INTRARENAL ANGIOTENSIN-II FORMATION IN HUMANS - EVIDENCE FROM RENIN INHIBITION

The intrarenal production of angiotensin II (Ang II) as a local hormone, suggested by multiple lines of investigation, has been difficult to buttress with evidence of functional significance in humans. During studies designed to assess the renal vascular responses to the renin inhibitor enalkiren, an agent (like others in its class) with great substrate specificity, we noted in some subjects that the time course of the effect of enalkiren on renal plasma flow was not congruent with the time course of its influence on the renin-angiotensin system in the plasma compartment. We pursued this discrepancy in the current study of 18 healthy men and 9 men with essential hypertension, who each received one or more doses of enalkiren while on a fixed sodium diet. Plasma enalkiren and Ang II concentration and renal plasma flow were measured in each subject at intervals during and after discontinuation of the enalkiren infusion. Plasma enalkiren concentration fell progressively in each subject after administration was discontinued, the fall becoming evident 10 minutes after discontinuation without exception. In plasma samples obtained 90 minutes after the end of the infusion, drug levels were generally less than half of their peak value. Plasma Ang II concentration, at nadir levels by the end of the enalkiren administration, rose consistently during recovery. Renal plasma flow, in contrast, rose during infusion but did not begin to fall when enalkiren was discontinued. In 26 of 31 studies, renal plasma flow remained at peak level or even continued to rise; this discordance in the effects on plasma Ang II concentration and on renal plasma flow after discontinuation of enalkiren was highly significant (P<.0005). Sustained renal vascular activity of the renin inhibitor, in marked contrast to waning enalkiren concentration and activity in the plasma compartment, provides strong evidence for an action at the tissue level and for a biological influence of intrarenal Ang II formation in humans.