Unique receptor dissociation kinetics of the novel endothelin receptor antagonist macitentan

Gatfield J, Mueller Grandjean C, Sasse T, Steiner B, Steiner P, Iglarz M, Kauser K, Clozel M, Nayler O


Actelion Pharmaceuticals Ltd, Allschwil, Switzerland

European Respiratory Society Congress, 2012, Vienna, Austria.

Pulmonary arterial hypertension (PAH) is caused by progressive pulmonary artery remodelling and constriction,1,2 and a central pathogenic role of endothelin-1 (ET-1) in PAH has been demonstrated in several clinical trials evaluating different ERAs. ET-1 responses are mediated via two G protein-coupled receptors (GPCR), ETA and ETB. 4,5 In pulmonary arterial smooth muscle cells (PASMC), ET receptors couple to the Gq pathway and increase inositol-trisphosphate (IP3) and diacylglycerol (DAG) levels. These cause a biphasic calcium response resulting in sustained elevation of intracellular calcium levels.3,6 Elevated calcium levels promote cytoskeletal contraction and cell proliferation and thereby mediate vasoconstriction and vascular remodelling

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