Welch W J, Tojo A, Lee J U, Kang D G, Schnackenberg C G, Wilcox C S
Division of Nephrology and Hypertension, Georgetown University Medical Center, Washington, District of Columbia 20007, USA.
Am J Physiol. 1999 Jul;277(1):F130-8. doi: 10.1152/ajprenal.1999.277.1.F130.
The spontaneously hypertensive rat (SHR) has an enhanced tubuloglomerular feedback (TGF) and a diminished buffering by juxtaglomerular apparatus (JGA)-derived NO. We examined the hypothesis that these effects are due to decreases in nitric oxide synthase (NOS) expression or limited availability of L-arginine or tetrahydrobiopterin (BH(4)). SHR had significantly (P < 0.05) greater mRNA abundance (by RT-PCR) or protein (by Western analysis) for neuronal NOS (nNOS, or type I) and endothelial cell NOS (ecNOS, or type III) in renal cortex or isolated glomeruli, respectively. There was prominent expression of ecNOS in glomerular endothelium and nNOS in macula densa. Maximal TGF responses, assessed from changes in proximal stop-flow pressure during orthograde loop of Henle (LH) perfusion, were greater in SHR [Wistar-Kyoto (WKY), 8.1 +/- 0.3 (n = 46) vs. SHR, 10.3 +/- 0.3 mmHg (n = 57); P < 0.001]. Unlike WKY, TGF responses of SHR were unresponsive to microperfusion of the nNOS inhibitor, 7-nitroindazole (7-NI, 10(-4) M) [WKY, 9.5 +/- 0.5 to 13.2 +/- 0.7 (n = 13, P < 0.001) vs. SHR, 11.8 +/- 0.7 to 12.5 +/- 0.6 mmHg (n = 19, not significant)], or to L-arginine (10(-3) M) [WKY, 7.7 +/- 0.8 to 6.3 +/- 0.4 (n = 10, P < 0.05) vs. SHR, 10.4 +/- 0.7 to 10.6 +/- 0.7 mmHg (n = 10, not significant)]. Neither BH(4) (10(-4) M) nor sepiapterin (10(-4) M), its stable precursor, modified TGF responses in WKY or in SHR, nor did they restore a response to microperfusion of 7-NI in SHR. In conclusion, there is a diminished role for NO from nNOS in blunting of TGF in SHR which cannot be ascribed to limited NOS expression or availability of substrate or BH(4).
自发性高血压大鼠（SHR）具有增强的肾小管-肾小球反馈（TGF），且肾小球旁器（JGA）衍生的一氧化氮（NO）缓冲作用减弱。我们检验了这样一种假说，即这些效应是由于一氧化氮合酶（NOS）表达降低、L-精氨酸或四氢生物蝶呤（BH₄）可用性受限所致。SHR肾皮质或分离的肾小球中，神经元型NOS（nNOS，或I型）和内皮细胞型NOS（ecNOS，或III型）的mRNA丰度（通过逆转录-聚合酶链反应测定）或蛋白质（通过蛋白质印迹分析）分别显著（P<0.05）更高。ecNOS在肾小球内皮细胞中显著表达，nNOS在致密斑中显著表达。在顺行性髓袢（LH）灌注期间，通过近端停流压力变化评估的最大TGF反应在SHR中更大[Wistar-Kyoto（WKY）大鼠，8.1±0.3（n = 46）vs. SHR大鼠，10.3±0.3 mmHg（n = 57）；P<0.001]。与WKY大鼠不同，SHR的TGF反应对nNOS抑制剂7-硝基吲唑（7-NI，10⁻⁴ M）的微灌注无反应[WKY大鼠，9.5±0.5至13.2±0.7（n = 13，P<0.001）vs. SHR大鼠，11.8±0.7至12.5±0.6 mmHg（n = 19，无显著性差异）]，对L-精氨酸（10⁻³ M）也无反应[WKY大鼠，7.7±0.8至6.3±0.4（n = 10，P<0.05）vs. SHR大鼠，10.4±0.7至10.6±0.7 mmHg（n = 10，无显著性差异）]。BH₄（10⁻⁴ M）及其稳定前体蝶酰三谷氨酸（10⁻⁴ M）均未改变WKY大鼠或SHR大鼠的TGF反应，也未恢复SHR大鼠对7-NI微灌注的反应。总之，nNOS产生的NO在减弱SHR的TGF方面作用减弱，这不能归因于NOS表达受限、底物或BH₄可用性受限。
