Effects of dual endothelin-converting enzyme/neutral endopeptidase inhibitors, CGS 26303 and CGS 26393, on lipopolysaccharide or interleukin-1 beta-stimulated release of endothelin from guinea pig tracheal epithelial cells.

A number of studies using endothelin (ET) receptor antagonists support the participation of ETs in a variety of cardiovascular, renal, and other disorders. It has also been established that a number of cytokines, which are released in such diseases, modulate the expression and production of ETs and thus activate the ET system. This effect may represent one pathway by which these inflammatory mediators operate. By regulating endothelin-converting enzyme (ECE) activities, and thus ET synthesis, one can potentiate or attenuate the production of ETs and the receptor affinity/density in such pathologic conditions. Here, the stimulated (lipopolysaccharide or interleukin-1 beta) production of ET-1 from guinea pig tracheal epithelial cells was abolished by CGS 26303 or CGS 26393, two ECE/neutral endopeptidase (NEP) inhibitors, but was unaffected by CGS 24592, a specific NEP inhibitor. Therefore, such dual, and eventually selective ECE inhibitors are effective agents to prevent the stimulated production of ETs.