Conversion of big endothelin-1 to 21-residue endothelin-1 is essential for expression of full vasoconstrictor activity: structure-activity relationships of big endothelin-1.

The vasoconstrictor activities of porcine big endothelin-1 (big ET-1), a 39-residue intermediate predicted from cDNA sequence analysis, and of its shorter derivative, big ET-1 [1-25], were characterized in vitro by measuring the contraction of porcine coronary artery strips. Synthetic big ET-1 [1-39] and big ET-1 [1-25] induced a slow developing, long-lasting, and strong vasoconstriction as in the case of 21-residue ET-1. However, the contractile molar potencies of big ET-1 [1-39] and big ET-1 [1-25] were approximately 140- and 50-fold lower than that of ET-1, respectively. These results indicate that the conversion of big ET-1 to "mature" ET-1 is essential for the expression of the full vasoconstrictor activity, suggesting the physiological importance of the unusual proteolytic processing catalyzed by the putative "ET converting enzyme."