Endothelins: Homeostatic and Compensatory Actions in the Circulatory and Endocrine Systems
ENDOTHELIN (ET) is a potent vasoconstrictive peptide which was originally isolated from the conditioned medium of cultured endothelial cells (1). It comprises 21 aminoacid residues, including four cysteine residues that form two disulfide bonds (see Fig. 1). ET elicits a sustained pressor response when administrated intravenously, which suggests its importance in blood pressure maintenance and generation of vasospasm. Accordingly, many investigators have been interested in this peptide. Analysis of ET genes revealed the existence of three distinct ET genes that encode different mature ET sequences, designated endothelin-1 (ET-1), ET-2, and ET-3 (Fig. 1) (2). Two and six amino acid residues of ET-1 are replaced in ET-2 and ET-3, respectively. There are no species differences among isoforms of human, porcine, rat, bovine, or dog. Interestingly, the structure of snake venom sarafotoxins are very similar to those of ETs. In endothelial cells, ET-1 is predominant, but ET-2 and ET-3 are not detected. As such, the question arose whether ET-2 and ET-3 are expressed in other tissues. Searching for complementary DNA (cDNA) clones of ET-2 and ET-3 in the cDNA library of human jejunum revealed the existence of all three cDNAs. Subsequent Northern blot analysis demonstrated that the three isoform messenger RNAs (mRNAs) are distributed widely throughout many tissues in different proportions. For instance, all three types of ET isoform mRNAs are present in human kidney and jejunum. Yet, in the central nervous system, ET-1 is the major isoform, while ET-3 is detected only to some extent. The diverse and uneven distribution of ET isoforms suggests that ET has multiple functions not only in the cardiovascular system but also in the nonvascular system.