RESUMEN

PURPOSE: The current study aimed to verify the usefulness of preoperative ultrasonographic evaluation of contralateral patent processus vaginalis (PPV) at the level of the internal inguinal ring. METHODS: This was a prospective study of patients undergoing unilateral inguinal hernia repair at two institutions during 2010-2011. The sex, age at initial operation, birth weight, initial operation side, and the preoperative diameter of the contralateral PPV as determined using ultrasonography (US) were recorded. We analyzed the incidence of contralateral inguinal hernia, risk factors, and the usefulness of the preoperative major diameter of the contralateral PPV. The follow-up period was 36 months. RESULTS: All 105 patients who underwent unilateral hernia repair completed 36 months of follow-up, during which 11 patients (10.5 %) developed a contralateral hernia. The following covariates were not associated with contralateral hernia development: sex (p = 0.350), age (p = 0.185), birth weight (p = 0.939), and initial operation side (p = 0.350). The preoperative major diameter of the contralateral PPV determined using US was significantly wider among patients with a contralateral hernia than those without a contralateral hernia (p = 0.001). When the 105 patients were divided into two groups according to cut-off values of the preoperative major diameter of the contralateral PPV (wide group, >2.0 mm; narrow group, ≤2.0 mm), a significant association was observed between the preoperative major diameter of the contralateral PPV and patient outcomes (p = 0.001). CONCLUSIONS: We used US and confirmed the usefulness of a preoperative evaluation of the major diameter of the contralateral PPV at the level of the internal inguinal ring in pediatric patients with unilateral inguinal hernias.

Asunto(s)

Hernia Inguinal/diagnóstico por imagen , Conducto Inguinal/diagnóstico por imagen , Adolescente , Niño , Preescolar , Femenino , Hernia Inguinal/cirugía , Humanos , Incidencia , Lactante , Recién Nacido , Masculino , Valor Predictivo de las Pruebas , Cuidados Preoperatorios , Estudios Prospectivos , Factores de Riesgo , Ultrasonografía

RESUMEN

PURPOSE: Previously, we established a pre-operative risk scoring system to predict contralateral inguinal hernia in children with unilateral inguinal hernias. The current study aimed to verify the usefulness of our pre-operative scoring system. METHODS: This was a prospective study of patients undergoing unilateral inguinal hernia repair from 2006 to 2009 at a single institution. Gender, age at initial operation, birth weight, initial operation side, and the pre-operative risk score were recorded. We analyzed the incidence of contralateral inguinal hernia, risk factors, and the usefulness of our pre-operative risk scoring system. The follow-up period was 36 months. We used forward multiple logistic regression analysis to predict contralateral hernia. RESULTS: Of the 372 patients who underwent unilateral hernia repair, 357 (96.0 %) were completely followed-up for 36 months, and 23 patients (6.4 %) developed a contralateral hernia. Left-sided hernia (OR = 5.5, 95 %, CI = 1.3-24.3, p = 0.023) was associated with an increased risk of contralateral hernia. The following covariates were not associated with contralateral hernia development: gender (p = 0.702), age (p = 0.215), and birth weight (p = 0.301). The pre-operative risk score (cut-off point = 4.5) of the patients with a contralateral hernia was significantly higher, compared with the patients without a contralateral hernia using the area under the receiver operating characteristic curve (p = 0.024). CONCLUSIONS: Using multivariate analysis, we confirmed usefulness of our pre-operative scoring system and initial side of the inguinal hernia, together, for the prediction of contralateral inguinal hernia in children.

Asunto(s)

Hernia Inguinal/epidemiología , Adolescente , Niño , Preescolar , Femenino , Indicadores de Salud , Hernia Inguinal/diagnóstico , Hernia Inguinal/cirugía , Humanos , Incidencia , Lactante , Recién Nacido , Masculino , Análisis Multivariante , Estudios Prospectivos , Factores de Riesgo , Tokio/epidemiología

RESUMEN

OBJECTIVE: We investigated the extent of apoptosis in crypt cells and Peyer's patches (PPs) during small bowel allograft rejection in rats to examine the effect of FTY720 and ex vivo graft irradiation during rejection. MATERIALS AND METHODS: Orthotopic small bowel transplantations (SBT) were performed from Brown Norway (BN) rats to Lewis (LEW) rats. Four groups of SBT animals were studied on days 3, 5, and 7 after operations: untreated allograft, allograft with FTY720, allograft with irradiation, and allograft with FTY720+irradiation. Cryostat sections were prepared from the grafts, including PPs. An in situ end-labeling (ISEL) technique was used to detect apoptotic cells. Indirect immunoperoxidase staining was also performed using monoclonal antibodies against rat Fas/FasL. RESULTS: The graft survival was prolonged in the FTY720-treated groups. In the FTY720-treated group, the number of ISEL-positive enterocytes was significantly down-regulated on days 3, 5, and 7 compared with the untreated allograft group. The number of ISEL-positive mononuclear cells was also significantly down-regulated compared with the untreated allograft group. The FTY720 the radiation and the FTY720+irradiation treated groups showed significantly down-regulated numbers of Fas/FasL-positive enterocytes on day 7 compared with the untreated allograft group. Fas/FasL-positive mononuclear cells were also significantly down-regulated in the allograft compared with the untreated allograft group. CONCLUSIONS: FTY720 and ex vivo graft irradiation prevented up-regulation of the number of apoptotic enterocytes, lymphocytes, and Fas/FasL-positive lymphocytes, and also prolonged small bowel allograft survival. Combination FTY720 and ex vivo graft irradiation did not affect graft survival and apoptotic cell expression compared with the FTY720 only group. These findings suggest that FTY720 may prevent both rejection-associated and sepsis-induced apoptosis during the late phase of small bowel graft rejection.

Asunto(s)

Apoptosis/efectos de los fármacos , Inmunosupresores/uso terapéutico , Intestino Delgado/efectos de la radiación , Intestino Delgado/trasplante , Linfocitos/citología , Glicoles de Propileno/uso terapéutico , Esfingosina/análogos & derivados , Trasplante Homólogo/patología , Animales , Apoptosis/efectos de la radiación , Clorhidrato de Fingolimod , Intestino Delgado/efectos de los fármacos , Intestino Delgado/patología , Linfocitos/efectos de los fármacos , Linfocitos/efectos de la radiación , Ratas , Ratas Endogámicas BN , Ratas Endogámicas Lew , Esfingosina/uso terapéutico , Análisis de Supervivencia

RESUMEN

AIM: We investigated the extent of apoptosis in crypt cells and Peyer's patches (PPs) during small bowel allograft rejection in rats to examine the effect of FTY720 during rejection. METHODS: Orthotopic small bowel transplantations (SBTs) were performed from BN to LEW rats. Isografted animals served as controls. Three groups of SBT animals were studied on days 3, 5, and 7 after operation: isograft, untreated allograft, allograft with FTY720. FTY720 was orally administered by gavage (1 mg/kg/d) to allograft recipients on 7 consecutive days. Cryostat sections were prepared from grafts, including PPs. An in situ end-labeling (ISEL) technique was used to detect apoptotic cells. Indirect immunoperoxidase staining was also performed using monoclonal antibodies against rat Fas/Fas-L. RESULTS: Graft survival was prolonged in the FTY720-treated group. The number of ISEL-positive enterocytes in the allografts increased significantly on days 3, 5, and 7 compared with the isograft group. In the FTY720-treated group, the number of ISEL-positive enterocytes in the allografts was down-regulated significantly on days 3, 5, and 7 compared with untreated allograft group. In the PPs, the number of ISEL-positive mononuclear cells increased significantly in the allografts compared with the isograft group. In the FTY720-treated groups, the number of ISEL-positive mononuclear cells were down-regulated significantly in the allografts compared with the untreated allograft group. The number of Fas/FasL-positive enterocytes were increased significantly in allografts compared with isograft group. In FTY720-treated groups, the number of Fas/FasL-positive enterocytes were down-regulated significantly on day 7 compared with the untreated allograft group. In the PPs, Fas/FasL-positive mononuclear cells also increased significantly on day 7 in the allografts compared with isografts. In the FTY720-treated groups, Fas/FasL-positive mononuclear cells were down-regulated significantly in the allografts compared with the untreated allograft group. CONCLUSIONS: The number of apoptotic enterocytes, lymphocytes, and Fas/FasL-positive lymphocytes increased during small bowel graft rejection. FTY720 prevented up-regulation of the number of apoptotic enterocytes, lymphocytes, and Fas/FasL-positive lymphocytes while also prolonging small bowel allograft survival.

Asunto(s)

Apoptosis/efectos de los fármacos , Inmunosupresores/uso terapéutico , Mucosa Intestinal/patología , Intestino Delgado/trasplante , Ganglios Linfáticos Agregados/inmunología , Glicoles de Propileno/uso terapéutico , Esfingosina/análogos & derivados , Animales , Proteína Ligando Fas/análisis , Clorhidrato de Fingolimod , Mucosa Intestinal/efectos de los fármacos , Intestino Delgado/patología , Modelos Animales , Ganglios Linfáticos Agregados/efectos de los fármacos , Ganglios Linfáticos Agregados/patología , Ratas , Ratas Endogámicas BN , Ratas Endogámicas Lew , Esfingosina/uso terapéutico , Trasplante Homólogo/patología , Trasplante Isogénico/patología

RESUMEN

AIM: Mucosal addressin cell adhesion molecule-1 (MAdCAM-1) mediates the homing of lymphocytes to gut-associated tissues (GALT). We performed a semiquantitative analysis of MAdCAM-1 expression during small bowel graft rejection in rat treated with FTY720. METHODS: Orthotopic small bowel transplantations (SBT) were performed from BN rats to LEW rats. Isografted animals served as controls. Three groups of SBT animals were studied on days 3, 5, 7 after operations (Isograft, untreated allograft, allograft with FTY720). FTY720 was orally administered by gavage (1 mg/kg/d) to allograft models on 7 consecutive days. Cryostat sections were prepared from grafts, including Peyer's patches (PPs). Indirect immunoperoxidase staining was performed using mAbs against MAdCAM-1. The degree of vascular endothelial staining on high endothelial venules (HEV) in the PPs was graded from 1 (low levels) to 5 (high levels), and in the vessels of the lamina propia from 1 (faint), to 2 (low at the base of villi), 3 (low to the middle of villi), 4 (high to the middle of villi), to 5 (high to villi tip). RESULTS: The graft survival was prolonged in the FTY720-treated group. MAdCAM-1 expression on HEVs in PPs was down-regulated during rejection. In contrast its expression on endothelial cells of vessels in the lamina propria was up-regulated during rejection. In the FTY720-treated groups, MAdCAM-1 expression on HEVs in PPs was up-regulated and its expression on endothelial cells of vessels in the lamina propria was down-regulated compared with untreated allograft group. CONCLUSIONS: Alteration in MAdCAM-1 expression may be associated with the development of SB graft rejection. The vessels at the base of villi, which are associated with lymphocyte recruitment, may become sites of intestine immune reactivity during the early phase of small bowel allograft rejection. FTY720 was found to prevent the down-regulation of MAdCAM-1 expression on HEVs in PPs and the up-regulation of its expression on endothelial cells of vessels in the lamina propria while also prolonging small bowel allograft survival.

Asunto(s)

Inmunoglobulinas/genética , Inmunosupresores/uso terapéutico , Mucosa Intestinal/fisiología , Yeyuno/trasplante , Mucoproteínas/genética , Glicoles de Propileno/uso terapéutico , Esfingosina/análogos & derivados , Trasplante Homólogo/fisiología , Animales , Clorhidrato de Fingolimod , Regulación de la Expresión Génica , Supervivencia de Injerto/efectos de los fármacos , Ratas , Ratas Endogámicas BN , Esfingosina/uso terapéutico , Trasplante Homólogo/patología , Trasplante Isogénico/patología , Trasplante Isogénico/fisiología

RESUMEN

Acute exacerbations of chronic obstructive pulmonary disease (COPD) accompanied with hypoxaemia may induce net protein catabolism and hypoxaemia could be an important trigger of a systemic catabolic response. The aim of this study was to examine the anabolic effects of recombinant human insulin-like growth factor-I (IGF-1) in rats exposed to hypoxia. Although acute hypoxia is usually accompanied with a decrease in dietary intake, the usual nitrogen intake was maintained in this study. Sprague-Dawley rats were maintained by continuous infusion of solution for total parenteral nutrition for 6 days. The animals were then randomly assigned to a normoxic (N) or a hypoxic (H) group. During the last 3 days of the experiment N and H rats were randomised to receive either IGF-I or vehicle. Exposure to hypoxia caused a decrease in body-weight gain accompanied by a negative nitrogen balance, which was mainly due to increased urinary nitrogen excretion. No effect of recombinant human IGF-I treatment on body weight was observed during exposure to hypoxia, although nitrogen balance normalised. The co-infusion of recombinant human insulin-like growth factor-1 and total parenteral nutrition has a significant net anabolic effect, as demonstrated by nitrogen retention and reduction in urine protein excretion observed in rats. Insulin-like growth factor-1 may help to ameliorate the protein catabolism observed under hypoxic conditions.

Asunto(s)

Hipoxia/sangre , Hipoxia/orina , Factor I del Crecimiento Similar a la Insulina/farmacología , Nitrógeno/sangre , Nitrógeno/orina , Nutrición Parenteral Total , Equilibrio Hidroelectrolítico/efectos de los fármacos , Pérdida de Peso/efectos de los fármacos , Animales , Modelos Animales de Enfermedad , Sinergismo Farmacológico , Humanos , Factor I del Crecimiento Similar a la Insulina/administración & dosificación , Masculino , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley

RESUMEN

Inhaled PGI2 has been reported to elicit pulmonary vasodilation, but whether it is also effective in treating chronic hypoxic pulmonary hypertension is still uncertain. We designed this study to address the in vivo effectiveness of inhaled Beraprost, a stable PGI2 analogue, on pulmonary vascular tone during hypoxic exposure in normoxic (N) and chronically hypoxic (CH) rats. Pulmonary vasodilation was observed by low-dose inhaled Beraprost in N rats, but not in CH rats. It was not until higher doses of Beraprost were given that pulmonary vasodilation was obtained in CH rats. When the agent was continuously administered by an intravascular route at the inhaled dose, it elicited no vasodilation in N rats. On the contrary, it elicited profound vasodilation in CH rats, although a concomitant systemic hypotension was observed. The PGI2 receptor mRNA expression was unchanged in the lungs of CH rats compared with that of N rats. We conclude that low doses of aerosolized Beraprost may reduce pulmonary vascular tone in rats without preexisting lung diseases. In contrast, when hypoxic pulmonary hypertension is present, the threshold of Beraprost inhalation was elevated to provoke pulmonary vasodilation.

Asunto(s)

Epoprostenol/análogos & derivados , Epoprostenol/uso terapéutico , Hipertensión Pulmonar/tratamiento farmacológico , Hipoxia/fisiopatología , Administración por Inhalación , Animales , Enfermedad Crónica , Epoprostenol/administración & dosificación , Epoprostenol/biosíntesis , Hemodinámica/efectos de los fármacos , Inyecciones Intravenosas , Masculino , ARN Mensajero/análisis , Ratas , Ratas Sprague-Dawley , Receptores de Epoprostenol , Receptores de Prostaglandina/genética

RESUMEN

Endothelin-1 (ET-1) is a potent vasoactive peptide, and is thought to play an important role in the regulation of pulmonary vascular tone. Previous studies suggested that ET-1 can act as a vasoconstrictor via the endothelin-A and -B 2 receptors located on smooth muscle cells, and also act as a vasodilator through the endothelin-B 1 receptor situated on endothelial cells in the pulmonary circulation. To determine the role of endothelin-B receptors in hypoxic pulmonary hypertension, we examined the hemodynamic effects of a selective endothelin-B receptor agonist (IRL 1620) in chronic hypoxic pulmonary hypertensive rats. In rat lungs perfused with a half-blood solution, vasoconstriction by KCl administration was gradually reversed by IRL 1620 in normoxic rats, but not in chronic hypoxic rats. In in vivo studies, small doses of IRL 1620 induced transient vasodilation in normoxic rats, but had no obvious effects in chronic hypoxic rats. A high dose of IRL 1620 mediated vasoconstriction only in chronic hypoxic rats. Endothelin-B receptor messenger-RNA expression was lower in the lungs of chronic hypoxic rats than in normoxic rats. These results suggested that although the vasodilatory response mediated by endothelin-B receptor can be expected to play a protective role in the development of pulmonary hypertension, that response is diminished in hypoxic pulmonary hypertension.

Asunto(s)

Hipertensión Pulmonar/fisiopatología , Hipoxia/fisiopatología , Receptores de Endotelina/fisiología , Animales , Endotelinas/farmacología , Técnicas In Vitro , Masculino , Fragmentos de Péptidos/farmacología , Circulación Pulmonar/fisiología , Ratas , Ratas Sprague-Dawley , Receptor de Endotelina B , Vasodilatación/fisiología

Asunto(s)

Quimiocina CCL2/metabolismo , Hipertensión Pulmonar/metabolismo , Animales , Modelos Animales de Enfermedad , Macrófagos Alveolares/metabolismo , Masculino , Monocrotalina , Ratas , Ratas Sprague-Dawley

RESUMEN

We investigated how signals arising from peripheral chemoreceptors could affect pulmonary vasculature in rats. Effects of the hypoxic exposure (10%) on mean pulmonary arterial pressure (mPAP), abdominal aortic flow (Q) and the estimated total pulmonary vascular resistance (mPAP/Q) were determined in anesthetized, artificially ventilated, carotid sinus nerve intact or chemodenervated rats. The pressor response of PAP to hypoxia seen in intact rats changed to the depressor response after chemodenervation. Hypoxia elicited a decrease in Q and an increase in mPAP/Q in both intact and chemodenervated rats. Selective carotid body stimulation by the intra-carotid injection of sodium cyanide (NaCN) in normoxia elicited an immediate but transient increase in PAP and Q before and after bilateral vagotomy. The peak change in PAP slightly preceded that in Q. These responses to NaCN were completely abolished by chemodenervation. These results indicate that the immediate chemoreflex contributes to the short-term regulation of pulmonary vasculature in rats.

Asunto(s)

Presión Sanguínea/fisiología , Cuerpo Carotídeo/fisiología , Circulación Pulmonar/fisiología , Animales , Presión Sanguínea/efectos de los fármacos , Células Quimiorreceptoras/efectos de los fármacos , Células Quimiorreceptoras/fisiología , Desnervación , Hipoxia/fisiopatología , Circulación Pulmonar/efectos de los fármacos , Ratas , Recurrencia , Cianuro de Sodio/farmacología , Estimulación Química , Resistencia Vascular/efectos de los fármacos

RESUMEN

Administration of monocrotaline (MCT) causes pulmonary vascular lesions consisting of monocyte/macrophage infiltration in the early phase and medial thickening in pulmonary arteries and arterioles associated with pulmonary hypertension (PH) in the later phase. However, the molecular mechanism of monocyte/macrophage infiltration and its roles remain elusive. Herein, we have evaluated the role of a potent monocyte chemotactic and activating chemokine/monocyte chemoattractant protein-1 (MCAF/MCP-1) in MCT-induced PH in rats. A single injection of MCT induced PH at Day 21, as evidenced by increases in the ratio of right ventricular to left ventricular and septum weights (RV/LV+S) and right ventricular systolic pressure (RVSP). A significant increase in macrophage number in lungs started at Day 14, reaching a maximum at Day 21. MCAF/MCP-1 levels in bronchoalveolar lavage fluids were elevated significantly at Day 14 and remained high until Day 28, whereas plasma MCAF/MCP-1 levels increased at Day 7, returning to normal levels by Day 21. Immunoreactive MCAF/MCP-1 proteins were mainly detected in macrophages in alveoli and in perivascular regions of pulmonary arterioles and venules. Intravenous administration of anti-MCAF/MCP-1 antibodies with MCT significantly decreased macrophage infiltration and eventually reduced the increases in RV/LV+S and RVSP, as well as medial thickening of pulmonary arterioles. Thus, MCAF/MCP-1 is essentially involved in MCT-induced PH by recruiting and activating macrophages.

Asunto(s)

Anticuerpos/inmunología , Anticuerpos/farmacología , Quimiocina CCL2/inmunología , Hipertensión Pulmonar/fisiopatología , Animales , Movimiento Celular/efectos de los fármacos , Quimiocina CCL2/biosíntesis , Hipertensión Pulmonar/inducido químicamente , Inmunohistoquímica , Inyecciones Subcutáneas , Macrófagos/fisiología , Masculino , Monocrotalina/farmacología , Ratas , Ratas Sprague-Dawley

RESUMEN

The pulmonary artery pressure (PAP) response to hypoxia is characterized by an initial vasoconstriction followed by vasodilation. Pulmonary vessels can release endothelium-derived relaxing factor (EDRF), which is considered to be nitric oxide (NO), but the role of EDRF in the regulation of normal and hypoxic pulmonary vascular tone is still uncertain. We designed this study to address the in vivo role of EDRF in vasodilation during sustained hypoxia. We studied the effects of an EDRF-synthesis inhibitor, Nomega-nitro-L-arginine methyl ester (L-NAME), on the pulmonary vascular response to sustained hypoxia (10% O2, 20 min) in normoxic (N) and chronically hypoxic (CH) rats. Biphasic PAP response was observed in N rats, whereas PAP was unchanged in CH rats during sustained hypoxic exposure. The L-NAME-induced PAP increase during normoxia was greater in CH than in N rats, suggesting that basal EDRF plays an important role in attenuating the severity of pulmonary hypertension in CH rats. Administration of L-NAME increased the initial increment in PAP by acute hypoxia and shifted the PAP response upward throughout sustained hypoxia, while still showing the biphasic pattern, in N rats. In contrast, PAP increased acutely and remained elevated with little recovery in the late phase in CH rats. The inducible NO synthase messenger RNA (mRNA) expression and protein showed greater increases in the lungs of CH than in N rats. These results suggest that EDRF release during sustained hypoxia may partly contribute to the roll-off in PAP response during sustained hypoxia in N rats, and that augmented EDRF may prevent a further increase in PAP during chronic hypoxia.

Asunto(s)

Hipoxia/fisiopatología , Óxido Nítrico/metabolismo , Circulación Pulmonar , Alcalosis , Animales , Northern Blotting , Peso Corporal , Dióxido de Carbono/sangre , Inhibidores Enzimáticos/farmacología , Regulación de la Expresión Génica , Hemodinámica/efectos de los fármacos , Lipopolisacáridos/farmacología , Pulmón/química , Pulmón/enzimología , Masculino , Miocardio/patología , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico Sintasa/genética , Óxido Nítrico Sintasa/metabolismo , Óxido Nítrico Sintasa de Tipo II , Tamaño de los Órganos , Oxígeno/sangre , ARN Mensajero/análisis , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Factores de Tiempo

RESUMEN

Monocrotaline (MCT) is bioactivated in liver cytochrome P-450s to MCT pyrrole (MCTP), which primarily injures the lung endothelium to result in the development of pulmonary hypertension (PH) in rats. However, whether there is a relation between the degree of PH and the activity of liver cytochrome P-450 to convert MCT to MCTP remains unclear. To examine the relation between these physiological and biochemical changes, we first measured the severity of MCT-induced (20 mg/kg) PH in male, female, castrated male, and phenobarbital (PB, liver P-450s inducer)-pretreated male rats. The degree of right ventricular hypertrophy was more severe in PB-pretreated male than in control male rats. It was also more severe in male than in either female or castrated male rats, suggesting that sex-specific P-450s could be involved in the metabolic pathways of MCT in the liver. Further to explore which of the isozymes (2A2, 2C11, and 3A) of P-450s in the liver is responsible for the bioactivation of MCT, we measured the rate of MCTP production in hepatic microsomes by a modified Mattock's method. Treatment of male rats with PB and pregnenolone 16alpha-carbonitrile (PCN), which is the specific inducer of P-450 3A, increased the rate of MCTP production, suggesting that P-450 3A may contribute to the conversion to pyrrole. Therefore we measured the amount of P-450 3A protein by immunoblotting and attempted to inhibit MCT metabolism by using antibodies to P-450 3A. P-450 3A was significantly induced by PCN (6.5-fold) and PB (4.6-fold) treatment and reduced by castration (0.38-fold). The amount of P-450 3A was closely correlated with the production of MCTP, and the conversion of MCT to MCTP was strongly inhibited by antibodies against P-450 3A. These results indicated that P-450 3A was predominantly responsible for the metabolism of MCT to MCTP in rat liver and suggested a tight linkage between the degree of PH and the activity of liver P-450 3A.

Asunto(s)

Hidrocarburo de Aril Hidroxilasas , Sistema Enzimático del Citocromo P-450/metabolismo , Hígado/enzimología , Monocrotalina/metabolismo , Oxidorreductasas N-Desmetilantes/metabolismo , Animales , Biotransformación , Citocromo P-450 CYP3A , Sistema Enzimático del Citocromo P-450/inmunología , Femenino , Corazón/efectos de los fármacos , Ventrículos Cardíacos/patología , Hipertensión Pulmonar/inducido químicamente , Hipertensión Pulmonar/metabolismo , Hipertensión Pulmonar/patología , Hipertensión Pulmonar/fisiopatología , Hipertrofia , Inmunoglobulina G/inmunología , Hígado/inmunología , Masculino , Microsomas Hepáticos/enzimología , Microsomas Hepáticos/inmunología , Monocrotalina/análogos & derivados , Monocrotalina/toxicidad , Orquiectomía , Tamaño de los Órganos , Oxidorreductasas N-Desmetilantes/inmunología , Ratas , Ratas Sprague-Dawley , Factores Sexuales , Presión Ventricular/efectos de los fármacos

RESUMEN

Endothelin-1 (ET-1) is a potent vasoactive peptide and is thought to play an important role in the regulation of vascular tone. ET-1 can both constrict blood vessels, via endothelin-A (ET-A) receptors in vascular smooth muscle cells, and dilate then via endothelin-B (ET-B) receptors in endothelial cells in the systemic circulation. To determine the role of ET-B receptors in the pulmonary circulation, we examined the hemodynamic effects of a selective ET-B receptor agonist (IRL 1620) in rats. In rat lungs perfused with a salt solution, IRL 1620 caused pulmonary vasoconstriction in a dose-dependent manner. In lungs perfused with a hypoxic half-blood solution (10% O2), doses of IRL 1620 less than 10 nM caused pulmonary vasodilation, but higher doses caused pulmonary vasoconstriction. IRL 1620 caused transient vasodilation of the systemic circulation at every dose used (0.1, 1, and 5 nmol/kg) in anesthetized rats. In contrast, the effects of IRL 1620 on the pulmonary circulation varied with the dose. Small doses (0.1 or 1 nmol/kg) caused pulmonary vasodilation, but a higher dose (5 nmol/kg) caused pulmonary vasoconstriction. These results show tachyphylaxis in the pulmonary vasodilator response to IRL 1620, but not in the systemic vasodilator response. The present data show the dual action (vasoconstriction and vasodilation) of ET-B receptors.

Asunto(s)

Circulación Pulmonar/fisiología , Receptores de Endotelina/fisiología , Animales , Endotelinas/farmacología , Técnicas In Vitro , Masculino , Fragmentos de Péptidos/farmacología , Ratas , Ratas Sprague-Dawley , Receptor de Endotelina B , Receptores de Endotelina/efectos de los fármacos , Vasoconstricción/fisiología , Vasodilatación/fisiología

Asunto(s)

Capilares/ultraestructura , Ciclosporina/uso terapéutico , Rechazo de Injerto/patología , Inmunosupresores/uso terapéutico , Trasplante de Riñón/patología , Túbulos Renales/irrigación sanguínea , Biopsia con Aguja , Capilares/patología , Enfermedad Crónica , Técnica del Anticuerpo Fluorescente , Glomerulonefritis/patología , Rechazo de Injerto/clasificación , Rechazo de Injerto/inmunología , Humanos , Glomérulos Renales/patología , Trasplante de Riñón/inmunología , Túbulos Renales/patología , Microscopía Electrónica , Estudios Retrospectivos , Tacrolimus/uso terapéutico , Trasplante Homólogo

Asunto(s)

Arteriolas/patología , Ciclosporina/efectos adversos , Glomeruloesclerosis Focal y Segmentaria/inducido químicamente , Rechazo de Injerto/inmunología , Inmunosupresores/efectos adversos , Trasplante de Riñón/inmunología , Adulto , Arteriolas/efectos de los fármacos , Biopsia con Aguja , Enfermedad Crónica , Estudios de Seguimiento , Glomeruloesclerosis Focal y Segmentaria/inmunología , Glomeruloesclerosis Focal y Segmentaria/patología , Rechazo de Injerto/mortalidad , Rechazo de Injerto/patología , Supervivencia de Injerto , Humanos , Trasplante de Riñón/mortalidad , Trasplante de Riñón/patología , Donadores Vivos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Tiempo

Asunto(s)

Ciclosporina/uso terapéutico , Inmunosupresores/uso terapéutico , Trasplante de Riñón/inmunología , Tacrolimus/uso terapéutico , Biopsia con Aguja , Estudios de Seguimiento , Rechazo de Injerto/inmunología , Rechazo de Injerto/patología , Humanos , Trasplante de Riñón/patología , Túbulos Renales Proximales/patología , Túbulos Renales Proximales/ultraestructura , Microscopía Electrónica , Factores de Tiempo , Trasplante Homólogo

Asunto(s)

Ciclosporina/efectos adversos , Inmunosupresores/efectos adversos , Trasplante de Riñón/patología , Tacrolimus/efectos adversos , Biopsia , Ciclosporina/sangre , Estudios de Seguimiento , Humanos , Inmunosupresores/sangre , Trasplante de Riñón/inmunología , Trasplante de Riñón/fisiología , Estudios Retrospectivos , Tacrolimus/sangre , Factores de Tiempo , Trasplante Homólogo

Asunto(s)

Capilares/patología , Rechazo de Injerto/patología , Glomérulos Renales/irrigación sanguínea , Trasplante de Riñón/patología , Túbulos Renales/irrigación sanguínea , Membrana Basal/patología , Biopsia , Cadáver , Creatinina/sangre , Ciclosporina/uso terapéutico , Rechazo de Injerto/inmunología , Rechazo de Injerto/terapia , Supervivencia de Injerto , Humanos , Inmunosupresores/uso terapéutico , Glomérulos Renales/patología , Glomérulos Renales/ultraestructura , Trasplante de Riñón/inmunología , Trasplante de Riñón/fisiología , Túbulos Renales/patología , Túbulos Renales/ultraestructura , Linfocitos/patología , Microscopía Electrónica , Nefritis Intersticial/patología , Estudios Retrospectivos , Tacrolimus/uso terapéutico , Donantes de Tejidos

RESUMEN

Chronic hypoxia (10% O2 for 2-3 weeks) causes pulmonary hypertension and vascular remodeling in the rat. To study the role of thromboxase A2 in chronic hypoxic pulmonary hypertension, the hemodynamic effects of intravenous administration of a thromboxane analogue (STA2) were measured in chronic hypoxic (H) and normoxic (N) Sprague-Dawley rats. During anesthesia baseline pulmonary arterial pressure (PAP) was higher in H rats (34.6 +/- 1.0 mmHg) than in N rats (18.4 +/- 1.2 mmHg). Intravenous STA2 (0.3 microgram) acutely increased pulmonary artery pressure by 74% +/- 11% (25 +/- 4 mmHg) in H rats and by 47% +/- 2% (9 +/- 1 mmHg) in N rats, which indicates that both the absolute and relative acute pulmonary vasoconstriction caused by STA2 were greater in H rats. The changes in systemic arterial pressure caused by STA2 were smaller than the changes in pulmonary arterial pressure both in H rats (11% +/- 3%) and in N rats (17% +/- 3%). Lungs were isolated and perfused with saline, and the vasoconstrictive response to 0.05 microgram of STA2 in lungs (14.5 +/- 2.4 mmHg) from H rats was greater than the response to 0.1 microgram of STA2 (5.6 +/- 1.3 mmHg) in lungs from N rats. To examine whether blockade of calcium channels could suppress the vasoconstrictor response to STA2, the effects of the calcium channel blocker nicardipine hydrochloride on vasoconstriction caused by STA2 were measured in H and N rats. In vivo, the blockade of calcium channels suppressed the increase in pulmonary artery pressure caused by STA2. This suppression was greater in H rats (56% +/- 11%) than in N rats (25% +/- 4%). Similar results were obtained with isolated perfused lungs. Blockade of calcium channels suppressed the vasoconstriction caused by STA2 and this suppression was greater in H rats than in N rats. The finding that thromboxane A2 induced greater vasoconstriction in H rats than in N rats indicates that thromboxane A2 may play an important role in pulmonary hypertension, and suggests that blockade thromboxane A2 may benefit some patients with primary and secondary pulmonary hypertension. Furthermore, the finding that suppression of thromboxane-induced vasoconstriction by blockade of calcium channels was greater in H rats than in N rats indicates that such treatment may also benefit some patients.

Asunto(s)

Hipertensión Pulmonar/fisiopatología , Hipoxia/complicaciones , Arteria Pulmonar/fisiología , Tromboxano A2/análogos & derivados , Tromboxano A2/farmacología , Vasoconstricción/efectos de los fármacos , Vasoconstrictores/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Femenino , Masculino , Ratas , Ratas Sprague-Dawley