Objectives: We compared resting and hyperemic pressure gradients induced by intrarenal papaverine for the assessment of renal artery stenosis (RAS). We also investigated the incidence of the QT interval prolongation and ventricular arrhythmias. Background: In the coronary circulation, maximal hyperemia is essential in determining the significance of a stenosis. In the renal circulation, the role of maximal hyperemia for the assessment of RAS has not been established. Methods: In 55 patients with RAS (67 RAS), resting P d/Pa ratio (the ratio between distal renal pressure to the aortic pressure), renal fractional flow reserve (FFR), and resting and hyperemic systolic gradients (RSG and HSG, respectively) were measured with a pressure guidewire. In a subset of 16 patients, renal vein renin activity (RVRA) was measured. Results: HSG was significantly greater than RSG (20 ± 14 mm Hg vs. 9.0 ± 13 mm Hg, respectively; P < 0.001). Renal FFR was significantly lower than baseline Pd/Pa ratio (0.91 ± 0.06 vs. 0.94 ± 0.06 vs. respectively; P < 0.001). RVRA increased from 50 ± 66% at rest to 122 ± 112% at hyperemia, P < 0.01. At HSG of 21 mm Hg or renal FFR of 0.90, RVRA increased markedly (120%), but RVRA increased modestly (18%) when RSG was 16 mm Hg or resting P d/Pa ratio was 0.93. The corrected QT intervals at baseline vs. hyperemia were not significantly different (433 ± 26 vs. 436 ± 25 msec, respectively; P = NS); no episodes of ventricular arrhythmias were noted. Conclusions: Renin production, an index of renal ischemia, was markedly greater at hyperemia than at rest, suggesting that RAS, with either an HSG of 21 mm Hg or a renal FFR of 0.90, can be considered a hemodynamically significant stenosis. Intrarenal papaverine neither prolonged the QT interval nor induced ventricular arrhythmias and the safety of which will need to be corroborated in a large study. Copyright © 2010 Wiley-Liss, Inc.