RESUMEN
Amfepramone (diethylpropion) is an appetite-suppressant drug used for the treatment of overweight and obesity. It has been suggested that the systemic and central activity of amfepramone produces cardiovascular effects such as transient ischemic attacks and primary pulmonary hypertension. However, it is not known whether amfepramone produces immediate vascular effects when applied in vitro to rat aortic rings and, if so, what mechanisms may be involved. We analyzed the effect of amfepramone on phenylephrine-precontracted rat aortic rings with or without endothelium and the influence of inhibitors or blockers on this effect. Amfepramone produced a concentration-dependent vasorelaxation in phenylephrine-precontracted rat aortic rings that was not affected by the vehicle, atropine, 4-AP, glibenclamide, indomethacin, clotrimazole, or cycloheximide. The vasorelaxant effect of amfepramone was significantly attenuated by NG-nitro-L-arginine methyl ester (L-NAME) and tetraethylammonium (TEA), and was blocked by removal of the vascular endothelium. These results suggest that amfepramone had a direct vasorelaxant effect on phenylephrine-precontracted rat aortic rings, and that inhibition of endothelial nitric oxide synthase and the opening of Ca2+-activated K+ channels were involved in this effect.
Asunto(s)
Animales , Masculino , Acetilcolina/farmacología , Aorta Torácica/efectos de los fármacos , Depresores del Apetito/farmacología , Dietilpropión/farmacología , Vasodilatadores/farmacología , Aorta Torácica/metabolismo , Canales de Calcio/efectos de los fármacos , Canales de Calcio/metabolismo , Endotelio Vascular/efectos de los fármacos , NG-Nitroarginina Metil Éster/metabolismo , Óxido Nítrico Sintasa de Tipo III/efectos de los fármacos , Fenilefrina/farmacología , Canales de Potasio/efectos de los fármacos , Canales de Potasio/metabolismo , Ratas Wistar , Tetraetilamonio/metabolismo , Vasoconstrictores/farmacología , Vasodilatación/efectos de los fármacosRESUMEN
Amfepramone (diethylpropion) is an appetite-suppressant drug used for the treatment of overweight and obesity. It has been suggested that the systemic and central activity of amfepramone produces cardiovascular effects such as transient ischemic attacks and primary pulmonary hypertension. However, it is not known whether amfepramone produces immediate vascular effects when applied in vitro to rat aortic rings and, if so, what mechanisms may be involved. We analyzed the effect of amfepramone on phenylephrine-precontracted rat aortic rings with or without endothelium and the influence of inhibitors or blockers on this effect. Amfepramone produced a concentration-dependent vasorelaxation in phenylephrine-precontracted rat aortic rings that was not affected by the vehicle, atropine, 4-AP, glibenclamide, indomethacin, clotrimazole, or cycloheximide. The vasorelaxant effect of amfepramone was significantly attenuated by NG-nitro-L-arginine methyl ester (L-NAME) and tetraethylammonium (TEA), and was blocked by removal of the vascular endothelium. These results suggest that amfepramone had a direct vasorelaxant effect on phenylephrine-precontracted rat aortic rings, and that inhibition of endothelial nitric oxide synthase and the opening of Ca2+-activated K+ channels were involved in this effect.
Asunto(s)
Acetilcolina/farmacología , Aorta Torácica/efectos de los fármacos , Depresores del Apetito/farmacología , Dietilpropión/farmacología , Vasodilatadores/farmacología , Animales , Aorta Torácica/metabolismo , Canales de Calcio/efectos de los fármacos , Canales de Calcio/metabolismo , Endotelio Vascular/efectos de los fármacos , Masculino , NG-Nitroarginina Metil Éster/metabolismo , Óxido Nítrico Sintasa de Tipo III/efectos de los fármacos , Fenilefrina/farmacología , Canales de Potasio/efectos de los fármacos , Canales de Potasio/metabolismo , Ratas Wistar , Tetraetilamonio/metabolismo , Vasoconstrictores/farmacología , Vasodilatación/efectos de los fármacosRESUMEN
The relaxant effect of the methyl ester of rosuvastatin was evaluated on aortic rings from male Wistar rats (250-300 g, 6 rats for each experimental group) with and without endothelium precontracted with 1.0 µM phenylephrine. The methyl ester presented a slightly greater potency than rosuvastatin in relaxing aortic rings, with log IC50 values of -6.88 and -6.07 M, respectively. Unlike rosuvastatin, the effect of its methyl ester was endothelium-independent. Pretreatment with 10 µM indomethacin did not inhibit, and pretreatment with 1 mM mevalonate only modestly inhibited the relaxant effect of the methyl ester. Nω-nitro-L-arginine methyl ester (L-NAME, 10 µM), the selective nitric oxide-2 (NO-2) inhibitor 1400 W (10 µM), tetraethylammonium (TEA, 10 mM), and cycloheximide (10 µM) partially inhibited the relaxant effect of the methyl ester on endothelium-denuded aortic rings. However, the combination of TEA plus either L-NAME or cycloheximide completely inhibited the relaxant effect. Inducible NO synthase (NOS-2) was only present in endothelium-denuded aortic rings, as demonstrated by immunoblot with methyl ester-treated rings. In conclusion, whereas rosuvastatin was associated with a relaxant effect dependent on endothelium and hydroxymethylglutaryl coenzyme A reductase in rat aorta, the methyl ester of rosuvastatin exhibited an endothelium-independent and only slightly hydroxymethylglutaryl coenzyme A reductase-dependent relaxant effect. Both NO produced by NOS-2 and K+ channels are involved in the relaxant effect of the methyl ester of rosuvastatin.
Asunto(s)
Animales , Masculino , Ratas , Aorta/efectos de los fármacos , Endotelio Vascular/efectos de los fármacos , Fluorobencenos/farmacología , Hidroximetilglutaril-CoA Reductasas/efectos de los fármacos , NG-Nitroarginina Metil Éster/farmacología , Pirimidinas/farmacología , Sulfonamidas/farmacología , Vasodilatación/efectos de los fármacos , Vasodilatadores/farmacología , Aorta/enzimología , Cicloheximida/farmacología , Fluorobencenos/química , Óxido Nítrico Sintasa de Tipo II/farmacología , Pirimidinas/química , Ratas Wistar , Sulfonamidas/química , Tetraetilamonio/farmacología , Vasodilatación/fisiologíaRESUMEN
The relaxant effect of the methyl ester of rosuvastatin was evaluated on aortic rings from male Wistar rats (250-300 g, 6 rats for each experimental group) with and without endothelium precontracted with 1.0 µM phenylephrine. The methyl ester presented a slightly greater potency than rosuvastatin in relaxing aortic rings, with log IC50 values of -6.88 and -6.07 M, respectively. Unlike rosuvastatin, the effect of its methyl ester was endothelium-independent. Pretreatment with 10 µM indomethacin did not inhibit, and pretreatment with 1 mM mevalonate only modestly inhibited the relaxant effect of the methyl ester. Nω-nitro-L-arginine methyl ester (L-NAME, 10 µM), the selective nitric oxide-2 (NO-2) inhibitor 1400 W (10 µM), tetraethylammonium (TEA, 10 mM), and cycloheximide (10 µM) partially inhibited the relaxant effect of the methyl ester on endothelium-denuded aortic rings. However, the combination of TEA plus either L-NAME or cycloheximide completely inhibited the relaxant effect. Inducible NO synthase (NOS-2) was only present in endothelium-denuded aortic rings, as demonstrated by immunoblot with methyl ester-treated rings. In conclusion, whereas rosuvastatin was associated with a relaxant effect dependent on endothelium and hydroxymethylglutaryl coenzyme A reductase in rat aorta, the methyl ester of rosuvastatin exhibited an endothelium-independent and only slightly hydroxymethylglutaryl coenzyme A reductase-dependent relaxant effect. Both NO produced by NOS-2 and K+ channels are involved in the relaxant effect of the methyl ester of rosuvastatin.
Asunto(s)
Aorta/efectos de los fármacos , Endotelio Vascular/efectos de los fármacos , Fluorobencenos/farmacología , Hidroximetilglutaril-CoA Reductasas/efectos de los fármacos , NG-Nitroarginina Metil Éster/farmacología , Pirimidinas/farmacología , Sulfonamidas/farmacología , Vasodilatación/efectos de los fármacos , Vasodilatadores/farmacología , Animales , Aorta/enzimología , Cicloheximida/farmacología , Fluorobencenos/química , Masculino , Óxido Nítrico Sintasa de Tipo II/farmacología , Pirimidinas/química , Ratas , Ratas Wistar , Rosuvastatina Cálcica , Sulfonamidas/química , Tetraetilamonio/farmacología , Vasodilatación/fisiologíaRESUMEN
1 The role of the extraendothelial and constitutive isoforms of cyclo-oxygenase-2 (COX-2) in the contractile effect of angiotensin II (Ang II) was investigated using thoracic and abdominal aortic rings without endothelium from young Wistar rats. 2 Ang II elicited similar contractions in both aortic segments, and the effect was inhibited by pretreatment with NS398 (a selective COX-2 inhibitor) but not SC-560 [selective cyclo-oxygenase-1 (COX-1) inhibitor]. 3 COX-2 mRNA was expressed under basal conditions in both aortic segments. Additionally, Ang II increased COX-2 mRNA expression in the abdominal but not the thoracic segment, while cycloheximide (a protein synthesis inhibitor) did not affect the contractile response to Ang II in either of the two segments; this suggests that the effect is not associated with de novo COX-2 synthesis. 4 In conclusion, the basal amount of COX-2 found in aortic smooth muscle cells is sufficient to explain the production of the prostanoids related to the contractile effect of Ang II. The production of these prostanoids, which are derived from constitutive COX-2, occurs independently of the endothelium vascular system.
Asunto(s)
Angiotensina II/metabolismo , Aorta/metabolismo , Ciclooxigenasa 2/metabolismo , Endotelio Vascular/fisiología , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Vasoconstricción/efectos de los fármacos , Animales , Aorta/efectos de los fármacos , Aorta Abdominal/efectos de los fármacos , Aorta Abdominal/metabolismo , Aorta Torácica/efectos de los fármacos , Aorta Torácica/metabolismo , Ciclooxigenasa 1/metabolismo , Ciclooxigenasa 2/genética , Inhibidores de la Ciclooxigenasa 2/farmacología , Inhibidores de la Ciclooxigenasa/farmacología , Endotelio Vascular/efectos de los fármacos , Técnicas In Vitro , Isoenzimas/genética , Isoenzimas/metabolismo , Masculino , Especificidad de Órganos , Concentración Osmolar , Biosíntesis de Proteínas , ARN Mensajero/metabolismo , Ratas , Ratas WistarRESUMEN
1 Alpha1-Adrenoceptor (alpha1-AR) subtypes were characterized in isolated omental arteries obtained after abdominal surgery in patients with end-stage renal disease (ESRD) or with Diabetes Mellitus type 2 plus ESRD (ESRD-DM). 2 Omental arteries from patients with ESRD and ESRD-DM elicited a significant increase in sensitivity to phenylephrine with a pD(2) (-log EC50) of 6.7 and 6.6, respectively, vs. the control (5.8, P < 0.001). 3 Stimulation with phenylephrine was conducted in the presence or absence of selective alpha1-AR competitive antagonists: 5-methylurapidil (alpha1A-), AH11110A (1-[biphenyl-2-yloxy]-4-imino-4-piperidin-1-yl-butan-2-ol; alpha1B-) and BMY7378 (8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro [4.5] decane-7,9-dione; alpha(1D)-). The relative abundance of mRNA for all three alpha(1)-ARs was determined. 4 The maximal contractile responses to phenylephrine were: E(max) 1.59 +/- 0.17, 1.48 +/- 0.08 and 1.55 +/- 0.14 g for the ESRD, ESRD-DM and control groups, respectively. 5 Functionally, there was an increment in the affinity for the alpha(1A)-AR antagonist (pA2: control 7.45, ESRD 8.36, ESRD-DM 8.0; P < 0.01), and a reduction in the alpha1B-AR antagonist affinity (8.3 for controls, 7.6 for ESRD and 7.3 for ESRD-DM; P < 0.01) associated with renal disease. The affinities for the alpha1D-AR antagonist were similar among the studied groups (8.5 for the controls, 8.7 for the ESRD and 8.1 for the ESRD-DM groups). 6 Renal disease increased mRNA expression of alpha(1B)-ARs and reduced both alpha1A- and alpha(1D)-ARs subtypes in ESRD and ESRD-DM patients. 7 The results suggest that human omental arteries exposed to chronic uraemia show vascular hypersensitivity to phenylephrine, because of functional alpha1-AR changes.
Asunto(s)
Diabetes Mellitus Tipo 2/metabolismo , Fallo Renal Crónico/metabolismo , Epiplón/irrigación sanguínea , Receptores Adrenérgicos alfa 1/metabolismo , Vasoconstricción , Agonistas alfa-Adrenérgicos/farmacología , Antagonistas Adrenérgicos alfa/farmacología , Adulto , Arterias/metabolismo , Arterias/fisiopatología , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/fisiopatología , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Iminas/farmacología , Fallo Renal Crónico/complicaciones , Fallo Renal Crónico/fisiopatología , Masculino , Persona de Mediana Edad , Fenilefrina/farmacología , Piperazinas/farmacología , Piperidinas/farmacología , ARN Mensajero/metabolismo , Receptores Adrenérgicos alfa 1/efectos de los fármacos , Receptores Adrenérgicos alfa 1/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Vasoconstricción/efectos de los fármacos , Vasoconstrictores/farmacologíaRESUMEN
BACKGROUND: Concurrent chemoradiation is the current standard of treatment for patients with advanced unresectable head and neck squamous cell carcinoma (HNSCC). Due to the potent radiosensitizing properties of gemcitabine, we decided to assess its efficacy and toxicity with concurrent radiation in patients with advanced HNSCC. PATIENTS AND METHODS: From January 1997 to December 2001, 27 patients with locally advanced HNSCC (stage III, 37%; stage IV, 63%) were enrolled. All received a course of radiotherapy (70 Gy over 7 weeks) concurrent with weekly infusions of gemcitabine at 100 mg/m2 or 50 mg/m2. RESULTS: All patients were assessable for toxicity and 26 for response. Severe mucositis (grade 3-4) was observed in 74% of patients (grade 4, 41%). Severe hematological toxicity was uncommon. Mild and moderate xerostomy was the most common late toxicity in 23 patients (85%). The median radiation dose delivered was 70 Gy (40-80 Gy), 25 patients (93%) received > or = 80% of the intended dose. Gemcitabine dose intensity was > or = 80% in only 13 (48%) patients. The rate of complete and partial responses were 61% and 27%, respectively, for an overall response rate of 88%. At a median follow-up of 13 months (range 6-62), the actuarial 3-year progression-free survival (PFS) and overall survival (OS) were 37% and 33%, respectively. The only variable associated with prolonged survival (P = 0.0001) was the degree of response. No difference was observed in response or toxicity with either gemcitabine 50 or 100 mg/m2. CONCLUSIONS: The concurrent use of radiotherapy and gemcitabine is effective but produces manageable severe mucositis in a high percentage of patients.
Asunto(s)
Antimetabolitos Antineoplásicos/farmacología , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/radioterapia , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacología , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/radioterapia , Adulto , Anciano , Antimetabolitos Antineoplásicos/administración & dosificación , Terapia Combinada , Desoxicitidina/administración & dosificación , Desoxicitidina/efectos adversos , Supervivencia sin Enfermedad , Femenino , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Traumatismos por Radiación , Ribonucleótido Reductasas/antagonistas & inhibidores , Resultado del Tratamiento , GemcitabinaAsunto(s)
Antiinflamatorios no Esteroideos/uso terapéutico , Diclofenaco/uso terapéutico , Hiperalgesia/tratamiento farmacológico , Complejo Vitamínico B/uso terapéutico , Animales , Conducta Animal/efectos de los fármacos , Carragenina , Femenino , Calor , Hiperalgesia/inducido químicamente , Dimensión del Dolor/efectos de los fármacos , Ratas , Ratas WistarAsunto(s)
Formaldehído , Inflamación/prevención & control , Dimensión del Dolor/efectos de los fármacos , Dolor/prevención & control , Complejo Vitamínico B/farmacología , Animales , Conducta Animal/efectos de los fármacos , Femenino , Inflamación/inducido químicamente , Naloxona/farmacología , Antagonistas de Narcóticos/farmacología , Dolor/inducido químicamente , Ratas , Ratas WistarRESUMEN
OBJECTIVE: The present study was designed to determine whether or not subrenal aortic coarctation (SAC) is able to modify aorta reactivity in pregnant rats. METHODS: Wistar female rats were subjected to SAC, and the responses to phenylephrine and acetylcholine of aortic segments above (thoracic) and below (abdominal) the coarctation from pregnant and non-pregnant rats were explored. RESULTS: Contractile responses to phenylephrine and relaxant responses to acetylcholine were similar in the thoracic segment from pregnant and non-pregnant SAC rats, whereas both kinds of response were higher in the abdominal segment from pregnant rats (p < 0.05). L-NAME (a nitric oxide synthase inhibitor) increased the effect of phenylephrine only in the aortic rings from pregnant animals (p < 0.05) and in general abolished the response to acetylcholine, with the exception of the abdominal segment from pregnant rats, in which only a partial inhibition was observed (p < 0.05). Indomethacin inhibited the contractile response to phenylephrine and increased the relaxant activity to acetylcholine in both aortic segments from the two groups of animals (p < 0.05). CONCLUSION: The lower contractile response to adrenergic agonists and higher relaxant response to acetylcholine that are associated with normal pregnancy are lost as a consequence of the coarctation procedure. Changes in the production of endothelial nitric oxide and contractile prostanoids appear to be associated with the vascular disturbances observed in SAC rats.
Asunto(s)
Placenta/irrigación sanguínea , Preeclampsia/fisiopatología , Útero/irrigación sanguínea , Vasoconstricción , Vasodilatación , Animales , Aorta Abdominal/patología , Coartación Aórtica/fisiopatología , Constricción Patológica , Femenino , Embarazo , Ratas , Ratas Wistar , Vasoconstricción/fisiología , Vasodilatación/fisiologíaAsunto(s)
Coartación Aórtica/fisiopatología , Músculo Liso Vascular/fisiopatología , Preñez/fisiología , Animales , Antiinflamatorios no Esteroideos/farmacología , Aorta Torácica/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Femenino , Feto/irrigación sanguínea , Técnicas In Vitro , Indometacina/farmacología , Contracción Muscular/fisiología , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico/fisiología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo III , Circulación Placentaria/fisiología , Embarazo , Ratas , Ratas Endogámicas WKYAsunto(s)
Aorta/efectos de los fármacos , Fenilefrina/farmacología , Vasoconstrictores/farmacología , Animales , Aorta Abdominal/efectos de los fármacos , Aorta Torácica/efectos de los fármacos , Endotelio Vascular/fisiología , Técnicas In Vitro , Masculino , Antagonistas de Prostaglandina/farmacología , Ratas , Ratas Wistar , Tromboxano A2/antagonistas & inhibidores , Tromboxano A2/fisiologíaRESUMEN
The role of vitamin B complex preparations as an analgesic adjuvant is controversial. Therefore, the purpose of the present study was to characterize the potentiation of the antinociceptive effect of diclofenac by a vitamin B complex preparation and its individual components by using the pain-induced functional-impairment model in the rat (PIFIR). Pain was produced by the intraarticular injection of uric acid in the right hind limb. Oral administration of diclofenac resulted in a dose-dependent antinociceptive effect. Oral administration of a vitamin B complex preparation containing thiamine (vitamin B(1)), pyridoxine (vitamin B(6)), and cyanocobalamin (vitamin B(12)) in a 1:1:0.01 proportion did not produce any antinociception by itself, but it significantly potentiated the effect of diclofenac. Coadministration of diclofenac with either thiamine or pyridoxine resulted in an antinociceptive effect similar to that of diclofenac alone. On the other hand, coadministration of cyanocobalamin significantly increased diclofenac-induced antinociception. It is concluded that the potentiation of diclofenac-induced antinociception in the PIFIR model is due to cyanocobalamin.