Salt intake and non-ACE pathways for intrarenal angiotensin II generation in man

Angiotensin-converting enzyme (ACE) plays a crucial role in the generation of angiotensin II (Ang II) via conversion from angiotensin I (Ang I). There has been substantial recent interest in non-ACE pathways of Ang II generation in the heart, large arteries, and the kidney. In the case of the human kidney, studied when in balance on a low-salt diet, the renal haemodynamic response to Ang II antagonists substantially exceeds the renal response to ACE inhibitors (ACE-I), suggesting that about 30-40% of Ang II-generation occurs via non-ACE pathways. In this study, we examined the relative contribution of non-ACE pathways, by comparing the response to candesartan and to captopril at the top of the dose-response in normal humans when in balance on a low-salt, as well as a high-salt, diet. As anticipated on a low-salt diet, the increase in renal plasma flow (RPF) in response to candesartan (165+/-14 mL/min/1.73 m2) significantly exceeded the response to captopril (118+/-12 mL/min/1.73 m2; p<0.01). In subjects studied on a high-salt diet, the response to candesartan (97+/-20 mL/min/1.73 m2) also significantly exceeded the response to captopril on the same diet(30+/-15 mL/min/1.73 m2; p<0.01). This remarkable response to candesartan in subjects on a high-salt diet,when compared with the response to captopril,suggests that non-ACE-dependent Ang II generation was influenced less than the classical renal pathway with an increase in salt intake, so that the percentage of Ang II generated via the non-ACE pathway rose to the 60-70% range.