The clinical role of endothelin antagonists

During thèKongreû fu È r Nephrologie 2000' (2±5 September 2000, Vienna, Austria) a pre-congressional symposium was held. The ®rst speaker was Ariela Benigni from Bergamo, Italy. As she said, exogenous endothelin 1 (Et-1) infusion reduces the renal plasma ¯ow (RPF) by approximately 25% at doses which do not yet alter systemic blood pressure (MAP). The effect of Et-1 on RPF is mediated by constriction of afferent and efferent glomerular arterioles. Furthermore, Et-1 at these doses decreases k f and GFR. Additional effects are tubular reduction of Na reabsorption, mesangial cell proliferation and increased synthesis of mesangial matrix. The effects are mediated by differentiated expression of Et-receptors (Et-R): while the Et-A-R resides primarily on afferent and efferent arterioles and on mesangial cells, Et-B-R will be found in the medulla and the vasa recta bundles; in addition Et-B-R occur on glomerular endothelial cells. Ariela Benigni postulated a role for Et in the following two conditions: i) Cyclosporine toxicity; ii) Chronic progressive nephropathies. In a model of subtotal nephrectomy in the rat, proteinuria increased 7-fold within the ®rst 120 days, and this was paralleled by a similar increase of urinary Et-1 excretion and a dramatic increase in the expression of the Et-B-R. An enhancement of urinary Et-1 excretion and/or renal Et-1 synthesis has also been shown in passive Heyman nephritis, STZ diabetes, chronic glomerulonephritis (CGN) in humans, SLE-nephritis, kidney transplantation, unilateral nephrec-tomy, NIDDM with albuminuria, and cyclosporine A nephrotoxicity. In CGN, enhanced transcription of the genes for Et-1, Et-A-R, Et-B-R and ECE-1-alpha (endothelin converting enzyme) have all been demonstrated. One possible mechanism of these changes is proteinuria according to Dr Benigni. It has also been shown some time ago that albumin (10 mg/ml) as well as IgG increase Et-1 secretion 2-to 3-fold if these proteins are added to proximal tubular cells in culture. Approximately 75% of this Et-1 is secreted basolat-erally, where proximal tubular cells in vivo abut against interstitial cells. The latter show high af®nity binding of Et-1. In response to stimulation by Et-1 they exhibit proliferation as well as upregulation of their collagen a-1 gene expression. Endothelin receptor antagonists have now been found to reduce proteinuria and to slow the progression of renal insuf®ciency in a number of animal models. T. Rabelink, Utrecht, The Netherlands, showed observations of the haemodynamic effects of Et-antagonists in healthy volunteers. He observed an effect of BQ 123, an Et-A-R speci®c antagonist, to cause an increase …