Effect of Nitric Oxide Synthase Inhibition on Intrarenal Oxygenation as Evaluated by Blood Oxygenation Level-Dependent Magnetic Resonance Imaging

Abstract

To investigate the feasibility of studying renal effects of nitric oxide synthase inhibition (NOSi) in humans by blood oxygenation level-dependent (BOLD) MRI. Nitric oxide (NO) is known to play a key role in the pathophysiology of hypertension and previous reports suggest reduced bioavailability of NO in the kidneys of hypertensive rats and hence show reduced response to NOSi using BOLD MRI. Ability to perform similar studies in humans could potentially lead to detection of early changes before development of symptoms, and to monitor novel interventions targeted toward improved NO bioavailability. The specific goals for this study were: (1) to examine whether lower doses and dose rate of administration of NOSi such as those previously used in humans can be detected by BOLD MRI in rat kidneys, (2) to compare changes in R2* to direct measures of renal medullary oxygen levels and blood flow using invasive probes (OxyLite/OxyFlo), and (3) to examine for the first time the effect of NOSi on intrarenal oxygenation in humans. In rat kidneys, acute changes in renal tissue oxygenation induced by different doses (2, 4, and 10 mg/kg) of N-nitro-L-arginine methyl ester were studied in 36 Sprague Dawley rats, which were equally divided into BOLD MRI and OxyLite/OxyFlo groups. Similarly in humans, acute changes in renal oxygenation were induced by 2 different NOS inhibitors NG-monomethyl-L-arginine (4.25 mg/kg) in 7 volunteers and N-nitro-L-arginine methyl ester (2 mg/kg and 4 mg/kg) in 6 healthy young volunteers. A multiple gradient echo sequence was used in both rats (TE = 4.4-57.8 milliseconds with 3.6 milliseconds interecho spacing) and humans (TE = 6.4-40.8 milliseconds with a 2.3 milliseconds interecho spacing) to acquire 16 T2*-weighted images. R2* maps were constructed by fitting a single exponential decay to the image data on pixel by pixel basis. R2* measurements in the cortex and medulla were performed by regions of interest analysis. Measurements were performed before and during infusion of NOSi. In rats, NOSi decreased medullary pO2 and blood flow in a dose-dependent manner, and BOLD MRI showed an increase in medullary R2* consistent with the invasive pO2 measurements. In humans, BOLD MRI similarly showed an increase in medullary and cortical R2* after NOSi in a dose-dependent manner. In both rats and humans, the R2* values fell back toward baseline before the end of the infusion period. Comparison of BOLD MRI measurements with those using invasive probes suggests that changes in blood flow are at least partly responsible for observed changes with BOLD MRI. Monitoring changes after NOSi by renal BOLD MRI in vivo in human kidneys are feasible, and preliminary findings are consistent with observations in rat kidneys. Future studies are warranted to fully understand the apparent reversal in R2* changes during the infusion of NOSi.