Endothelin in renal disease: role of endothelin antagonists.

In spite of tremendous progress in the understanding of human disease, the search for new mediators continues as numerous conditions remain poorly understood. In particular in many forms of renal disease, effective and cause-orientated forms of therapy are still lacking. The discovery of new pathogenetic mechanisms often leads to the development of new drugs with previously unknown properties which may offer new treatment modalities. Endothelin is a recently discovered potent biological mediator which exists in three closely related isoforms (i.e. endothelin-1,-2 and-3 [1-3]. Endothelins belong to a family of 21 amino acid peptides with two disulphide bridges [1,3]. The main vascular effects of endothelin are transient vasodilat-ation and profound and sustained vasoconstriction [4]. Endothelin also exerts marked renal effects, acts as a mitogen and stimulates proliferation of vascular smooth muscle and glomerular mesangial cells [5-7]. Important sources of the peptides are endothelial cells, neurons, renal cells and at least under certain conditions also vascular smooth muscle cells. Stimuli for the release of endothelins include hypoxia and/or ischaemia [8], but also humoral factors (angiotensin II, vasopressin, transforming growth factor-beta, insulin , thrombin and several cytokines) and potentially nephrotoxic drugs such as radiocontrast agents, cyclo-sporin, amphotericin B and OKT-3 [1,3,9,10-22]. On the other hand, nitric oxide and atrial natriuretic peptide inhibit endothelin production via a cyclic GMP-dependent mechanism [1,3,11,20]. In addition, smooth muscle cells appear to release an inhibitory factor which limits the production of the peptide. This may explain why intact tissues such as the blood vessel wall produce markedly less endothelin than isolated cells in culture. In vivo in humans, endothelin plasma levels are very low [21]. However, in different disease states, elevated endothelin plasma levels have been described (see below, Table 1). In the kidney, endothelin reduces renal blood flow and glomerular filtration rate [10,22-25]; this is mainly due to vasoconstriction of both afferent and efferent arterioles. Systemic infusion of endothehn-1 in humans in vivo leads to blood pressure increase, sodium retention and reduction in urine flow [24,25]. Although in vitro endothelin inhibits renin release [23,26], in the intact organism renin plasma levels do not change or increase (due to renal vasoconstriction) after infusion of endothelin-1 [25]. Endothelin stimulates release of aldosteron, vasopressin and atrial natriuretic peptide under experimental conditions [9,10]. However, in vivo in humans, it does not influence the plasma levels of these hormones [24]. The role of the mitogenic properties of endothelin [5-7] in the kidney …