To determine the influence of chronic ANG II infusion on urinary, plasma, and renal tissue levels of immunoreactive endothelin (ET), ANG II (65 ng/min) or saline vehicle was delivered via osmotic minipump in male Sprague-Dawley rats given either a high-salt diet (10% NaCl) or normal-salt diet (0.8% NaCl). High-salt diet alone caused a slight but not statistically significant increase (7 Ϯ 1%) in mean arterial pressure (MAP). MAP was significantly increased in ANG II-infused rats (41 Ϯ 10%), and the increase in MAP was significantly greater in ANG II rats given a high-salt diet (59 Ϯ 1%) compared with the increase observed in rats given a high-salt diet alone or ANG II infusion and normal-salt diet. After a 2-wk treatment, urinary excretion of immunoreactive ET was significantly increased by ϳ50% in ANG II-infused animals and by over 250% in rats on high-salt diet, with or without ANG II infusion. ANG II infusion combined with high-salt diet significantly increased immunoreactive ET content in the cortex and outer medulla, but this effect was not observed in other groups. In contrast, high-salt diet, with or without ANG II infusion, significantly decreased immunoreactive ET content within the inner medulla. These data indicate that chronic elevations in ANG II levels and sodium intake differentially affect ET levels within the kidney and provide further support for the hypothesis that the hypertensive effects of ANG II may be due to interaction with the renal ET system. dietary sodium chloride; blood pressure; kidney THE RENIN-ANGIOTENSIN SYSTEM plays an important role in the regulation of arterial pressure and renal function. It has traditionally been thought that ANG II exerts its vasoconstrictor and sodium-retaining actions via action on the angiotensin type 1 receptor (AT 1 ) and, therefore, directly participates in the pathogenesis of cardiovascular and renal diseases (10). However, recent studies indicate that ANG II may exert some of its effects via interaction with the endothelin (ET) system. One possible mechanism for this interaction is that ANG II may regulate ET-1 synthesis in the kidney. Several lines of evidence support this hypothesis. First, it has been reported that ANG II stimulates release of ET-1 by cultured vascular smooth muscle cells, endothelial cells, and mesangial cells (5,12,19). ANG II has also been shown to stimulate the expression of preproendothelin-1 mRNA in rat vascular smooth muscle cells and in rat and bovine endothelial cells (5, 9, 19). Second, in vivo studies showed that rats with chronic ANG II hypertension have elevated ET-1 levels in renal tissue but not in myocardial tissue and enhanced preproendothelin mRNA expression in the renal cortex and medulla (2, 4). Finally, the hypertension associated with chronic ANG II infusion can be attenuated by a mixed ET type A (ET A ) and ET type B (ET B ) receptor antagonist and by selective ET A -receptor antagonists (3,4,8,18). ET A -receptor antagonists have also been shown to prevent some of the changes in endothelial function obser...