EFFICACY OF INTRARENAL ACE-INHIBITION ESTIMATED FROM THE RENAL RESPONSE TO ANGIOTENSIN-I AND ANGIOTENSIN-II IN HUMANS

Recent studies on the nature of the renin-angiotensin system (RAS) in animals have led to the concept that systemic and intrarenal RAS can be influenced to different degrees by angiotensin converting enzyme (ACE) inhibitors. Assessment of efficacy of intrarenal ACE inhibition by ACE inhibitors in humans is necessarily indirect and has not been reported. We therefore monitored the renal response to acute angiotensin (Ang) I infusion in volunteers taking 20 mg enalapril twice daily, and related the responses to the obtained increments in plasma Ang II levels. Ang I infusion rates of 4, 8, 16, and 32 pmol/kg/min caused gradual increments in plasma Ang I (maximal change from 26 +/- 18 to 578 +/- 120 pmol/liter, P < 0.05) and, despite treatment with enalapril, also of Ang II (from 3 +/- 1 to 29 +/- 5 pmol/liter, P < 0.05). This was associated with large reductions in renal plasma flow (para-aminohippurate clearance), filtration fraction, maximal urine flow, sodium excretion, lithium and uric acid clearance, and increments in mean arterial pressure and plasma aldosterone (P < 0.05 for each variable). Strong correlations existed between the changes in either variable and the increment in plasma Ang II. Infusions of Ang II at 1 and 4 pmol/kg/min in the same subjects caused comparable increments in plasma Ang II and had similar physiological effects as found during the Ang I infusion. Analysis of covariance of the changes in plasma Ang II and each of the measured variables revealed no differences between Ang I and Ang II infusions. Since Ang I had no functional effects in the kidney independent of the increments in plasma Ang II, additional intrarenal Ang I to Ang II conversion in the present experimental setting is unlikely. This protocol provides an indirect method to assess efficacy of intrarenal ACE inhibition in humans.