Turkstra E, Braam B, Koomans H A
Department of Nephrology and Hypertension, University Hospital Utrecht, The Netherlands.
J Am Soc Nephrol. 1998 Sep;9(9):1596-603. doi: 10.1681/ASN.V991596.
Nitric oxide synthase inhibition in the kidney enhances tubuloglomerular feedback (TGF) responsiveness. This may reflect either the effect of reduced basal nitric oxide (NO) availability or the effect of impaired NO release that is physiologically induced by TGF activation. However, it is unknown whether the latter actually takes place. In this study, it was hypothesized that NO is released (from macula densa cells or endothelium) as part of the normal TGF loop, and mitigates the TGF response. In Sprague Dawley rats, TGF responsiveness was assessed (fall in tubular stop flow pressure, deltaSFP, upon switching loop of Henle perfusion rates from 0 to 40 nl/min) during an intrarenal NO clamp (systemic infusion of nitro-L-arginine, 10 microg/kg per min, followed by intrarenal nitroprusside infusion adjusted to restore renal blood flow [RBF]). This maneuver was presumed to fix intrarenal NO impact at a physiologic level. To validate the approach, TGF responsiveness during an intrarenal angiotensin II (AngII) clamp (systemic infusion of enalaprilat 0.2 mg/kg per min, followed by intrarenal AngII infusion) was also studied. AngII is presumed to modulate but not mediate, TGF, thus not to increase as part of the TGF loop. In untreated animals, RBF was 7.4 +/- 0.4 ml/min, and deltaSFP was 5.7 +/- 1.6 mmHg. Nitro-L-arginine infusion alone reduced RBF to 5.3 +/- 0.5 ml/min (P < 0.05); with nitroprusside infusion, RBF was restored to 8.3 +/- 0.7 ml/min. In this condition (NO clamp), deltaSFP was markedly increased to 19.6 +/- 3.2 mmHg (P < 0.05). By contrast, deltaSFP, which was virtually abolished during enalaprilat alone (0.2 +/- 0.3 mmHg), was not significantly different from controls during AngII clamp (8.2 +/- 1.0 mmHg). These data suggest that NO may well be released upon TGF activation. By contrast, AngII is not dynamically involved in TGF activation, but may modulate the TGF response. Thus, dynamic release of NO during TGF activation mitigates the TGF response, so that it will offset the action of a primary, as yet undefined, vasoconstrictor mediator. The source of this NO, macula densa or endothelium, remains to be elucidated.
抑制肾脏中的一氧化氮合酶可增强肾小管-肾小球反馈（TGF）反应性。这可能反映了基础一氧化氮（NO）可用性降低的影响，或者是TGF激活生理诱导的NO释放受损的影响。然而，后者是否实际发生尚不清楚。在本研究中，假设NO作为正常TGF环路的一部分被释放（从致密斑细胞或内皮细胞），并减轻TGF反应。在Sprague Dawley大鼠中，在肾内NO钳夹期间（全身输注硝基-L-精氨酸，10μg/kg每分钟，随后输注肾内硝普钠以恢复肾血流量[RBF]）评估TGF反应性（当髓袢灌注速率从0切换到40 nl/分钟时，肾小管停流压力下降，ΔSFP）。该操作被认为将肾内NO的影响固定在生理水平。为了验证该方法，还研究了肾内血管紧张素II（AngII）钳夹期间（全身输注依那普利拉0.2 mg/kg每分钟，随后输注肾内AngII）的TGF反应性。AngII被认为调节但不介导TGF，因此不作为TGF环路的一部分增加。在未治疗的动物中，RBF为7.4±0.4 ml/分钟，ΔSFP为5.7±1.6 mmHg。单独输注硝基-L-精氨酸使RBF降至5.3±0.5 ml/分钟（P<0.05）；输注硝普钠后，RBF恢复至8.3±0.7 ml/分钟。在这种情况下（NO钳夹），ΔSFP显著增加至19.6±3.2 mmHg（P<0.05）。相比之下，单独使用依那普利拉时几乎消失的ΔSFP（0.2±0.3 mmHg）在AngII钳夹期间与对照组无显著差异（8.2±1.0 mmHg）。这些数据表明，TGF激活时可能会释放NO。相比之下，AngII不动态参与TGF激活，但可能调节TGF反应。因此，TGF激活期间NO的动态释放减轻了TGF反应，从而抵消了一种尚未明确的主要血管收缩介质的作用。这种NO的来源，致密斑还是内皮细胞，仍有待阐明。
