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

Abstract

Objective 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 bio-availability 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. Material and Methods 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. Results 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. Conclusion 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.

Nitric Oxide Synthase Inhibition Induces Renal Medullary Hypoxia in Conscious Rats

“…Cortical pO 2 normalized and increased slightly during chronic L‐NNA treatment, whereas renal medullary pO 2 decreased progressively during the 2‐week treatment period up to 19%. The observation that chronic NOS inhibition preferentially induces renal medullary hypoxia extends previous findings acquired in acute settings 23, 25…”

“…We measured this after 2 weeks; however, NO inhibition by l ‐arginine analogues is known to acutely induce reductions in RBF 9, 23, 25. Reduced perfusion leads to reduced GFR and hence metabolic demand.…”

“…Long‐term N(ω)‐nitro‐ l ‐arginine methyl ester (L‐NAME) treatment reduced oxygenation in kidneys of healthy and diabetic rats as measured by blood oxygen level–dependent magnetic resonance imaging 24. Also, in humans, acute administration of l ‐arginine analogues was associated with blood oxygen level–dependent magnetic resonance imaging detectable reductions in renal pO 2 that were most prominent in the medulla 25. These studies point to a preferential reduction of pO 2 in the renal medulla during acute NOS inhibition.…”

Non-invasive investigation of kidney disease in type 1 diabetes by magnetic resonance imaging

“…Such approaches offer significant advantages in detecting pathological changes that may be regional or heterogeneous in their effects, and are forming the basis of our future studies. Renal T 2 * and BOLD contrast Although we could confirm the previously reported differences between the R 2 * of the cortex and medulla [17,19], we observed no change in renal R 2 * on physiological perturbation [21,34,35] as previously ascribed to changes in tissue oxygenation via BOLD contrast mechanisms [36]. Some earlier studies have employed hand-placed regions of interest to assess changes in R 2 * , typically using T 2 * or R 2 * maps to guide selection of ROI position.…”

Using BOLD Imaging to Measure Renal Oxygenation Dynamics in Rats Injected with Diuretics

“…4,5 Recently, BOLD MRI has been used for noninvasive evaluation of renal oxygenation in humans and animals. 4,6 BOLD MRI is based on the principle that variations in the oxygen saturation of hemoglobin result in changes in local magnetic susceptibility and, hence, in the signal intensity of apparent transverse relaxation time (T 2 *)-weighted MR images. 7 Diuretics are well known to inhibit renal tubular reabsorption.…”