Leuchte HH, Meis T, El-Nounou M, Michalek J, Behr J. Inhalation of endothelin receptor blockers in pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 294: L772-L777, 2008. First published February 22, 2008 doi:10.1152/ajplung.00405.2007.-Endothelin 1 (ET-1) is a potent pulmonary vasoconstrictor and mediator of lung diseases. Antagonism of the ET-1-mediated effects has become an important therapeutic approach. ET-1 (A and B) receptors are differentially distributed in the lung vasculature. Whereas the ETA receptors mainly mediate vasoconstriction, the endothelial ETB receptor seems to have vasodilative properties. We sought to determine if antagonism of ET receptors can be achieved by inhalation of specific blockers in a model of ET-1-mediated pulmonary hypertension.endothelin-1 ENDOTHELIN-1 (ET-1) is a potent pulmonary vasoconstrictor and mediator of lung diseases. Antagonizing ET-1-mediated effects in the lungs has become an important therapeutic approach. ET-1 causes elevated pulmonary pressures in acute (5, 10, 15) and chronic pulmonary hypertension (PH) (4). Blocking the ET-1 pathway is an established therapy in PH. Since pulmonary vasoconstriction is an important component of the pathophysiology of PH, the application of vasoactive substances has been in focus to attenuate pulmonary artery pressures in pulmonary hypertensive states (21,22). To restrict the action of these substances to the lungs and maximize their deposition, the inhalative route of application has been suggested.ET-1 is one of the most potent endogenous vasoconstrictors in systemic and pulmonary circulation. It is predominantly released from endothelial cells and mediates its vasoactive properties via two different G protein-coupled receptors, namely the ET A and the ET B receptor (4). With regard to the pulmonary vasculature, the ET A receptor is localized on vascular smooth muscle cells, whereas under normal conditions the ET B receptor is preferentially found on endothelial cells and only to a minor extent on smooth muscle cells of pulmonary vessels (12,17). Both receptors expressed on vascular smooth muscle cells mediate vasoconstriction (9, 19) via activation of phospholipase C. Stimulation of ET B receptors on endothelial cells leads to a release of vasodilating factors, such as nitric oxide and prostacyclin. These opposite ET-1-mediated effects suggest an equilibrium between the receptors under normal conditions (12, 16).Besides its acute vasoactive properties, ET-1 is an important smooth muscle and fibroblast mitogen, chemoattractant, and stimulant of collagen synthesis and is a mediator of different lung diseases (3). Consequently, ET-1 is in the scope of extensive work on lung diseases. ET-1 has been shown to be crucially involved in the remodeling in models of chronic proliferating diseases (6) and PH (2,7,26,27). Moreover, systemic administration of ET-1 blockers has been proven beneficial in experimental and clinical PH (12). However, despite extensive earlier studies on chronic systemic administration of endothelin r...

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We conclude that RX monorail systems seem to enhance the technical success of femoropopliteal angioplasty. Although smaller sheath sizes can be used due to the lower profile of the RX systems, there is only a tendency toward lower complication rates.

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Background and Hypothesis:Endothelin 1 (ET−1) is a potent pulmonary vasoconstrictor and mediator of lung diseases. Antagonism of the ET−1 mediated effects has become an important therapeutic approach. ET−1 (A and B) receptors are differentially distributed in the lung vasculature. While the ETA receptors mainly mediate vasoconstriction, the endothelial ETB receptor has vasodilative and clearing properties. The hypothesis of this study was that antagonism of ET receptors can be achieved by inhalation of specific blockers in a model of ET−1 mediated pulmonary vasoconstriction. Materials and Methods:The isolated ventilated and buffer perfused rabbit lung was used to establish a model of ET−1 induced and sustained pulmonary vasoconstriction. Two selective ET (A or B) and one dual ET−1 (A and B) receptor antagonist (ETRA) (Tezosentan) were administered into pulmonary circulation or as an aerosol. Results:During intravascular application, the mono−selective ET−A receptor antagonist BQ−123 and the dual ETRA Tezosentan dose dependently attenuated ET−1 induced vasoconstriction. The selective ET−B receptor antagonist BQ−788 augmented the ET−1 effects. Equimolar doses of aerosolized BQ−788 did not influence pulmonary vasoconstriction, but the BQ−123 aerosol exerted its specific effects. Antagonising both ET−1 receptors via aerosol induced a greater effect on ET−1 mediated pulmonary vasoconstriction than aerosol administration of a selective ETA receptor antagonist. Conclusions:Antagonizing pulmonary vasoconstriction as an indicator of ET−1 mediated lung disease is possible via aerosolization of a selective ET−A receptor and even stronger by a dual ET−receptor blocker. This abstract is funded by: Actelion Pharmaceuticals, Germany. Am J Respir Crit Care Med 179;2009:A6258 Internet address: www.atsjournals.org Online Abstracts Issue