Angiotensin II exerts positive feedback on the intrarenal renin-angiotensin system by an angiotensin converting enzyme-dependent mechanism

Background. Plasma angiotensin II (ANG II) is not increased significantly in renovascular hypertension (RVH), but tissue ANG II levels are elevated in both kidneys of renovascular rats. Because the contralateral, non-ischemic kidney is critical for maintenance of hypertension in RVH, this study sought to understand the mechanism by which intrarenal ANG II levels are augmented in the non-ischemic kidney. This study tested the hypothesis that an incremental increase in plasma ANG II induces the intrarenal renin-angiotensin system (RAS) in the non-ischemic kidney by an angiotensin converting enzyme (ACE) dependent mechanism. Methods. To simulate the incremental increase in plasma ANG II induced by the ischemic kidney in RVH, an ANG II infusion model was used. This model used a chronic infusion of ANG II (40 ng/min) or vehicle by osmotic minipump into uninephrectomized rats. Parallel groups were treated with the ACE inhibitor Enalaprilat (200 mg/kg/day). Intrarenal ACE activity was measured by radioenzymatic assay. ANG II levels were quantified by radioimmunoassay. Results. Hypertension was evident in ANG II-infused rats, compared to control rats (155 ± 4 versus 112 ± 1 mmHg; P < 0.001). Concurrent treatment with Enalaprilat reversed the hypertension induced by ANG II infusion (98 ± 3 versus 155 ± 4 mmHg; P < 0.001). ANG II up-regulated intrarenal ACE activity in the non-ischemic kidney (59.2 ± 11.9 versus 25.2 ± 6.8 units/mg protein; P < 0.01). Enalaprilat significantly decreased renal ACE activity in ANG II-treated rats, compared to ANG II alone (11.4 ± 1.0 versus 59.2 ± 11.9 units/mg protein; P < 0.001). Intrarenal ANG II was increased in ANG II-infused rats, compared to control animals (52.9 ± 7.1 versus 23.0 ± 3.2 fmol/mg tissue; P < 0.001), and Enalaprilat prevented ANG II-induced increases in intrarenal ANG II (29.9 ± 2.6 versus 52.9 ± 7.1 fmol/mg tissue; P < 0.05). Conclusion. Incremental changes in plasma ANG II induce de novo production of ANG II in the non-ischemic kidney to augment intrarenal ANG II content. ACE inhibition blocks this positive feedback loop, suggesting that ANG II activates the intrarenal RAS by an ACE-dependent mechanism. The impact of ACE inhibition on blood pressure suggests that this feedback loop may be an important mechanism for maintenance of hypertension in RVH.