Inhalation of endothelin receptor blockers in pulmonary hypertension

Abstract

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...

Preserved pulmonary vasodilative properties of aerosolized brain natriuretic peptide

“…This aerosolization system has been described before [4]. Placebo (NaCl 0.9%) and BNP (total dose 200 nM) were aerosolized with an ultrasonic device (Optineb ®, Nebutec, Elsenfeld, Germany).…”

“…Antagonizing the deleterious effects of endothelin-1 is also a mainstay in the treatment of pulmonary hypertension which can be achieved by different endothelin receptor antagonists [3]. It has also been suggested that the therapeutic activity of such antagonists is preserved during aerosolization [4]. Due to the advances of an inhalative approach, additional substances that can be applied as an aerosol have been proposed in pulmonary hypertension [5;6].…”

Augmentation of the effects of vasoactive intestinal peptide aerosol on pulmonary hypertension via coapplication of a neutral endopeptidase 24.11 inhibitor

“…This model and our modifications have been described elsewhere (13,14) and have been used to characterize pulmonary vasodilators during intravascular and aerosol application before. This lung model facilitates a focused investigation of substances that mediate pulmonary vasodilation in a quasi in vivo setting without interference of central or humoral influences (e.g., circulating blood cells).…”

“…Our modification of this aerosolization system has been described before (13,14). Placebo (NaCl 0.9%), VIP, and thiorphan were aerosolized with an ultrasonic device (Optineb, Nebutec, Elsenfeld, Germany).…”

“…Nevertheless, because a deficiency of VIP has also been suggested to be involved in other lung diseases the aerosol approach is of special interest (19,22,24). In terms of PH, the inhalative approach has been beneficial in acute (13,26,27) and chronic (28) experimental studies as well as in human PH (16). The present study aimed to characterize the biological activity of inhaled VIP alone and during coapplication with thiorphan, an inhibitor of NEP 24.11 in a model of acute PH.…”