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

The intrarenal production of angiotensin II (Ang II) as a local hormon e, suggested by multiple lines of investigation, has been difficult to buttress with evidence of functional significance in humans. During s tudies designed to assess the renal vascular responses to the renin in hibitor enalkiren, an agent (like others in its class) with great subs trate specificity, we noted in some subjects that the time course of t he effect of enalkiren on renal plasma flow was not congruent with the time course of its influence on the renin-angiotensin system in the p lasma compartment. We pursued this discrepancy in the current study of 18 healthy men and 9 men with essential hypertension, who each receiv ed one or more doses of enalkiren while on a fixed sodium diet. Plasma enalkiren and Ang II concentration and renal plasma flow were measure d 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 becom ing evident 10 minutes after discontinuation without exception. In pla sma samples obtained 90 minutes after the end of the infusion, drug le vels were generally less than half of their peak value. Plasma Ang II concentration, at nadir levels by the end of the enalkiren administrat ion, rose consistently during recovery. Renal plasma flow, in contrast , rose during infusion but did not begin to fall when enalkiren was di scontinued. In 26 of 31 studies, renal plasma flow remained at peak le vel or even continued to rise; this discordance in the effects on plas ma Ang II concentration and on renal plasma flow after discontinuation of enalkiren was highly significant (P<.0005). Sustained renal vascul ar activity of the renin inhibitor, in marked contrast to waning enalk iren concentration and activity in the plasma compartment, provides st rong evidence for an action at the tissue level and for a biological i nfluence of intrarenal Ang II formation in humans.