitization of ovalbumin (OVA) and adjuvant followed by 3 days of OVA aerosol to induce allergic airway disease characterized by bronchoalveolar lavage (BAL) eosinophilia, increased mucus production, and elevated IgE and IL-13. Using a small animal ventilator (Flexi-vent) and the forced oscillatory technique fit to the constant phase model of the lung, a variety of features associated with human asthma can be evaluated in mouse models. For example, this protocol describes the methods to evaluate central and peripheral airway mechanics, airway resistance (R aw) and tissue damping (G), and tissue elastance (H) in response to U46619. The contribution of autonomic nerves in this response is determined by severing both the left and right vagus nerves prior to aerosol challenge.
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Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/administración & dosificación , Alérgenos/inmunología , Asma/inmunología , Líquido del Lavado Bronquioalveolar/inmunología , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/inmunología , Animales , Asma/inducido químicamente , Asma/complicaciones , Asma/patología , Modelos Animales de Enfermedad , Humanos , Ratones , Eosinofilia Pulmonar/inducido químicamente , Eosinofilia Pulmonar/complicaciones , Eosinofilia Pulmonar/inmunología , VagotomíaRESUMEN
A previous study of Gulf War veteran's illnesses (GWVI) observed evidence of platelet activation in a majority of patients with GWVI. To further characterize platelet function, we studied 43 patients (40 men) with GWVI (GWVI+) and 21 veterans who served concurrently in the Gulf War but who lacked criteria for GWVI (GWVI-). All participants were free of infection and known inflammatory diseases. Studies performed included platelet count, immature platelet fraction (IPF), plasma thrombopoietin (TPO), C-reactive protein (CRP), platelet aggregation and ATP secretion in response to six agonists, and spontaneous aggregation. Platelet counts and CRP were significantly elevated in GWVI+ compared to GWVI- patients without elevation in IPF or TPO. Platelet aggregation did not differ between GWVI+ and GWVI- patients except for spontaneous aggregation that was significantly greater in GWVI+ patients. Platelet ATP secretion was similar in the two groups, except the response to 50 µmol/l thrombin receptor agonist peptide 6 (TRAP 6) was significantly greater in GWVI+ patients. When platelet aggregation was analyzed in relation to CRP, the response to 0.5 µmol/l U46619 was significantly greater in patients whose CRP was at least 2 µg/ml. Therefore, GWVI+ patients had elevated platelet counts, spontaneous aggregation, TRAP 6-induced secretion, and CRP, but no impairment of platelet function. The increased platelet counts and U46619-induced aggregation appear to be consequences of an underlying inflammatory state in GWVI.
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Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/administración & dosificación , Proteína C-Reactiva/metabolismo , Guerra del Golfo , Inflamación/sangre , Trombopoyetina/sangre , Tromboxanos/administración & dosificación , Veteranos , Adulto , Anciano , Enfermedad Crónica , Femenino , Humanos , Masculino , Persona de Mediana Edad , Agregación Plaquetaria , Recuento de PlaquetasRESUMEN
We previously reported that both nitric oxide (NO) generated from NO synthase by bombesin and NO generated from SIN-1 (NO donor) activate the brain cyclooxygenase (COX) (COX-1 for bombesin), thereby eliciting the secretion of both catecholamines (CA) from the adrenal medulla by brain thromboxane A(2)-mediated mechanisms in rats. NO exerts its effects via not only soluble guanylate cyclase, but also protein S-nitrosylation, covalent modification of a protein cysteine thiol. In this study, we clarified the central mechanisms involved in the bombesin-induced elevation of plasma CA with regard to the relationship between NO and COX-1 using anesthetized rats. Bombesin (1 nmol/animal, i.c.v.)-induced elevation of plasma CA was attenuated by carboxy-PTIO (NO scavenger) (0.5 and 2.5 µmol/animal, i.c.v.), but was not influenced by ODQ (soluble guanylate cyclase inhibitor) (100 and 300 nmol/animal, i.c.v.). The bombesin-induced response was effectively reduced by dithiothreitol (thiol-reducing reagent) (0.4 and 1.9 µmol/kg/animal, i.c.v.) and by N-ethylmaleimide (thiol-alkylating reagent) (0.5 and 2.4 µmol/kg/animal, i.c.v.). The doses of dithiothreitol also reduced the SIN-1 (1.2 µmol/animal, i.c.v.)-induced elevation of plasma CA, but had no effect on the U-46619 (thromboxane A(2) analog) (100 nmol/animal, i.c.v.)-induced elevation of plasma CA even at higher doses (1.9 and 9.7 µmol/kg/animal, i.c.v.). Immunohistochemical studies demonstrated that the bombesin increased S-nitroso-cysteine-positive cells co-localized with COX-1 in the spinally projecting neurons of the hypothalamic paraventricular nucleus (PVN). Taken together, endogenous NO seems to mediate centrally administered bombesin-induced activation of adrenomedullary outflow at least in part by S-nitrosylation of COX-1 in the spinally projecting PVN neurons in rats.
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Médula Suprarrenal/efectos de los fármacos , Bombesina/farmacología , Catecolaminas/sangre , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/administración & dosificación , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/farmacología , Médula Suprarrenal/metabolismo , Animales , Benzoatos/administración & dosificación , Benzoatos/farmacología , Bombesina/administración & dosificación , Bombesina/antagonistas & inhibidores , Encéfalo/efectos de los fármacos , Cisteína/análogos & derivados , Cisteína/metabolismo , Ditiotreitol/administración & dosificación , Ditiotreitol/farmacología , Relación Dosis-Respuesta a Droga , Etilmaleimida/administración & dosificación , Etilmaleimida/farmacología , Imidazoles/administración & dosificación , Imidazoles/farmacología , Inyecciones Intraventriculares , Masculino , Molsidomina/administración & dosificación , Molsidomina/análogos & derivados , Molsidomina/antagonistas & inhibidores , Molsidomina/farmacología , Donantes de Óxido Nítrico/administración & dosificación , Donantes de Óxido Nítrico/farmacología , Oxadiazoles/administración & dosificación , Oxadiazoles/farmacología , Núcleo Hipotalámico Paraventricular/efectos de los fármacos , Núcleo Hipotalámico Paraventricular/metabolismo , Quinoxalinas/administración & dosificación , Quinoxalinas/farmacología , Ratas , Ratas Wistar , S-Nitrosotioles/metabolismo , Reactivos de Sulfhidrilo/administración & dosificación , Reactivos de Sulfhidrilo/farmacologíaRESUMEN
INTRODUCTION: Adverse drug reactions may be manifested through changes in microvascular function (e.g. angioedema) or by subtle modification of the mechanisms controlling vascular tone, such as flow-mediated dilatation. Until now the early detection of such adverse drug reactions has been hampered by the lack of a predictive in vitro model. This in vitro model can be utilised to test potential effect of drugs on the normal responses of the vascular system. METHODS: The PM-1, a new automated perfusion myograph, allows detection of the external and internal dimensions of tubular biological structures and regulates both the intraluminal pressure and flow independently. Drugs can be infused intraluminally or extraluminally (by adding to the bathing solution) to determine effects on constriction, relaxation or modulation of vascular tone. The novel imaging system also facilitates the measurement of vascular permeability using dyes introduced intraluminally into the vessel. RESULTS: To assess effects on flow-mediated dilatation we increased flow rate in pressurised human subcutaneous arteries (<500mum diameter) in the absence and presence of various drugs. Increasing flow from 0.04ml/min to 0.3ml/min resulted in a 39+/-3% relaxation of a U46619 pre-constriction (10(-6)M). This was enhanced in the presence of Ivermectin and inhibited in the presence of 100microM L-NAME (316+/-169% and 16+/-1% respectively).To assess effects on vascular permeability we infused albumin-bound Evans blue dye through the lumen of human subcutaneous arteries as a marker, in the absence and presence of a modulatory drug. Infusion of thrombin (0.5units/ml) through the vessel lumen caused an 11.8% increase in vessel permeability compared to vehicle infusion. CONCLUSION: The development of the PM-1 allows new drugs to be tested in relevant human or animal tissues at an early stage allowing crucial go/no-go decisions to be made early in development and giving a more complete picture of the overall effects of test compounds on vascular function.
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Arterias/efectos de los fármacos , Arterias/fisiología , Permeabilidad Capilar/efectos de los fármacos , Microvasos/efectos de los fármacos , Microvasos/fisiología , Vasodilatación/efectos de los fármacos , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/administración & dosificación , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/farmacología , Acetilcolina/administración & dosificación , Acetilcolina/farmacología , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/farmacología , Hemostáticos/administración & dosificación , Hemostáticos/farmacología , Humanos , Ivermectina/administración & dosificación , Ivermectina/farmacología , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/fisiología , Músculo Liso Vascular/fisiopatología , Miografía , NG-Nitroarginina Metil Éster/administración & dosificación , NG-Nitroarginina Metil Éster/farmacología , Presión , Trombina/administración & dosificación , Trombina/farmacología , Vasoconstrictores/administración & dosificación , Vasoconstrictores/farmacología , Vasodilatadores/administración & dosificación , Vasodilatadores/farmacologíaRESUMEN
Previously, we reported the involvement of brain omega-6 prostanoids, especially prostaglandin E(2) and thromboxane A(2), in the activation of central sympatho-adrenomedullary outflow in rats. omega-3 Prostanoids, including prostaglandin E(3) and thromboxane A(3), are believed to be less bioactive than omega-6 prostanoids, although studies on the functions of omega-3 prostanoids in the central nervous system have not been reported. In the present study, therefore, we compared the effects of centrally administered omega-3 prostanoids, prostaglandin E(3) and thromboxane A(3), with those of omega-6 prostanoids, prostaglandin E(2) and thromboxane A(2), on the plasma catecholamines in anesthetized rats. Intracerebroventricularly (i.c.v.) administered prostaglandin E(2) (0.15, 0.3 and 1.5 nmol/animal) and prostaglandin E(3) (0.3 and 3 nmol/animal) predominantly elevated plasma noradrenaline but not adrenaline, but the latter was less efficient than the former. On the other hand, U-46619 (an analog of thromboxane A(2)) (30, 100 and 300 nmol/animal, i.c.v.) and Delta(17)-U-46619 (an analog of thromboxane A(3)) (100 and 300 nmol/animal, i.c.v.) both elevated plasma catecholamines (adrenaline>>noradrenaline) to the same degree. These results suggest that centrally administered prostaglandin E(3) is less effective than prostaglandin E(2) to elevate plasma noradrenaline, and that thromboxane A(3) is almost as equipotent as thromboxane A(2) to elevate plasma catecholamines in rats.
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Epinefrina/sangre , Norepinefrina/sangre , Prostaglandinas E/administración & dosificación , Prostaglandinas E/farmacología , Tromboxanos/administración & dosificación , Tromboxanos/farmacología , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/administración & dosificación , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/análogos & derivados , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/farmacología , Alprostadil/administración & dosificación , Alprostadil/análogos & derivados , Alprostadil/farmacología , Anestesia , Animales , Catecolaminas/sangre , Dinoprostona/administración & dosificación , Dinoprostona/farmacología , Masculino , Ratas , Ratas Wistar , Tromboxano A2/administración & dosificación , Tromboxano A2/análogos & derivados , Tromboxano A2/farmacología , Uretano/farmacologíaRESUMEN
The small GTP-binding protein Rho and its downstream effector, Rho-kinase, are important regulators of vasoconstrictor tone. Rho-kinase is upregulated in experimental models of pulmonary hypertension, and Rho-kinase inhibitors decrease pulmonary arterial pressure in rodents with monocrotaline and chronic hypoxia-induced pulmonary hypertension. However, less is known about responses to fasudil when pulmonary vascular resistance is elevated on an acute basis by vasoconstrictor agents and ventilatory hypoxia. In the present study, intravenous injections of fasudil reversed pulmonary hypertensive responses to intravenous infusion of the thromboxane receptor agonist, U-46619 and ventilation with a 10% O(2) gas mixture and inhibited pulmonary vasoconstrictor responses to intravenous injections of angiotensin II, BAY K 8644, and U-46619 without prior exposure to agonists, which can upregulate Rho-kinase activity. The calcium channel blocker isradipine and fasudil had similar effects and in small doses had additive effects in blunting vasoconstrictor responses, suggesting parallel and series mechanisms in the lung. When pulmonary vascular resistance was increased with U-46619, fasudil produced similar decreases in pulmonary and systemic arterial pressure, whereas isradipine produced greater decreases in systemic arterial pressure. The hypoxic pressor response was enhanced by 5-10 mg/kg iv nitro-L-arginine methyl ester (L-NAME), and fasudil or isradipine reversed the pulmonary hypertensive response to hypoxia in control and in L-NAME-treated animals, suggesting that the response is mediated by Rho-kinase and L-type Ca(2+) channels. These results suggest that Rho-kinase is constitutively active in regulating baseline tone and vasoconstrictor responses in the lung under physiological conditions and that Rho-kinase inhibition attenuates pulmonary vasoconstrictor responses to agents that act by different mechanisms without prior exposure to the agonist.
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1-(5-Isoquinolinesulfonil)-2-Metilpiperazina/análogos & derivados , Anestesia , Inhibidores de Proteínas Quinasas/farmacología , Circulación Pulmonar/efectos de los fármacos , Vasodilatadores/farmacología , Quinasas Asociadas a rho/antagonistas & inhibidores , 1-(5-Isoquinolinesulfonil)-2-Metilpiperazina/administración & dosificación , 1-(5-Isoquinolinesulfonil)-2-Metilpiperazina/farmacología , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/administración & dosificación , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/farmacología , Ácido 3-piridinacarboxílico, 1,4-dihidro-2,6-dimetil-5-nitro-4-(2-(trifluorometil)fenil)-, Éster Metílico/farmacología , Angiotensina II/farmacología , Animales , Análisis de los Gases de la Sangre , Presión Sanguínea/efectos de los fármacos , Gasto Cardíaco/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Hipoxia/enzimología , Inyecciones Intravenosas , Isradipino/administración & dosificación , Isradipino/farmacología , Pulmón/enzimología , Masculino , NG-Nitroarginina Metil Éster/farmacología , Inhibidores de Proteínas Quinasas/administración & dosificación , Ratas , Ratas Sprague-Dawley , Resistencia Vascular/efectos de los fármacosRESUMEN
PURPOSE: Retinal hyperperfusion resulting from disturbances in the regulation of arteriolar tone is involved in the pathophysiology of a variety of retinal diseases. The mechanisms underlying this regulation of tone involve cellular components in both the vascular wall and the perivascular tissue. However, previous in vitro studies of the influence of perivascular retinal tissue on retinal tone regulation have been hampered by the release of an endogenous relaxing factor that renders the arteriole insensitive to vasoconstrictors. The purpose of the present study was to test whether N-methyl-D-aspartate (NMDA) and gamma-amino butyric acid (GABA) receptors, and a cyclooxygenase (COX) product influence this effect of perivascular retinal tissue in vitro. METHODS: Porcine retinal arterioles were mounted in a wire myograph for isometric force measurements. The contractile effect of the prostaglandin analogue U46619 was studied on vessels with preserved perivascular retinal tissue and after this tissue had been removed. The influence of the perivascular tissue was studied after addition of NMDA (a specific agonist for a subtype of the glutamate receptor), DL-amino-5-phosphonovaleric acid (DL-APV, an antagonist at the same receptor), the natural inhibitory transmitter GABA, and picrotoxin (an antagonist at ionotropic GABA receptors). These experiments were made in the absence and presence of the COX inhibitor, ibuprofen. RESULTS: U46619 caused a concentration-dependent contraction of isolated retinal arterioles. This vasoconstriction was significantly smaller in the presence of perivascular tissue. The NMDA-receptor antagonist, DL-APV, reduced this attenuating influence of the perivascular tissue on the response to U46619, and the response could be modified by NMDA and GABA, but not by picrotoxin. However, ibuprofen totally blocked the attenuating influence of the perivascular tissue on the response to U46619. CONCLUSIONS: The inhibition of vascular contractility induced by perivascular retinal tissue in vitro involves NMDA-receptors and an effect of GABA-mimetic substance on retinal tissue. The generation of these effects involves a COX product.
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Agonistas de Aminoácidos Excitadores/farmacología , N-Metilaspartato/farmacología , Antagonistas de Prostaglandina/farmacología , Retina/fisiología , Vasos Retinianos/efectos de los fármacos , Vasos Retinianos/fisiología , Vasodilatación/fisiología , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/administración & dosificación , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/farmacología , 2-Amino-5-fosfonovalerato/farmacología , Animales , Arteriolas/efectos de los fármacos , Arteriolas/fisiología , Relación Dosis-Respuesta a Droga , Antagonistas de Aminoácidos Excitadores/farmacología , Técnicas In Vitro , Porcinos , Vasoconstricción/fisiología , Vasoconstrictores/administración & dosificación , Vasoconstrictores/farmacología , Ácido gamma-Aminobutírico/farmacologíaRESUMEN
Pulmonary veins (PV) make a significant contribution to total pulmonary vascular resistance. We investigated the cellular mechanisms by which the intravenous anesthetics propofol and thiopental alter adenosine triphosphate-sensitive potassium (KATP+) channel relaxation in canine PV. The effects of KATP+ channel inhibition (glybenclamide), cyclooxygenase inhibition (indomethacin), nitric oxide synthase inhibition (L-NAME), and L-type voltage-gated Ca2+ channel inhibition (nifedipine) on vasorelaxation responses to levcromakalim (KATP+ channel activator) alone and in combination with the anesthetics were assessed. The maximal relaxation response to levcromakalim was attenuated by removing the endothelium and by L-NAME, but not by indomethacin. Propofol (10(-5), 3x10(-5), and 10(-4) M) and thiopental (10(-4) and 3x10(-4) M) each attenuated levcromakalim relaxation in endothelium-intact (E+) rings, whereas propofol (3x10(-5) and 10(-4) M) and thiopental (3x10(-4) M) attenuated levcromakalim relaxation in endothelium-denuded (E-) rings. In E+ rings, the anesthesia-induced attenuation of levcromakalim relaxation was decreased after pretreatment with L-NAME but not with indomethacin. In E-strips, propofol (10(-4) M) and thiopental (3x10(-4) M) inhibited decreases in tension and intracellular Ca2+ concentration ([Ca2+]i) in response to levcromakalim, and these changes were abolished by nifedipine. These findings indicate that propofol and thiopental attenuate the endothelium-dependent component of KATP+ channel-induced PV vasorelaxation via an inhibitory effect on the nitric oxide pathway. Both anesthetics also attenuate the PV smooth muscle component of KATP+ channel-induced relaxation by reducing the levcromakalim-induced decrease in [Ca2+]i via an inhibitory effect on L-type voltage-gated Ca2+ channels.
Asunto(s)
Adenosina Trifosfato/metabolismo , Anestésicos Intravenosos/farmacología , Canales de Potasio/metabolismo , Propofol/farmacología , Venas Pulmonares/fisiología , Tiopental/farmacología , Vasodilatación/fisiología , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/administración & dosificación , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/farmacología , Animales , Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio Tipo L/efectos de los fármacos , Cromakalim/farmacología , Inhibidores de la Ciclooxigenasa/farmacología , Perros , Esquema de Medicación , Endotelio Vascular/fisiología , Inhibidores Enzimáticos/farmacología , Técnicas In Vitro , Masculino , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/fisiología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Venas Pulmonares/metabolismo , Vasoconstrictores/administración & dosificación , Vasoconstrictores/farmacología , Vasodilatación/efectos de los fármacos , Vasodilatadores/farmacologíaRESUMEN
Experiments were conducted in the anesthetized rabbit to investigate mechanisms for arrhythmias that occur after left atrial injection of the thromboxane A(2) (TxA(2)) mimetic U-46619. Arrhythmias were primarily of ventricular origin, dose dependent in frequency, and TxA(2) receptor mediated. The response was receptor specific since arrhythmias were absent after pretreatment with a specific TxA(2) receptor antagonist (SQ-29548) and did not occur in response to another prostaglandin, PGF(2alpha). Alterations in coronary blood flow were unlikely the cause of these arrhythmias because coronary blood flow (as measured with fluorescent microspheres) was unchanged after U-46619, and there were no observable changes in the ECG-ST segment. In addition, arrhythmias did not occur after administration of another vasoconstrictor (phenylephrine). The potential involvement of autonomic cardiac efferent nerves in these arrhythmias was also investigated because TxA(2) has been shown to stimulate peripheral nerves. Pretreatment of animals with the beta-adrenergic receptor antagonist propranolol did not reduce the frequency of these arrhythmias. Pretreatment with atropine or bilateral vagotomy resulted in an increased frequency of arrhythmias, suggesting that parasympathetic nerves may actually inhibit the arrhythmogenic activity of TxA(2). These experiments demonstrate that left atrial injection of U-46619 elicits arrhythmias via a mechanism independent of a significant reduction in coronary blood flow or activation of the autonomic nervous system. It is possible that TxA(2) may have a direct effect on the electrical activity of the heart in vivo, which provides significant implications for cardiac events where TxA(2) is increased, e.g., after myocardial ischemia or administration of cyclooxygenase-2 inhibitors.
Asunto(s)
Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/administración & dosificación , Arritmias Cardíacas/inducido químicamente , Arritmias Cardíacas/fisiopatología , Velocidad del Flujo Sanguíneo/efectos de los fármacos , Circulación Coronaria/efectos de los fármacos , Receptores de Tromboxano A2 y Prostaglandina H2/metabolismo , Tromboxano A2/administración & dosificación , Anestesia , Animales , Frecuencia Cardíaca/efectos de los fármacos , Masculino , Conejos , Vasoconstrictores/administración & dosificaciónRESUMEN
The aim of this study was to determine the involvement of the central cholinergic system in the rise in blood pressure evoked by the thromboxane A2 (TxA2) analog, U-46619, given centrally. Intracerebroventricular (i.c.v.) injections of U-46619 (0.5, 1.0 and 2.0 microg) caused dose- and time-related increases in blood pressure and decreased heart rate in awake rats. U-46619 (1 microg; i.c.v.) also produced an approximately 65% increase in posterior hypothalamic extracellular acetylcholine and choline levels. Pretreatment with SQ-29548 (8 microg; i.c.v.), selective TxA2 receptor antagonist, completely inhibited both the cardiovascular responses and the increase in acetylcholine and choline levels to subsequent injection of U-46619 (1 microg; i.c.v.). Atropine (10 microg; i.c.v.), nonselective muscarinic receptor antagonist, pretreatment did not affect the cardiovascular responses observed after U-46619 (1 microg; i.c.v.). Pretreatment with the nonselective nicotinic receptor antagonist, mecamylamine (50 microg; i.c.v.) attenuated the pressor effect of U-46619 (1 microg; i.c.v.). Higher doses of mecamylamine (75 and 100 microg; i.c.v.) pretreatments did not change the magnitude of the blockade of pressor response to U-46619; however, they abolished the bradycardic effect of U-46619 dose-dependently. Interestingly, pretreatment of rats with methyllycaconitine (10 microg; i.c.v.) or alpha-bungarotoxin (10 microg; i.c.v.), selective antagonists of alpha7 subtype of nicotinic acetylcholine receptors (alpha7nAChRs), partially abolished the pressor response to i.c.v. injection of U-46619 (1 microg). Similar to the mecamylamine data, the use of higher doses of methyllycaconitine (25 and 50 microg; i.c.v.) produced the same magnitude of blockade that was observed after the 10 microg methyllycaconitine pretreatment, but it completely abolished the bradycardic effect of U-46619 (1 microg; i.c.v.) at the dose of 25 microg. The present results show that central administration of U-46619 produces pressor and bradycardic effect and increase in hypothalamic acetylcholine and choline levels by activating central TxA2 receptors. The activation of central nicotinic receptors, predominantly alpha7nAChRs, partially mediates the cardiovascular responses to i.c.v. injection of U-46619.
Asunto(s)
Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/farmacología , Sistema Nervioso Central/efectos de los fármacos , Hipotálamo Posterior/efectos de los fármacos , Vasoconstrictores/farmacología , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/administración & dosificación , Acetilcolina/metabolismo , Aconitina/administración & dosificación , Aconitina/análogos & derivados , Animales , Presión Sanguínea/efectos de los fármacos , Compuestos Bicíclicos Heterocíclicos con Puentes , Bungarotoxinas/administración & dosificación , Sistema Nervioso Central/metabolismo , Colina/metabolismo , Ácidos Grasos Insaturados , Frecuencia Cardíaca/efectos de los fármacos , Hidrazinas/administración & dosificación , Hipotálamo Posterior/metabolismo , Inyecciones Intraventriculares , Masculino , Mecamilamina/administración & dosificación , Antagonistas Nicotínicos/administración & dosificación , Ratas , Ratas Sprague-Dawley , Receptores Nicotínicos/efectos de los fármacos , Receptores de Tromboxano A2 y Prostaglandina H2/antagonistas & inhibidores , Factores de Tiempo , Vasoconstrictores/administración & dosificación , Receptor Nicotínico de Acetilcolina alfa 7RESUMEN
1. In the present study, we aimed to determine the involvement of brain thromboxane A2 (TXA2) in blood pressure decreases evoked by acute and/or graded haemorrhage in rats. 2. Sprague-Dawley rats were used throughout the study. Acute haemorrhage was achieved by withdrawing a total volume of 2.1 and 2.5 mL blood/100 g bodyweight over a period of 10 min. A microdialysis study was performed in a hypothalamic area to measure extracellular TXA2 levels. Graded haemorrhage was conducted successively by withdrawing carotid arterial blood (0.55 mL/100 g bodyweight) over a 10 s period four times (S1-S4) at 5 min intervals. Furegrelate (125, 250 and 500 microg), a TXA2 synthase inhibitor, was injected intracerebroventricularly (i.c.v.) 60 min before acute or graded haemorrhage was initiated. U-46619 (0.5, 1 and 2 microg, i.c.v.), a synthetic TXA2 analogue, was administered 5 min before acute haemorrhage (2.1 mL/100 g bodyweight). 3. Acute haemorrhage produced a severe and long-lasting decrease in blood pressure and had a tendency to increase heart rate. Both haemorrhage protocols (2.1 or 2.5 mL/100 g) generated similar approximate twofold increases in extracellular hypothalamic TXA2 levels. Intracerebroventricular furegrelate (250 microg) pretreatment completely blocked the TXA2 increases induced by acute haemorrhage. Furegrelate administration (100, 250 and 500 microg, i.c.v.) attenuated the fall in arterial pressure evoked by acute haemorrhage and caused significant increases in heart rate at all doses injected. 4. Graded haemorrhage progressively lowered arterial pressure and increased plasma vasopressin and adrenaline levels in the last period. Furegrelate-injected rats were greatly resistant to the hypotensive effect of haemorrhage for all degrees of blood removed. Plasma adrenaline and vasopressin levels were significantly elevated in furegrelate-pretreated rats compared with the saline-treated group during S2-S3 and S4, respectively. U-46619 administration caused small but statistically significant decreases in arterial pressure induced by haemorrhage. 4. The results show that acute hypotensive haemorrhage increases extracellular hypothalamic TXA2 levels. The increase in brain endogenous TXA2 levels involves a decrease in blood pressure evoked by haemorrhage because the blockade of TXA2 synthesis by furegrelate pretreatment attenuated the haemorrhagic hypotension. Increases in plasma adrenaline and vasopressin levels may mediate this effect.
Asunto(s)
Hemorragia/fisiopatología , Hipotensión/enzimología , Hipotálamo/enzimología , Tromboxano A2/metabolismo , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/administración & dosificación , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/farmacología , Animales , Benzofuranos/administración & dosificación , Benzofuranos/farmacología , Presión Sanguínea/efectos de los fármacos , Modelos Animales de Enfermedad , Epinefrina/sangre , Frecuencia Cardíaca/efectos de los fármacos , Hipotensión/sangre , Hipotensión/prevención & control , Hipotálamo/efectos de los fármacos , Inyecciones Intraventriculares , Masculino , Ratas , Ratas Sprague-Dawley , Tromboxano-A Sintasa/antagonistas & inhibidores , Tromboxano-A Sintasa/metabolismo , Factores de Tiempo , Vasoconstrictores/administración & dosificación , Vasoconstrictores/farmacología , Vasopresinas/sangreRESUMEN
We examined whether cysteinyl leukotrienes (CysLTs) and thromboxane (TX) A2 are synergistically involved in a cedar pollen-induced allergic late phase nasal blockage in guinea pigs. Sensitized animals were repeatedly challenged by pollen inhalation once every week. Combined treatment with pranlukast (a CysLT antagonist) and seratrodast (a TXA2 antagonist) inhibited late phase nasal blockage, but the magnitude of inhibition (approximately 50%) was equal to those of the respective single treatments, suggesting that CysLTs produced late after challenge induces TXA2 production in the nasal tissue, as in the case of the lung of this species. However, pranlukast did not affect TXB2 increase in the nasal tissue. In contrast, combined intranasal instillation of LTD4 and U-46619 (a TXA2 mimetic) produced much greater nasal blockage than single administration of each agonist in sensitized animals. Therefore, allergic late phase nasal blockage should be induced by synergistic activity of CysLTs and TXA2 at the effector organ.
Asunto(s)
Hipersensibilidad/fisiopatología , Leucotrienos/fisiología , Tromboxano A2/fisiología , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/administración & dosificación , Animales , Benzoquinonas/administración & dosificación , Cromonas/administración & dosificación , Cobayas , Ácidos Heptanoicos/administración & dosificación , Leucotrieno D4/administración & dosificación , Masculino , Cavidad Nasal/fisiopatología , Tromboxano A2/biosíntesisRESUMEN
Lipid mediators, thromboxane A2 (TxA2) and platelet-activating factor (PAF), are potent vasoconstrictors, and have been implicated as mediators of liver diseases, such as ischemic-reperfusion injury. We determined the effects of a TxA2 analogue (U-46619) and PAF on the vascular resistance distribution and liver weight (wt) in isolated guinea pig livers perfused with blood via the portal vein. The sinusoidal pressure was measured by the double occlusion pressure (P(do)), and was used to determine the pre- (R(pre)) and post-sinusoidal (R(post)) resistances. U-46619 and PAF concentration-dependently increased the hepatic total vascular resistance (R(t)). The minimum concentration at which significant vasoconstriction occurs was 0.001 microM for PAF and 0.1 microM for U-46619. Moreover, the concentration of U-46619 required to increase R(t) to the same magnitude is 100 times higher than PAF. Thus, the responsiveness to PAF was greater than that to U-46619. Both agents increased predominantly R(pre) over R(post). U-46619 caused a sustained liver weight loss. In contrast, PAF also caused liver weight loss at lower concentrations, but it produced liver weight gain at higher concentrations (2.5 +/- 0.3 per 10g liver weight at 1 microM PAF), which was caused by substantial post-sinusoidal constriction and increased P(do). In conclusion, both TxA2 and PAF contract predominantly the pre-sinusoidal veins. TxA2 causes liver weight loss, while PAF at high concentrations increases liver weight due to substantial post-sinusoidal constriction in isolated guinea pig livers.
Asunto(s)
Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/administración & dosificación , Bombas de Infusión , Hepatopatías/fisiopatología , Hígado/irrigación sanguínea , Hígado/fisiopatología , Factor de Activación Plaquetaria/administración & dosificación , Daño por Reperfusión/fisiopatología , Tromboxano A2/administración & dosificación , Vasoconstrictores/administración & dosificación , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/metabolismo , Animales , Bilis/metabolismo , Permeabilidad Capilar/efectos de los fármacos , Cobayas , Técnicas In Vitro , Circulación Hepática/efectos de los fármacos , Masculino , Tamaño de los Órganos/efectos de los fármacos , Factor de Activación Plaquetaria/metabolismo , Vena Porta/fisiopatología , Tromboxano A2/metabolismo , Resistencia Vascular/efectos de los fármacos , Vasoconstricción/efectos de los fármacos , Vasoconstrictores/metabolismoRESUMEN
In the present study, we investigated the cardiovascular effects of centrally injected U-46619, a thromboxane A(2) (TXA(2)) analog, and the central and peripheral mechanisms of these effects in hemorrhagic shock conditions. Hemorrhage was performed by withdrawing a total volume of 2.1 ml of blood/100 g body weight over a period of 10 min. Injections were made into the lateral cerebral ventricle (LCV), nucleus tractus solitarius (NTS), rostral ventrolateral medulla (RVLM) and paraventricular nucleus of hypothalamus (PVN). U-46619 (0.1, 1 and 2 microg) increased blood pressure and reversed hypotension in hemorrhagic shock. The pressor effect was dose- and time-dependent in all investigated brain areas. Heart rate changes were not significantly different in all groups. Pretreatment of rats with an injection of SQ-29548 (4 or 8 microg), a TXA(2) receptor antagonist, into the LCV, NTS, RVLM and PVN completely blocked the pressor effect of U-46619 (1 microg) injected into respective brain areas. Hemorrhage itself increased plasma adrenaline, noradrenaline, vasopressIN levels and renin activity. U-46619 (1 microg) injected into the LCV, PVN, RVLM and NTS produced additional increases in these hormone levels and in renin activity. Intravenous pretreatments of rats with prazosin (0.5 mg/kg), an alpha(1)-adrenoceptor antagonist, [beta-mercapto-beta,beta-cyclopentamethylenepropionyl(1), O-Me-Tyr(2),Arg(8)]- vasopressin (10 microg/kg), a vasopressin V(1)-receptor antagonist, or saralasin (250 microg/kg), an angiotensin II receptor antagonist, in hemorrhaged rats partially blocked the pressor response to U-46619 (1 microg) injected into the LCV, PVN, RVLM and NTS. Results show that centrally administered U-46619, a TXA(2) analog, increases blood pressure and reverses hypotension in hemorrhagic shock. Activation of central TXA(2) receptors mediates the pressor effect of the drug. Furthermore, the increases in plasma adrenaline, noradrenaline, vasopressin levels and renin activity are involved in these effects.
Asunto(s)
Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/uso terapéutico , Presión Sanguínea/fisiología , Encéfalo/fisiología , Hemorragia/fisiopatología , Hipotensión/tratamiento farmacológico , Tromboxano A2/análogos & derivados , Vasoconstrictores/uso terapéutico , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/administración & dosificación , Antagonistas de Receptores Adrenérgicos alfa 1 , Bloqueadores del Receptor Tipo 1 de Angiotensina II , Animales , Antagonistas de los Receptores de Hormonas Antidiuréticas , Presión Sanguínea/efectos de los fármacos , Compuestos Bicíclicos Heterocíclicos con Puentes , Catecolaminas/sangre , Ácidos Grasos Insaturados , Frecuencia Cardíaca/efectos de los fármacos , Frecuencia Cardíaca/fisiología , Hemodinámica/efectos de los fármacos , Hidrazinas/farmacología , Hipotensión/etiología , Hipotensión/fisiopatología , Inyecciones , Inyecciones Intraventriculares , Masculino , Bulbo Raquídeo , Núcleo Hipotalámico Paraventricular , Ratas , Ratas Sprague-Dawley , Renina/sangre , Choque Hemorrágico/fisiopatología , Núcleo Solitario , Vasoconstrictores/administración & dosificación , Vasopresinas/sangreRESUMEN
1. The purpose of this study was to investigate whether a membrane-permeable superoxide dismutase mimetic, tempol, added either alone or in combination with the nitric oxide (NO) donor molsidomine, prevents the development of pulmonary hypertension (PH) in chronic hypoxic rats. 2. Chronic hypobaric hypoxia (10% oxygen) for 2 weeks increased the right ventricular systolic pressure (RVSP), right ventricle and lung wet weight. Relaxations evoked by acetylcholine (ACh) and the molsidomine metabolite SIN-1 were impaired in isolated proximal, but not distal pulmonary arteries, from chronic hypoxic rats. 3. Treatment with tempol (86 mg x kg(-1) day(-1) in drinking water) normalized RVSP and reduced right ventricular hypertrophy, while systemic blood pressure, lung and liver weights, and blunted ACh relaxation of pulmonary arteries were unchanged. 4. Treatment with molsidomine (15 mg x kg(-1) day(-1) in drinking water) had the same effects as tempol, except that liver weight was reduced, and potassium and U46619-evoked vasoconstrictions in pulmonary arteries were increased. Combining tempol and molsidomine did not have additional effects compared to tempol alone. ACh relaxation in pulmonary arteries was not normalized by these treatments. 5. The media to lumen diameter ratio of the pulmonary arteries was greater for the hypoxic rats compared to the normoxic rats, and was not reversed by treatment with tempol, molsidomine, or the combination of tempol and molsidomine. 6. We conclude that tempol, like molsidomine, is able to correct RVSP and reduce right ventricular weight in the rat hypoxic model. Functional and structural properties of pulmonary small arteries were little affected. The results support the possibility that superoxide dismutase mimetics may be a useful means for the treatment of PH.
Asunto(s)
Óxidos N-Cíclicos/uso terapéutico , Modelos Animales de Enfermedad , Hipertrofia Ventricular Derecha/prevención & control , Hipoxia/tratamiento farmacológico , Molsidomina/análogos & derivados , Superóxido Dismutasa/uso terapéutico , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/administración & dosificación , Acetilcolina/farmacología , Administración Oral , Animales , Peso Corporal/efectos de los fármacos , Peso Corporal/fisiología , Enfermedad Crónica , Óxidos N-Cíclicos/administración & dosificación , Óxidos N-Cíclicos/farmacocinética , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Quimioterapia Combinada , Endotelina-1/farmacología , Depuradores de Radicales Libres/administración & dosificación , Depuradores de Radicales Libres/farmacocinética , Depuradores de Radicales Libres/uso terapéutico , Frecuencia Cardíaca/efectos de los fármacos , Hipertrofia Ventricular Derecha/complicaciones , Hipertrofia Ventricular Derecha/fisiopatología , Hipoxia/complicaciones , Hipoxia/fisiopatología , Masculino , Molsidomina/metabolismo , Molsidomina/farmacología , Molsidomina/uso terapéutico , Músculo Liso Vascular , Tamaño de los Órganos/efectos de los fármacos , Arteria Pulmonar/anatomía & histología , Arteria Pulmonar/efectos de los fármacos , Ratas , Ratas Wistar , Marcadores de Spin , Superóxido Dismutasa/administración & dosificación , Vasoconstricción/efectos de los fármacos , Vasodilatación/efectos de los fármacos , Presión Ventricular/efectos de los fármacosRESUMEN
Several prostanoids were investigated for a potential to induce emesis in Suncus murinus. The TP receptor agonist 11alpha,9alpha-epoxymethano-15S-hydroxyprosta-5Z,13E-dienoic acid (U46619) induced emesis at doses as low as 3 microg/kg, i.p. but the DP receptor agonist 5-(6-Carboxyhexyl)-1-(3-cyclohexyl-3-hydroxypropyl) hydantoin (BW245C) was approximately 1000 times less potent. The emetic action of U46619 (300 microg/kg, i.p.) was antagonized significantly by the TP receptor antagonist, vapiprost (P<0.05). EP (prostaglandin E(2), 17-phenyl-omega-trinor prostaglandin E(2), misoprostol and sulprostone), FP (prostaglandin F(2alpha) and fluprostenol) and IP (iloprost and cicaprost) receptor agonists failed to induce consistent emesis at doses up to 300-1000 microg/kg, i.p. Fluprostenol reduced nicotine (5 mg/kg, s.c.)-but not copper sulphate (120 mg/kg, intragastric)-induced emesis; the other inconsistently emetic prostanoids were inactive to modify drug-induced emesis. The results indicate an involvement of TP and possibly DP and FP receptors in the emetic reflex of S. murinus.
Asunto(s)
Prostaglandinas/efectos adversos , Musarañas/fisiología , Vómitos/prevención & control , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/administración & dosificación , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/efectos adversos , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/antagonistas & inhibidores , Animales , Compuestos de Bifenilo/administración & dosificación , Compuestos de Bifenilo/farmacocinética , Compuestos de Bifenilo/uso terapéutico , Sulfato de Cobre/administración & dosificación , Sulfato de Cobre/efectos adversos , Relación Dosis-Respuesta a Droga , Femenino , Ácidos Heptanoicos/administración & dosificación , Ácidos Heptanoicos/farmacocinética , Ácidos Heptanoicos/uso terapéutico , Hidantoínas/administración & dosificación , Inyecciones Intraperitoneales , Inyecciones Subcutáneas , Intubación Gastrointestinal , Masculino , Náusea/fisiopatología , Nicotina/administración & dosificación , Nicotina/efectos adversos , Nicotina/antagonistas & inhibidores , Prostaglandinas/administración & dosificación , Prostaglandinas F Sintéticas/administración & dosificación , Prostaglandinas F Sintéticas/farmacocinética , Prostaglandinas F Sintéticas/uso terapéutico , Tiempo de Reacción , Receptores de Tromboxanos/efectos de los fármacos , Receptores de Tromboxanos/fisiología , Factores de Tiempo , Vómitos/inducido químicamente , Vómitos/fisiopatologíaRESUMEN
1. A variety of prostanoids were examined for their ability to alter the periarterial nerve stimulation-induced release of noradrenaline (NA) and neuropeptide Y immunoreactive compounds (NPY-ir) from the perfused mesenteric arterial bed of the rat. 2. Periarterial nerve stimulation (16 Hz) increased the overflow of NA, NPY-ir and perfusion pressure. 3. The prostacyclin (PGI2) analogues, carbaPGI2 and cicaprost both produced a concentration-dependent attenuation of the nerve stimulation-induced increase in NA, NPY-ir overflow and perfusion pressure. 4. The prostaglandin (PG) analogue PGE2 attenuated the evoked increase in NPY-ir overflow as well as a modest decrease in NA. 5. PGE1, sulprostone and iloprost attenuated the nerve stimulation-induced increase in NA overflow but not NPY-ir. 6. Neither PGF2alpha nor the thromboxane A2 analogue U46619 altered the evoked increase in NA or NPY-ir overflow. 7. The results support the view that sympathetic co-transmitter release can be differentially modulated by paracrine/autocrine mediators at sympathetic neuroeffector junctions.