Differential Modulation of the Renal and Myocardial Endothelin System by Angiotensin II In Vivo

Angiotensin II (Ang II) stimulates endothelin-1 (ET-1) production in glomerular endothelial and mesangial cells and in cardiac fibroblasts in vitro. We investigated the effects of Ang II in vivo (200 ng/kg/min for 2 weeks) with or without the ETA receptor antagonist LU135252 (50 mg/kg/day) on blood pressure, renal and myocardial ET-1 protein expression, and [125I]ET-1 uptake in male Wistar-Kyoto (WKY) rats. ET-1 was extracted from whole kidneys and ventricular myocardium and was measured by radioimmunoassay (pg ET-1/g tissue). Organ tissue uptake was calculated as percentage of total DPM recovered after i.v. administration of radiolabeled [125I]ET-1. Ang II treatment increased blood pressure by 35 +/- 3 mm Hg, which was partly reduced by LU135252 (15 +/- 2 mm Hg, p < 0.05). LU135252 in part prevented the impaired weight gain induced by Ang II (p < 0.05). Ang II induced a threefold increase in expression of ET-1 (pg/g tissue) in kidneys (from 19 +/- 2 to 58 +/- 10, p < 0.05), which was normalized by LU135252 (20 +/- 9, p < 0.05). In myocardial tissue, Ang II had only minor effects (5 +/- 1 vs. 3.6 +/- 1, n.s.). However, concomitant LU135252 treatment reduced myocardial ET-1 levels (1.4 +/- 0.4, p < 0.05 vs. Ang II and control). Ang II increased uptake of [125I]ET-1 in kidneys (from 6.9 +/- 0.1% to 10.9 +/- 0.9% of total DPM, p < 0.05) but not in myocardium (1.45 +/- 0.26% vs. 1.59 +/- 0.18% of total DPM), which was unaffected by LU135252 treatment. These data suggest that the kidney, but not the ventricular myocardium, is a target for Ang II-mediated activation of the ET system in vivo, leading to expression and uptake of ET-1. ETA antagonists may provide a new approach to inhibit production and effects of ET-1 in diseases associated with increased activity of the renin-angiotensin system.