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Prevention of chronic renal allograft rejection in rats with an oral endothelin A receptor antagonist. Transplantation 1999; 68: 739. Braun C, Conzelmann T, Vetter S, Schaub M, Back WE, Yard B, Kirchengast M, Tullius SG, Schnülle P, van der Woude FJ, Rohmeiss P. In 1998 Yanagisawa and coworkers found that porcine vascular endothelial cells generated a 21-amino acid peptide, endothelin, that turned out to be one of the most potent endogenous vasoconstrictors ever identified (1). Since then, the understanding of the biology of endothelins and their role in health and disease has accumulated rapidly (for references, see 2, 3). It is now known that in humans, three distinct endothelin genes, located in three different chromosomes, encode three distinct endothelins, ET1, ET2, and ET3. Endothelin peptides are produced initially as large pre-pro-endothelins, cleaved at two sites by neutral endopeptidases forming thereby biologically inactive precursors, big endothelins, which are ultimately converted to final peptides by endothelin-converting enzymes. Endothelins are synthesized not only by endothelium but also by other tissues, including the parenchymal cells of brain, lung, and kidney. Importantly, plasma concentrations of endothelins are usually within picomolar range, indicating that local synthesis leading to autocrine and paracrine responses is more important than systemic release. The effect of endothelins on tissue cells is regulated by two endothelin receptors, ET-A and ET-B. Both represent seven-transmembrane G protein-coupled receptors coded by genes in two different chromosomes. ET1 and ET2 have a higher affinity to ET-A than ET3, whereas ET-B binds all three isopeptides at identical affinity. The detailed mechanisms whereby endothelins (or better their receptors) regulate biological functions is still largely unclarified. ET-A are found in vascular smooth muscle cells and mediate vasoconstriction and cell proliferation, whereas ET-B receptors are found on endothelial cells and mediate vasodilation via nitric oxide (3). On certain occasions, however, ET-B receptors may elicit vessel constriction, instead. A wealth of experimental evidence on the functions of endothelins on various tissues, including kidney, derives from the experiments with receptor subtype-specific endothelin receptor antagonists. For example, ET-A receptor antagonist BQ-123 prevents ET1-induced mitogenesis of rat smooth muscle cells (4). SB209670, antagonizing both ET-A and ET-B, protects rat carotid artery from neointimal formation after endothelial denudation (5). Another "nonselective" antagonist, bosentan, has been shown to prevent graft arteriosclerosis in rat cardiac transplantation (6). Considering renal transplantation, both BQ-123 and bosentan protect rat kidneys from ischemia-reperfusion injury (7, 8). Similarly, both ET-A specific and "nonspecific" antagonists prevent acute cyclosporine-induced renal vasoconstriction (9-11). Considering the vasodilatatory and renoprotective effects of endothelin antagonists, and particularly, the inhibitory effects on smooth muscle cell replication, migration, and neointima formation, the communication by Braun et al. (in this issue, page 739) is of interest. The authors demonstrated an inhibitory effect of a selective ET-A receptor blocker LU135252 on chronic allograft rejection of F344 kidneys transplanted into Lewis recipients that have received a short course of cyclosporine. The authors found that the LU132252-treated animals had a better graft survival and graft function and that by and large the renal graft histology remained better preserved and had less cellular infiltration in LU135252-treated than in control animals not receiving the antagonist. Unexpectedly, LU135252-treated animals had more proteinuria and higher blood pressure compared with vehicle-treated controls. Additionally, there was significant reduction of macrophages, T cells, and the expression of class II antigens in the allograft parenchyma. It is still rather speculative how these impressive effects are mediated. One possibility is inhibition of inflammation via reduced expression of leukocyte-binding ligands in graft endothelial cells, though in this study only the expression level of MHC-II but not of ICAM-1 was reduced. Another possibility is a direct antiproliferative effect on graft parenchymal cells, in which the intensity of glomerulopathy, interstitial fibrosis, and tubular atrophy were reduced in rats given LU135252. Astonishingly, I find no remark in the results in regard to an antiarteriosclerotic effect (which would have been expected on the basis of an earlier communication; 6). On the other hand, this model, even within extended observation time, is not very prone for arteriosclerotic changes. Endothelin is among the most potent vasoconstrictors described as yet. It has been shown in healthy human volunteers that brachial arterial infusion of BQ-123 causes progressive forearm vasodilatation (12) and the nonselective receptor antagonist TAK-044 lowers peripheral vascular resistance and blood pressure after systemic administration (13). It is highly unlikely, however, that vasorelaxation plays any role in the observations by Braun et al. LU135252-treated animals had actually more proteinuria and higher blood pressure compared with vehicle-treated controls. In analogy with previously published results, there was an increased expression of ET mRNA and protein at the site of injury. The receptor antagonist seems rather to interfere with an in situ autocrine or paracrine cycle within the allograft itself. Transplant surgeons and physicians may, however, be relaxed. This and the previous study (6) clearly document an alternative, independent treatment paradigm for the improvement of long-term graft survival, a model not based on improved immunosuppression. Pekka Häyry Transplantation Laboratory; University of Helsinki and Helsinki University Central Hospital; FIN 00014 Helsinki, Finland