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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.(ABSTRACT TRUNCATED AT 250 WORDS)

We compared the renal vascular responses to angiotensin converting enzyme inhibition and renin inhibition to assess the influence of angiotensin II (Ang II). We examined the renal and endocrine responses to the renin inhibitor enalkiren, to captopril, and to placebo in nine healthy and nine hypertensive men on a 10-mmol sodium diet. Ang II was infused to assess effects of the agents on renal and adrenal responsiveness to Ang II. Plasma Ang II concentration was suppressed similarly with enalkiren and captopril--an identical level of blockade was achieved. Although renal plasma flow was stable during placebo, a substantial rise was seen with both enalkiren (+133 +/- 26 mL/min per 1.73 m2) and captopril (+99.4 +/- 22.6). There was remarkable intrasubject concordance between the renal plasma flow responses to renin inhibition and converting enzyme inhibition (r = .90, P < .004). The vasodilator response to both agents correlated inversely with the fall in renal plasma flow induced by Ang II alone (r = -.66, P < .05). Both agents significantly enhanced the renal vascular response to Ang II (P = .01), and, furthermore, the renal vasodilator response to captopril predicted the potentiation of the renal plasma flow response to Ang II after either agent (enalkiren: r = .91, P < .001; captopril: r = .56, P < .05). Concordance of the maximal renal plasma flow response to the two agents appeared in the hypertensive men as well. Our results indicate that the acute renal response to captopril largely reflects a reduction in Ang II formation.(ABSTRACT TRUNCATED AT 250 WORDS)