Endothelin Receptor Antagonism

Abstract

Following the original report by Yanagisawa et al. (1988) more than 7 years ago, compelling evidence that ET plays an important role in the local regulation of smooth muscle tone and cell growth has been reported. In addition, many studies point to a significant role for endothelin in nonvascular function. The investigation of the endothelin system has been greatly advanced in the last 2 to 3 years through significant advances in the development of potent and selective ET receptor antagonists. These agents have proven to be essential tools for elucidating the biological significance of the ET system, leading to the realization that antagonism of the ET system may have significant therapeutic potential. As emphasized in this review, the importance of chronic blockade of the ET system may be a critical aspect of future research in this exciting area. Confounding issues remain the lack of information about the role of the ETB receptor, the apparent pharmacological evidence for additional ET receptor subtypes, and species variation in the tissue distribution of ET isoforms and receptor subtypes. Along with the greater ability to understand the endothelin system provided by potent and selective pharmacological agents, is the important contribution of modern molecular biology techniques, highlighted by the insights gained from recent reports of results from ET gene disruption studies. Kurihara et al. (1994) found that ET-1-deficient homozygous mice die at birth of apparent respiratory failure secondary to severe craniofacial abnormalities. Subsequently, Yanagisawa's laboratory has presented and published a series of complementary gene disruption studies. First, Hosoda et al. (1994) demonstrated remarkably, that ETA receptor knockout mice bear morphological abnormalities nearly identical to ET-1 knockout mice. Second, they found that disruption of the ET-3 peptide and ETB receptor genes result in homozygous mice that share identical phenotypic traits (i.e., coloration changes and aganglionic megacolon) which are similar to a previously known natural mutation, the Piebald-Lethal mouse (Hosoda et al., 1994; Baynash et al., 1994). This phenotype has a human corollary known as Hirschsprung's Disease and it is now known that the disease, though multigenic, results from a missense mutation of the ETB receptor gene in some individuals (Puffenberger et al., 1994). Taken together these data indicate that the endothelin system is essential to correct embryonic neural crest development, a completely novel finding within the superfamily of guanine-protein-linked receptors.(ABSTRACT TRUNCATED AT 400 WORDS)