Interactions between endothelin-1 and the renin- angiotensin-aldosterone system

The renin-angiotensin-aldosterone (RAA) system and the endothelin (ET) syst em entail the most potent vasopressor mechanisms identified to date. Althou gh they were studied in depth in relation to arterial hypertension and card iovascular diseases, limited information on their interrelationships in cau sing hypertension and related target organ damage exists. The identificatio n of consensus sequences for jun in the regulatory region of the preproendo thelin-1 (ppET-1) gene raised the possibility of its transcriptional regula tion by angiotensin II (Ang II). This was confirmed by the finding that sti mulation with Ang II of cultured vascular smooth muscle cells (VSMCs) and e ndothelial cells (ECs) induced expression of the ppET-1 gene and synthesis of ET-1. Endogenously produced ET-1 was found to contribute to the hypertro phic response of cardiomyocytes to Ang II and thereby to cardiac hypertroph y. Furthermore, ET-1 exerts multifaceted effects on the RAA system, such as dose-dependent inhibition of renin synthesis, and stimulation of aldostero ne secretion. The finding of abundant specific ET-1 receptors in the adreno cortical zona glomerulosa (ZG) suggested a direct secretagogue effect of ET -1. In rats, ETB receptors mediate such an effect, whilst in humans, both E TA and ETB receptor subtypes intervene in regulating the transcription of t he aldosterone synthase gene. In addition, ET-1 stimulates DNA synthesis an d proliferation of ZG cells via ETA receptors and, therefore, might play a role in cell turnover of the normal adrenal cortex and in the onset of adre nal tumours. Studies on the in vivo interactions between ETs and the RAA sy stem have given conflicting results, insofar as some suggested a participat ion of ET-1 in the presser and cellular effects of exogenously administered Ang II, whereas others did not in the transgenic TGR(Ren 2m)27 rats and in the two-kidney, one clip. (C) 1999 Elsevier Science B,V. All rights reserv ed.