Nishiyama Akira, Seth Dale M, Navar L Gabriel
Department of Physiology, Tulane University School of Medicine, New Orleans, Louisiana, USA.
J Am Soc Nephrol. 2002 Sep;13(9):2207-12. doi: 10.1097/01.asn.0000026610.48842.cb.
It was recently demonstrated that angiotensin II (AngII) concentrations in the renal interstitial fluid (RIF) of anesthetized rats were in the nanomolar range and were not reduced by intra-arterial infusion of an angiotensin-converting enzyme (ACE) inhibitor (enalaprilat). This study was performed to determine changes in RIF AngI and AngII concentrations during interstitial administration of ACE inhibitors (enalaprilat and perindoprilat). Studies were also performed to determine the effects of enalaprilat on the de novo formation of RIF AngII elicited by interstitial infusion of AngI. Microdialysis probes (cut-off point, 30,000 D) were implanted in the renal cortex of anesthetized rats and were perfused at 2 micro l/min. The effluent dialysate concentrations of AngI and AngII were measured by RIA, and reported values were corrected for the equilibrium rates at this perfusion rate. Basal RIF AngI (0.74 +/- 0.05 nM) and AngII (3.30 +/- 0.17 nM) concentrations were much higher than plasma AngI and AngII concentrations (0.15 +/- 0.01 and 0.14 +/- 0.01 nM, respectively; n = 27). Interstitial infusion of enalaprilat through the microdialysis probe (1 or 10 mM in the perfusate; n = 5 and 8, respectively) significantly increased RIF AngI concentrations but did not significantly alter AngII concentrations. However, perindoprilat (10 mM in the perfusate, n = 7) significantly decreased RIF AngII concentrations by 22 +/- 4% and increased RIF AngI concentrations. Interstitial infusion of AngI (100 nM in the perfusate, n = 7) significantly increased the RIF AngII concentration to 8.26 +/- 0.75 nM, whereas plasma AngI and AngII levels were not affected (0.15 +/- 0.02 and 0.14 +/- 0.02 nM, respectively). Addition of enalaprilat to the perfusate (10 mM) prevented the conversion of exogenously added AngI. These results indicate that addition of AngI in the interstitial compartment leads to low but significant conversion to AngII via ACE activity (blocked by enalaprilat). However, the addition of ACE inhibitors directly into the renal interstitium, via the microdialysis probe, either did not reduce RIF AngII levels or reduced levels by a small fraction of the total basal level, suggesting that much of the RIF AngII is formed at sites not readily accessible to ACE inhibition or is formed via non-ACE-dependent pathways.
最近有研究表明，麻醉大鼠肾间质液（RIF）中的血管紧张素II（AngII）浓度处于纳摩尔范围，且动脉内输注血管紧张素转换酶（ACE）抑制剂（依那普利拉）并不会使其降低。本研究旨在确定在间质给予ACE抑制剂（依那普利拉和培哚普利拉）期间RIF中AngI和AngII浓度的变化。同时还进行了研究以确定依那普利拉对间质输注AngI引发的RIF中AngII从头合成的影响。将微透析探针（截留分子量为30,000 D）植入麻醉大鼠的肾皮质，并以2 μl/min的速度进行灌注。通过放射免疫分析法（RIA）测量流出的透析液中AngI和AngII的浓度，并根据该灌注速度下的平衡速率对报告值进行校正。基础RIF中AngI（0.74±0.05 nM）和AngII（3.30±0.17 nM）的浓度远高于血浆中AngI和AngII的浓度（分别为0.15±0.01和0.14±0.01 nM；n = 27）。通过微透析探针进行间质输注依那普利拉（灌注液中为1或10 mM；分别为n = 5和8）可显著增加RIF中AngI的浓度，但对AngII的浓度没有显著影响。然而，培哚普利拉（灌注液中为10 mM，n = 7）可使RIF中AngII的浓度显著降低22±4%，并增加RIF中AngI的浓度。间质输注AngI（灌注液中为100 nM，n = 7）可使RIF中AngII的浓度显著增加至8.26±0.75 nM，而血浆中AngI和AngII的水平未受影响（分别为0.15±0.02和0.14±0.02 nM）。在灌注液中添加依那普利拉（10 mM）可阻止外源性添加的AngI的转化。这些结果表明，在间质区添加AngI会通过ACE活性导致低水平但显著的向AngII的转化（被依那普利拉阻断）。然而，通过微透析探针将ACE抑制剂直接添加到肾间质中，要么不会降低RIF中AngII的水平，要么仅使水平降低总基础水平的一小部分，这表明大部分RIF中的AngII是在ACE抑制不易到达的部位形成的，或者是通过非ACE依赖性途径形成的。
