RESUMEN
Osteoporosis is a complex multifactorial disease that can lead to an increased risk of fracture. However, selective and effective osteoporosis drugs are still lacking. We showed that Asperosaponin VI (AVI) has the implications to be further developed as an alternative supplement for the prevention and treatment of bone loss. AVI has been found to have beneficial effects on metabolic diseases such as bone loss, obesity, and atherosclerosis. Our study was designed to determine the effect and mechanism of action of AVI against bone loss through regulating microbial dysbiosis. A hindlimb unloading mouse model was established to determine the effect of AVI on bone microarchitecture, gut microbiota, and serum metabolites. Eighteen female C57BL/6 J mice were divided into three groups: control, hindlimb unloading with vehicle (HLU), and hindlimb unloading treated with AVI (HLU-AVI, 200 mg/kg/day). AVI was administrated orally for 4 weeks. The results demonstrated that AVI improved the bone microstructure by reversing the decrease in bone volume fraction and trabecular number, and the increase in trabecular separation and structure model index of cancellous bone in hindlimb suspension mice. The results of 16sRNA gene sequencing suggested that the therapeutic effect of AVI on bone loss may be achieved through it regulating the gut microbiota, especially certain specific microorganisms. Combined with the analysis of ELISA, immunohistochemistry, and serum metabolome results, it could be speculated that AVI played an important role in adjusting the balance of bone metabolism by influencing specific flora such as Clostridium and its metabolites to regulate the 5-hydroxytryptophan pathway. The study explored the novel mechanism of AVI against osteoporosis, and has implications for the further development of AVI as an alternative supplement for the prevention and treatment of bone loss.
Asunto(s)
Suspensión Trasera , Osteoporosis , Ratones , Femenino , Animales , Suspensión Trasera/fisiología , Serotonina , Disbiosis , Ratones Endogámicos C57BL , Osteoporosis/etiologíaRESUMEN
UNLABELLED: The purpose of this study is to investigate the anti-osteoporotic effects of Radix Dipsaci total saponins (RTS). We showed that RTS was able to improve bone properties by either an increase of osteoblastic activity or a decrease in osteoclastic activity. INTRODUCTION: Radix Dipsaci has long been used as an anti-osteoporotic drug. The present study investigates the anti-osteoporotic effects of RTS. METHODS: Three-month-old female rats were randomly assigned into a sham-operated group (sham) and five ovariectomy (OVX) subgroups, namely, OVX with vehicle (OVX), OVX with 17ß-ethinylestradiol (E(2)), and OVX with graded doses of RTS (50, 100, or 200 mg/kg/d). RTS and E(2) were administered orally, daily from 1 week after OVX treatment for 4 months. Bone mass, turnover, and strength were evaluated by dual-energy X-ray absorptiometry, biochemical markers, and the three-point bending test. The trabecular bone microarchitecture was assessed by microCT. In vitro experiments were performed to determine the potential molecular mechanisms of the anti-osteoporotic effect of RTS. RESULTS: RTS prevented the loss of bone mass induced by OVX. The preventive effect on bone loss was primarily indicated by decreasing levels of bone turnover markers and confirmed by the changes in urinary calcium and phosphorus excretion. The treatment also enhanced the biomechanical strength of bone and prevented the deterioration of trabecular bone microarchitecture. RTS induced MC3T3-E1 and primary osteoblastic cell maturation and differentiation and increased bone formation by increasing BMP-2 synthesis. In addition, RTS inhibited osteoclastogenesis through an increase in osteoprotegrin and a decrease in NF-kB ligand expression in vitro. CONCLUSIONS: RTS treatment can effectively suppress the loss of bone mass induced by OVX and in vitro evidence suggests this could be through actions on both osteoblasts and osteoclasts.
Asunto(s)
Conservadores de la Densidad Ósea/uso terapéutico , Dipsacaceae , Medicamentos Herbarios Chinos/uso terapéutico , Osteoporosis/prevención & control , Saponinas/uso terapéutico , Animales , Peso Corporal/efectos de los fármacos , Densidad Ósea/efectos de los fármacos , Conservadores de la Densidad Ósea/farmacología , Proteína Morfogenética Ósea 2/biosíntesis , Calcio/metabolismo , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos/métodos , Medicamentos Herbarios Chinos/farmacología , Estradiol/uso terapéutico , Femenino , Fémur/diagnóstico por imagen , Fémur/fisiopatología , Tamaño de los Órganos/efectos de los fármacos , Osteoblastos/efectos de los fármacos , Osteoblastos/patología , Osteoclastos/efectos de los fármacos , Osteoclastos/patología , Osteoporosis/diagnóstico por imagen , Osteoporosis/patología , Osteoporosis/fisiopatología , Osteoprotegerina/biosíntesis , Ovariectomía , Fósforo/metabolismo , Ligando RANK/biosíntesis , Ratas , Ratas Sprague-Dawley , Saponinas/farmacología , Tomografía Computarizada por Rayos X , Regulación hacia Arriba/efectos de los fármacos , Útero/patologíaRESUMEN
A novel polysaccharide isolated from Angelica sinensis, named APS-1d showed cytotoxic activity towards several cancer cell lines in vitro. However, the precise antitumor mechanisms of this compound are unknown. In this study, we investigated the pro-apoptotic effects of APS-1d in human cervical cancer HeLa cells both in vitro and in vivo, and further elucidated the mechanisms of this action. Inhibition of HeLa cell proliferation was determined by MTT assay and the therapeutic efficacy of APS-1d was evaluated by human cancer xenografts in nude mice. Cell apoptosis was examined with flow cytometry and TUNEL assay. The mechanism of action of APS-1d was investigated by Western blot analysis. APS-1d decreased HeLa cell proliferation in a concentration- and time-dependent manner in vitro. In addition, APS-1d significantly inhibited tumor growth in athymic nude mice. Characteristic manifestations of apoptosis including apoptotic morphological features and the sub- G(0)/G(1) peaks were observed when the cells were treated with APS-1d. Further analysis showed that APS-1d-induced apoptosis was associated with the regulation of Bcl-2 family protein expression, a decrease in the mitochondrial membrane potential, and an increase in the cytosolic cytochrome c levels. Sequentially, APS-1d increased the activities of caspase-9, -3, and poly (ADP-ribose) polymerase in a concentration-dependent manner, however, no obvious activation of Bid and caspase-8 was observed. Pretreatment with Z-LEHD-FMK, a specific inhibitor of caspase-9, significantly attenuated APS-1d-induced cell apoptosis, and activation of caspase-3. Taken together, our studies indicate that APS-1d is capable of inhibiting HeLa cell proliferation and inducing apoptosis in these cells which primarily involves the activation of the intrinsic mitochondrial pathway.
Asunto(s)
Angelica sinensis/química , Antineoplásicos Fitogénicos/farmacología , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Extractos Vegetales/farmacología , Polisacáridos/farmacología , Neoplasias del Cuello Uterino/tratamiento farmacológico , Animales , Antineoplásicos Fitogénicos/uso terapéutico , Western Blotting , Caspasas/metabolismo , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Citocromos c/metabolismo , Citocromos c/farmacología , Relación Dosis-Respuesta a Droga , Femenino , Citometría de Flujo , Células HeLa , Humanos , Etiquetado Corte-Fin in Situ , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Oligopéptidos , Fitoterapia , Extractos Vegetales/uso terapéutico , Poli(ADP-Ribosa) Polimerasas/metabolismo , Polisacáridos/aislamiento & purificación , Polisacáridos/uso terapéutico , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Transducción de Señal/efectos de los fármacos , Neoplasias del Cuello Uterino/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Du-Zhong, rich in polyphenolic compounds such as lignans, phenolic acid, and flavonoids, is a kidney-tonifying herbal medicine with a long history of safe use for treatment of bone fractures and joint diseases in China. In the present study, we examined whether Du-Zhong cortex extract (DZCE) with graded doses exerted its preventive effects on estrogen deficiency-induced osteoporosis. Eighty 3-month-old female Sprague-Dawley rats were used and randomly assigned into sham-operated group (Sham) and five ovariectomy (OVX) subgroups, i.e. OVX with vehicle (OVX); OVX with 17alpha-ethinylestradiol (E(2), 25 microg/kg/day); OVX with DZCE of graded doses (100, 300, or 500 mg/kg/day). Daily oral administration of DZCE or E(2) started on week 4 after OVX for 16 weeks. Treatment with DZCE at higher doses (300 or 500 mg/kg/day) was found to be able to significantly prevent OVX-induced decrease in biomechanical quality of femur such as maximum stress and Young's modulus. The mechanical changes were associated with the prevention of a further bone mineral density (BMD) decrease or even with some improvements in microarchitecture. DZCE dose-dependently inhibited total BMD decrease in the femur caused by OVX, which was accompanied by a significant decrease in skeletal remodeling, as was evidenced by the decreased levels of the bone turnover markers osteocalcin (OC), alkaline phosphatese (ALP), deoxypyridinoline (DPD), and urinary Ca and P excretions. muCT analysis of the femoral metaphysis showed that DZCE at the highest doses (500 mg/kg/day) significantly prevents decrease in bone volume/tissue volume (BV/TV), connect density (Conn.D), trabecula number (Tb.N) and trabecula thickness (Tb.Th), and increase in trabecula separation (Tb.Sp) and structure model index (SMI) in OVX rats. We conclude that 16 weeks of DZCE treatment improves bone biomechanical quality through modifications of BMD, and trabecular microarchitecture without hyperplastic effect on uterus, and it might be a potential alternative medicine for treatment of postmenopausal osteoporosis.
Asunto(s)
Medicamentos Herbarios Chinos/uso terapéutico , Eucommiaceae/química , Osteoporosis/prevención & control , Ovariectomía/efectos adversos , Animales , Biomarcadores/metabolismo , Densidad Ósea/efectos de los fármacos , Femenino , Fémur/efectos de los fármacos , Fémur/fisiopatología , Osteoporosis/etiología , Osteoporosis/fisiopatología , Distribución Aleatoria , Ratas , Ratas Sprague-DawleyRESUMEN
AIM: To evaluate colonic delivery and therapeutic effect of the newly synthesized dexamethasone (DX)-dextran (500 000) conjugate (DXD50) in the rat. METHODS: The amount of dexamethasone was measured in the contents from different parts of rat gastrointestinal tract and in plasma after ig conjugate. Therapeutic effect of conjugate and DX was tested in trinitrobenzenesulfonic acid-induced colitis in rat. Repair of colitis was assessed by measuring colonic ulceration area, colon weight, and colonic myeloperoxidase (MPO) activity. Systemic immunosuppression of DX was evaluated with weight of thymus and spleen and lymphocyte count in peripheral blood from rat with ulcerative colitis. RESULTS: Dexamethasone released from conjugate was mainly distributed in contents of cecum and colon. When DXD50 and DX 0.25 micromol . kg-1 . d-1 were used ig to treat ulcerative colitis in rat, the ulcerative area of colon was reduced by 55.6 % and 33.3 %, respectively whereas colon weight was reduced by 17.9 % and 2.6 %, respectively. The conjugate had no effect on lymphocyte count in peripheral blood, spleen weight, and thymus weight of rat which could be reduced markedly by the same dose of DX (P < 0.05 vs control). CONCLUSION: DXD50, which could specifically deliver DX to large intestine, is a promising agent in the treatment of human inflammatory bowel disease.
Asunto(s)
Colitis Ulcerosa/tratamiento farmacológico , Colon/metabolismo , Dexametasona/farmacocinética , Dextranos/farmacocinética , Animales , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/metabolismo , Dexametasona/administración & dosificación , Dextranos/administración & dosificación , Sistema Digestivo/metabolismo , Sistemas de Liberación de Medicamentos , Ratas , Ratas Sprague-DawleyRESUMEN
The P2X4 receptor is a newly identified receptor expressed in the heart cell. Its function was elucidated with cardiac transgenic (TG) expression of the receptor by using the myocardium-specific a-myosin heavy chain promoter. The presence of the transgene was determined by polymerase chain reaction by using primers specific to the receptor and the vector linker region, by Southern blotting of the genomic DNA, and by immunoblotting and immunohistochemistry of both isolated cardiac myocytes and intact hearts. In intact heart study, the P2X4 receptor TG mouse exhibited significantly elevated basal cardiac contractility with greater rates of contraction and relaxation, left ventricular developed pressure, and cardiac output compared with nontransgenic (NTG) animals but showed no evidence of hypertrophy or heart failure. The TG heart also showed a greater increase of cardiac contractility in response to the P2X receptor agonist 2-methylthioATP, consistent with overexpression of a functional P2X4 receptor with consequent increase in the receptor-mediated response. In isolated cardiac cell study, the TG heart cell showed a similar level of basal contraction amplitude as the NTG heart cell while exhibiting a threefold greater increase in contractility during stimulation by 2-methylthioATP. Thus, an increased responsiveness of the overexpressed P2X4 receptor to endogenous ATP is responsible for the enhanced basal cardiac performance in the intact TG heart. The sustained enhanced contractile function with no associated heart pathology in the P2X4 receptor TG mouse suggests a novel physiologic role of the P2X4 receptor, that of stimulating the cardiac contractility.
Asunto(s)
Adenosina Trifosfato/análogos & derivados , Contracción Miocárdica/fisiología , Miocardio/metabolismo , Receptores Purinérgicos P2/fisiología , Adenosina Trifosfato/farmacología , Animales , Gasto Cardíaco/efectos de los fármacos , Corazón/efectos de los fármacos , Corazón/fisiología , Humanos , Inmunohistoquímica , Ratones , Ratones Endogámicos , Ratones Transgénicos , Modelos Biológicos , Contracción Miocárdica/efectos de los fármacos , Contracción Miocárdica/genética , Miocardio/química , Miocardio/citología , Cadenas Pesadas de Miosina/genética , Fenotipo , Regiones Promotoras Genéticas/genética , Receptores Purinérgicos P2/análisis , Receptores Purinérgicos P2/genética , Receptores Purinérgicos P2X4 , Proteínas Recombinantes de Fusión/análisis , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/fisiología , Tionucleótidos/farmacologíaRESUMEN
Production of nitric oxide (NO) by inducible nitric oxide synthase (iNOS) has been proposed as a pathogenic factor in acute pancreatitis, but its role has still not been fully examined. The present study explored the role of iNOS in cerulein-induced acute pancreatitis using iNOS-deficient mice. Twelve- to 14-week-old male mice (C57B1/6 and iNOS-deficient) were administered cerulein by intraperitoneal (i.p.) injection at hourly intervals for 7 hours and killed 24 hours later after the first dose. Pancreatic wet weight, pancreatic myeloperoxidase (MPO) activity, and levels of plasma nitrite and serum amylase were measured. In another experiment isosorbide dinitrate (an NO donor) was given by oral gavage every 6 hours for 24 hours beginning simultaneously with cerulein injections in iNOS-deficient mice. Cerulein administration dose-dependently increased pancreatic wet weight, myeloperoxidase activity, and levels of nitrite and amylase in C57B1/6 mice. These parameters (except nitrite levels) were significantly intensified in iNOS-deficient mice. At the dose employed, cerulein failed to increase nitrite levels in iNOS-deficient mice. The susceptibility to cerulein toxicity in iNOS-deficient mice was abolished by NO donor treatment. NO release from an iNOS source appears to play a protective role in cerulein-induced pancreatitis. At least in part, NO may prevent neutrophil accumulation after cerulein administration.
Asunto(s)
Ceruletida/toxicidad , Óxido Nítrico Sintasa/fisiología , Pancreatitis/inducido químicamente , Enfermedad Aguda , Amilasas/sangre , Animales , Predisposición Genética a la Enfermedad , Inyecciones Intraperitoneales , Dinitrato de Isosorbide/farmacología , Dinitrato de Isosorbide/uso terapéutico , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neutrófilos/enzimología , Neutrófilos/patología , Donantes de Óxido Nítrico/farmacología , Donantes de Óxido Nítrico/uso terapéutico , Óxido Nítrico Sintasa/deficiencia , Óxido Nítrico Sintasa/genética , Óxido Nítrico Sintasa de Tipo II , Nitritos/sangre , Pancreatitis/sangre , Pancreatitis/genética , Peroxidasa/análisisRESUMEN
BACKGROUND/AIMS: Cigarette smoking is closely related to the development and recurrence of inflammatory bowel disease (IBD). The present study aimed to investigate the underlying mechanisms of the adverse action of cigarette smoke (CS) exposure on trinitrobenzene sulfonic acid (TNBS)-induced IBD. METHODS: Rats were preexposed to CS once daily for 4 days before receiving a TNBS enema, and they were killed 24 h afterwards. The colonic myeloperoxidase (MPO) and xanthine oxidase (XO) activities, leukotriene B(4) (LTB(4)) and glutathione (GSH) levels, as well as the production of reactive oxygen metabolites (ROMs) were measured. RESULTS: CS preexposure significantly augmented the adverse effects of the TNBS enema on colonic damage and increase in MPO activity, while it did not significantly alter the XO activity. Meanwhile, the elevation of ROM production and LTB(4) concentration in colonic tissues after the TNBS enema was also markedly enhanced by CS exposure. In contrast, the depressive action of the TNBS enema on cellular antioxidant GSH levels was reduced further by CS exposure. Pretreatment with a specific LTB(4) antagonist, ONO-4057, protected against colonic damage, particularly in the CS group. CONCLUSION: CS exposure aggravated experimental IBD. This adverse action could be due to the depletion of GSH together with overproduction of LTB(4), followed by the accumulation of neutrophils and ROMs in the colonic tissue.
Asunto(s)
Colitis Ulcerosa/etiología , Colitis Ulcerosa/fisiopatología , Glutatión/metabolismo , Leucotrieno B4/metabolismo , Peroxidasa/metabolismo , Contaminación por Humo de Tabaco/efectos adversos , Xantina Oxidasa/metabolismo , Análisis de Varianza , Animales , Biomarcadores/análisis , Modelos Animales de Enfermedad , Glutatión/análisis , Mucosa Intestinal/patología , Leucotrieno B4/análisis , Mediciones Luminiscentes , Masculino , Peroxidasa/análisis , Probabilidad , Ratas , Ratas Sprague-Dawley , Medición de Riesgo , Sensibilidad y Especificidad , Xantina Oxidasa/análisisRESUMEN
AIM: To screen optimal drugs against postmenopausal osteoporosis with cardiovascular protective activities. METHODS: A series of benzodihydropyran derivatives were designed and synthesized in view of comprehensive observations of raloxifene and ipriflavone. The antiosteoporosis activities of compounds a-e (10(-7) mol.L-1) on the proliferation of human osteoblast cell HOS TE85 were studied. The cardiovascular protective activities were evaluated by observing their effects on proliferation of human vascular endothelium cell ECV-304 and their protective effects on ECV-304 damaged by H2O2. RESULTS: Their structures were determined by spectrums. Compounds a, b and c (10(-7) mol.L-1) were shown to significantly help proliferation of HOS TE85. In addition, b, d and e (10(-8) mol.L-1) helped proliferation of ECV-304 significantly. Compounds b and c (10(-6) mol.L-1) showed strong protective activity on ECV-304 damaged by H2O2. Compounds b and c shifted the KCl dose-response curves to the right and decreased the maximal response. CONCLUSION: Compounds b and c showed some bone and vascular protective activities which benefit postmenopausal and cardiovascular diseases.
Asunto(s)
Benzopiranos/farmacología , Endotelio Vascular/efectos de los fármacos , Contracción Muscular/efectos de los fármacos , Osteoblastos/efectos de los fármacos , Animales , Aorta/efectos de los fármacos , Benzopiranos/síntesis química , Benzopiranos/química , División Celular/efectos de los fármacos , Línea Celular , Endotelio Vascular/citología , Femenino , Humanos , Técnicas In Vitro , Masculino , Músculo Liso Vascular/efectos de los fármacos , Osteoblastos/citología , Ratas , Ratas Sprague-Dawley , Cordón Umbilical/citologíaRESUMEN
AIM: To explore whether dexamethasone-dextran (260,000) has the characteristics of site-specific delivery in rat gastrointestinal tract. METHODS: Dexamethasone prodrug and dexamethasone were administered to rat ig at the dose of 5 mumol.kg-1. The distribution of dexamethasone in the contents and mucosa of different parts of the rat GI tract at different time intervals and its concentration in plasma were determined by HPLC. RESULTS: Dexamethasone was mainly released in the cecum and colon contents and mucosa after oral administration of dexamethasone prodrug. The absorption was reduced significantly. The peak time of the drug in plasma was 8.1 h, and the peak concentration was 32 micrograms.L-1. However, free dexamethasone was found mainly in the contents and mucosa of the stomach, proximal and distal small intestine. The peak time of the drug in plasma was 2.2 h, and the peak concentration was 2120 micrograms.L-1. CONCLUSION: Dexamethasone can be specifically delivered to the large intestine by using dexamethasone-dextran (260,000). It appears that the prodrug has a potential in the treatment of inflammatory bowel disease.
Asunto(s)
Dexametasona/farmacocinética , Dextranos/química , Tracto Gastrointestinal/metabolismo , Profármacos/farmacocinética , Animales , Antiinflamatorios/administración & dosificación , Antiinflamatorios/farmacocinética , Dexametasona/administración & dosificación , Femenino , Masculino , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Distribución TisularRESUMEN
We studied the protective effects of polysaccharides isolated from the root of Angelica sinensis (Oliv.) (Danggui) on gastrointestinal damage induced by ethanol or indomethacin in rats. Oral administration of ethanol provoked a marked hemorrhagic damage in the glandular mucosa, which was accompanied with a significant increase of myeloperoxidase (MPO) activity, a marker enzyme for inflammation and neutrophil infiltration. An extract from Angelica, which mainly consisted of polysaccharides (95%) (AP), dose-dependently prevented gastric mucosal damage. This ulcer protective effect could last at least 12 h after administration. Prostaglandin E2 produced a similar anti-lesion effect. AP and prostaglandin E2 also reduced mucosal MPO activity. Indomethacin-induced gastrointestinal damage, another neutrophil-dependent lesion model in the gastrointestinal tract, was also prevented by AP pretreatment. The present findings suggest that polysaccharides from Angelica possess an anti-inflammatory action, perhaps through the inhibitory action on neutrophil infiltration in the gastrointestinal mucosa. AP could potentially be useful to prevent any neutrophil-dependent mucosal injury in the gastrointestinal tract.
Asunto(s)
Fármacos Gastrointestinales/farmacología , Plantas Medicinales/química , Polisacáridos/farmacología , Animales , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
AIM: To study the effects of MN-9202, a new effective Ca2+ channel blocker, on platelet aggregation, 5-HT and TXB2 release, and calcium transport induced by platelet activators. METHODS: The mobilization of cytosolic-free calcium induced by thrombin in washed platelets was observed by Ca(2+)-sensitive fluorescent indicator, Fura-2 AM and time scan measurement. Aggregation induced by ADP and thrombin in rabbits citrate platelet-rich plasma (PRP) was measured by aggregometer. 5-HT and TXB2 were assayed by HPLC/ECD and RIA, respectively. RESULTS: MN-9202 inhibited platelet aggregation induced by ADP and thrombin in a concentration-dependent manner. MN-9202 1 mumol.L-1 inhibited release of 5-HT in PRP induced by collagen at 15 mg.L-1 (113 +/- 15 vs 178 +/- 18, P < 0.05), however, MN-9202 did not have effect on 5-HT secreted by high dose of collagen. MN-9202 0.1 and 1 mumol.L-1 blocked extracellular calcium influx and sarcoplasmic calcium release, and the suppression on extracellular calcium influx was more obvious. Furthermore, treatment with MN-9202 0.01, 0.1, and 1 mumol.L-1 markedly decreased ADP-induced TXB2 (pg/10(8) platelet) release from PRP (906 +/- 200, 881 +/- 131, and 793 +/- 169 vs 1264 +/- 202, P < 0.01). CONCLUSION: MN-9202 acts as an effective Ca2+ antagonist and blocks platelet activation by inhibiting platelet Ca2+ influx and arachidonic acid metabolism.
Asunto(s)
Calcio/sangre , Dihidropiridinas/farmacología , Nitrobencenos/farmacología , Agregación Plaquetaria/efectos de los fármacos , Serotonina/sangre , Tromboxano B2/biosíntesis , Animales , Transporte Biológico Activo , Plaquetas/metabolismo , Bloqueadores de los Canales de Calcio/farmacología , Masculino , ConejosRESUMEN
Cigarette smoking and nonsteroidal antiinflammatory drugs (NSAIDs) have been associated with gastroduodenal ulcers. The present study aimed to clarify the ulcerogenic mechanisms of passive cigarette smoking on gastrointestinal damage induced by indomethacin in fasted or in fasted and refed rats. Rats were exposed to cigarette smoke (0%, 1%, 2%, or 4%, v/v) before and/or after indomethacin administration. Cigarette smoke dose-dependently potentiated indomethacin-induced gastric mucosal lesions in the fasted animals and further lowered gastric blood flow. The gastric myeloperoxidase activity (a marker enzyme for neutrophils) was also potentiated. In addition, passive cigarette smoking increased the mortality and aggravated duodenal ulceration and also the reduction of duodenal blood flow in the fasted and refed rats after indomethacin treatment. The results indicated that the potentiating effect of passive cigarette smoking on indomethacin-induced gastroduodenal lesions is probably due to the depression of blood flow in the gastroduodenal mucosa and to the aggravation of neutrophil infiltration in the gastric mucosa.
Asunto(s)
Sistema Digestivo/efectos de los fármacos , Indometacina/efectos adversos , Fumar , Animales , Relación Dosis-Respuesta a Droga , Ayuno , Mucosa Gástrica/irrigación sanguínea , Mucosa Intestinal/irrigación sanguínea , Masculino , Ratas , Ratas Sprague-Dawley , Flujo Sanguíneo RegionalRESUMEN
OBJECTIVE: To investigate whether or not heparin can accelerate the healing process of acetic acid-induced gastric ulcers in rats and to identify the mechanisms for heparin to produce this effect, so that we can develop a new therapeutic application to heparin besides its traditional anticoagulant activity. METHODS: Male Sprague-Dawley rats were used to produce acetic acid-induced gastric ulcers. Heparin in the doses of 100, 500, and 1000 U/kg were administered intravenously through the tail vein once daily, starting 1 day after ulcer induction for 7 days in the dose-response experiment or heparin 1000 U/kg at a time schedule of 3, 5, and 7 days in the time-response study, respectively. The gastric mucosal blood flow (GMBF) was measured using a laser Doppler flowmeter under ether anesthesia. The rats were then sacrificed and the ulcer areas were measured. The gastric mucosa was then scraped for the determinations of mucosal prostaglandin E2 (PGE2) level and myeloper-oxidase (MPO) activity. RESULTS: Heparin in the doses of 500 and 1000 U/kg accelerated the healing of acetic acid ulcers in a dose-dependent manner. The highest dose of heparin also reduced the ulcer areas in a time-dependent fashion. The effect was accompanied by an increase in gastric mucosal PGE2 levels. The same dose of heparin not only decreased the gastric mucosal MPO activity but also increased the GMBF in a time-related manner. CONCLUSIONS: Heparin with the doses used in the present study accelerated the healing of acetic acid-induced gastric ulcers in rats in a dose- and time-dependent manner, and this action was related to its effects to increase the levels of gastric mucosal PGE2 and GMBF as well as to decrease the gastric mucosal MPO activity.
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Antiulcerosos/farmacología , Heparina/farmacología , Úlcera Gástrica/fisiopatología , Ácido Acético , Animales , Dinoprostona/metabolismo , Relación Dosis-Respuesta a Droga , Mucosa Gástrica/irrigación sanguínea , Mucosa Gástrica/metabolismo , Masculino , Peroxidasa/metabolismo , Ratas , Ratas Sprague-Dawley , Flujo Sanguíneo Regional , Úlcera Gástrica/inducido químicamenteRESUMEN
The beta-adrenoceptor subtypes and the roles of myeloperoxidase and prostaglandin E2 in the anti-ulcer effect of beta-adrenoceptor antagonists were studied. A non-selective beta-adrenoceptor antagonist, propranolol, or selective beta-adrenoceptor antagonists, metoprolol (a beta 1-adrenoceptor antagonist) or butoxamine (a beta 2-adrenoceptor antagonist) were used. Propranolol given either intraperitoneally or orally reduced ethanol-induced mucosal damage and myeloperoxidase activity. Oral administration of butoxamine produced similar effects. The blood neutrophil count was increased after ethanol administration and this was reversed by the two drugs. Metoprolol did not affect myeloperoxidase activity, neutrophil count and mucosal damage under these experimental conditions. Oral administration of propranolol or butoxamine increased mucosal prostaglandin E2 level. It is concluded that the inflammatory responses to ethanol, as indicated by neutrophil infiltration in gastric mucosa, can be specifically inhibited by drugs that block beta 2-adrenoceptors. This action would explain in part why propranolol and butoxamine but not metoprolol lessened gastric damage. In addition, oral administration of propranolol and butoxamine increased the mucosal prostaglandin E2 level, which could partially contribute to their anti-ulcer effects.
Asunto(s)
Antagonistas Adrenérgicos beta/farmacología , Depresores del Sistema Nervioso Central/toxicidad , Etanol/toxicidad , Úlcera Gástrica/prevención & control , Animales , Butoxamina/farmacología , Dinoprostona/metabolismo , Mucosa Gástrica/efectos de los fármacos , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patología , Recuento de Leucocitos/efectos de los fármacos , Peróxidos Lipídicos/metabolismo , Masculino , Malondialdehído/metabolismo , Metoprolol/farmacología , Peroxidasa/metabolismo , Propranolol/farmacología , Ratas , Ratas Sprague-Dawley , Úlcera Gástrica/inducido químicamente , Úlcera Gástrica/patologíaRESUMEN
The effects of 5-hydroxytryptamine (5-HT) on gastric mucosal blood flow and lesion formation have been established. However, the mechanisms accounting for the reduction of gastric mucosal blood flow have not been defined. The current study aimed to test the hypothesis that decrease of gastric mucosal blood flow in rats is the result of changes of systemic blood pressure and/or platelet aggregation. 5-HT (given i.p. 5 or 10 mg/kg) time and dose dependently reduced gastric mucosal blood flow and systemic arterial blood pressure; it also potentiated ethanol-induced mucosal damage. Methysergide (a 5-HT2-receptor blocker) pretreatment alleviated the decrease of gastric mucosal blood flow and lesion formation but not the systemic blood pressure. Also in the 5-HT-treated animals, the mucosal oxygen (O2) and haemoglobin levels as well as the systemic blood CO2 were reduced, but the blood O2 was increased. The latter two parameters correlated with an elevation of the respiratory rate. The blood platelet count was not affected by 5-HT pretreatment. Adenosine diphosphate (ADP) dose dependently induced a similar degree of platelet aggregation in platelet rich plasma fractions in the saline and 5-HT-treated rats in vitro. 5-HT in the concentrations of 1 or 10 microM, promoted the platelet aggregation produced by ADP. However, this action was attenuated in the 5-HT-pretreated rats, indicating that tachyphylaxis of 5-HT action on platelet aggregation could occur.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Mucosa Gástrica/irrigación sanguínea , Hemodinámica/efectos de los fármacos , Agregación Plaquetaria/efectos de los fármacos , Serotonina/farmacología , Adenosina Difosfato/antagonistas & inhibidores , Adenosina Difosfato/farmacología , Animales , Análisis de los Gases de la Sangre , Presión Sanguínea/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Etanol , Mucosa Gástrica/efectos de los fármacos , Mucosa Gástrica/patología , Inyecciones Intraperitoneales , Masculino , Metisergida/farmacología , Ratas , Ratas Sprague-Dawley , Flujo Sanguíneo Regional/efectos de los fármacos , Respiración/efectos de los fármacos , Serotonina/administración & dosificación , Úlcera Gástrica/inducido químicamente , Úlcera Gástrica/prevención & controlRESUMEN
Intravenous injections of flunarizine 0.25, 0.5, or 1.0 mg.kg-1 10 min before hemorrhage increased the maximal bleeding volume from 4.3 +/- 1.1 to 5.5 +/- 1.1 ml. As the dose of flunarizine increased, the survival time in rats subjected to hemorrhage was prolonged in a dose-dependent manner. Five hours after the reinfusion, flunarizine 1 mg.kg-1 markedly improved the survival rate to 70% compared with nil in the shock group. Flunarizine reduced the increase of lactate in blood, ameliorated the depletion of ATP stores in tissues, and prevented the calcium accumulation in heart and liver. The results suggest that flunarizine may produce a protective effect on hemorrhagic shock, probably related to the decrease of calcium accumulation in the ischemic tissues.