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Inactivation of endothelin B receptors (ETB), either through selective pharmacological antagonism or genetic mutation, increases the circulating concentration of endothelin-1 (ET-1), suggesting ETB plays an important role in clearance of this peptide. However, the cellular site of ETB-mediated clearance has not yet been determined. We have used a novel mouse model of endothelial cell-specific knockout (KO) of ETB (EC ETB-/-) to evaluate the relative contribution of EC-ETB to the clearance of ET-1. Phenotypic evidence of EC-specific ETB KO was confirmed by immunocytochemistry and autoradiography. Binding of the radiolabelled selective ETB ligand BQ3020 was significantly and selectively decreased in EC-rich tissues of EC ETB-/- mice, including the lung, liver, and kidney. By contrast, ETA binding was unaltered. RT-PCR confirmed equal expression of ET-1 in tissue from EC ETB-/- mice and controls, despite increased concentration of plasma ET-1 in EC ETB-/-. Clearance of an intravenous bolus of [125I]ET-1 was impaired in EC ETB-/- mice. Pretreatment with the selective ETB antagonist A192621 impaired [125I]ET-1 clearance in control animals to a similar extent, but did not further impair clearance in EC ETB-/- mice. These studies suggest that EC-ETB are largely responsible for the clearance of ET-1 from the circulation. L’inactivation des récepteurs de type B de l’endothéline (ETB), par un antagonisme pharmacologique sélectif ou une mutation génétique, augmente la concentration d’endothéline-1 circulante, ce qui laisse supposer que l’ETB joue un rôle important dans la clairance de ce peptide. Toutefois, le site cellulaire de la clairance véhiculée par l’ETB n’est pas connu. Nous avons utilisé un nouveau modèle d’inactivation (KO) de l’ETB spécifique des cellules endothéliales (ETB−/− CE) chez la souris dans le but d’évaluer la contribution relative de l’ETB-CE à la clairance de l’ET-1. Nous avons confirmé, par immunocytochimie et autoradiographie, le caractère phénotypique de l’inactivation (KO) de l’ETB-CE. La fixation d’un ligand radiomarqué sélectif de l’ETB, BQ3020, a diminué significativement et sélectivement dans les tissus riches en CE des souris ETB−/− CE, y compris le poumon, le foie et le rein. En revanche, la fixation sur l’ETA est demeurée inchangée. La RT-PCR a confirmé une expression identique d’ET-1 dans les tissus des souris CE ETB−/− et témoins, malgré une augmentation de la concentration d’ET-1 plasmatique chez les souris ETB−/− CE. La clairance d’un bolus intraveineux d’[125I]ET-1 a été altérée chez les souris CE ETB−/−. Un prétraitement avec l’antagoniste sélectif de l’ETB, A192621, a perturbé la clairance de l’[125I]ET-1 à un degré similaire chez les animaux témoins, mais n’a pas altéré davantage celle des souris ETB−/− CE. Ces études donnent à penser que l’ETB-CE joue un rôle de premier plan dans la clairance de l’ET-1 de la circulation. [ABSTRACT FROM AUTHOR]

Background: We hypothesised that the potential protective effects of endothelial ETB are important in limiting pulmonary vascular muscularisation, vasoconstriction and the development of pulmonary arterial hypertension in response to hypoxia. Methods: EC-specific ETB knockout mice (EC ETB–/–) and control mice (ETBf/f) were subjected to hypobaric hypoxic (10% FiO2) or normoxic conditions for 14 days before assessment of right ventricular pressure and pulmonary vascular morphology and function. Results: During normoxia, no difference in right ventricular pressure was detected between EC ETB–/– (23.7 ± 1.7 mm Hg) and ETBf/f mice (20.2 ± 1.5 mm Hg). Hypoxia induced an exaggerated increase in right ventricular pressure in EC ETB–/– mice (34.4 ± 1.2 mm Hg vs. 24.6 ± 1.4 mm Hg), accompanied by an increase in right ventricular mass. No effect was observed in ETBf/f mice. Endothelin-1 constricted pulmonary arteries from both groups, although maximum response was similar irrespective of inspired oxygen or genotype. Hypoxia increased the percentage of muscularised vessels in both groups of mice, but the percentage increase was significantly greater in EC ETB–/– mice. Conclusions: The potential protective effects of endothelial ETB are important in limiting pulmonary vascular muscularisation and the development of pulmonary arterial hypertension in response to hypoxia. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

This study uses a large malpractice database from Florida to assess the concentration of losses among physicians, predictability of claims experience, characteristics of physicians with favorable vs unfavorable experience, and effects of claims experience on physicians' practice decisions and on actions taken by the state's licensing board. Most payments by insurers involved a comparatively small number of physicians. Physicians with relatively prestigious credentials had no better, and on some indicators, worse claims experience. If anything, physicians with adverse claims experience were less likely to make subsequent changes in their practice, such as quitting practice or moving to another state. Physicians with very poor claims histories were more likely to have complaints filed against them with the Florida licensing board, but the sanctions against physicians with either poor or excellent histories were not severe. Physicians with adverse claims experience from incidents that arose between 1975 and 1980 had appreciably worse claims experience from incidents that arose during 1981 to 1983. [ABSTRACT FROM AUTHOR]