Ni X, Cheng Y, Cao L, Gardner D G, Humphreys M H
Division of Nephrology, San Francisco General Hospital, CA, USA.
J Am Soc Nephrol. 1996 Oct;7(10):2110-8. doi: 10.1681/ASN.V7102110.
Blunted volume expansion (VE) natriuresis and renal resistance to atrial natriuretic peptide (ANP) characterize states of pathological sodium retention. This study examined rats 1 to 3 wk after common bile-duct ligation (CBDL), at which time they had hyperbilirubinemia and hypoalbuminemia. Sham-operated normal rats (Sham) showed an increased sodium excretion rate (UNaV) from 1.0 +/- 0.1 to 16.3 +/- 3.9 muEq/min in response to acute VE (iv saline, 2 mL/100 g body wt over 5 min), whereas CBDL rats had a blunted response that was apparent after 1 wk and became maximal at 2 and 3 wk (0.3 +/- 0.1 to 3.2 +/- 0.4 muEq/min at 3 wk, P < 0.01 versus Sham response). The peak urinary cGMP excretion rate (UcGMPV) was also blunted (37.9 +/- 3.6 versus 87.5 +/- 8.3 pmol/min, P < 0.01) despite an even greater increase in plasma ANP concentration (Sham, 9.6 +/- 0.4 pg/mL in hydropenia to 22.8 +/- 2.6 pg/mL after VE; CBDL, 15.3 +/- 2.3 to 41.8 +/- 6.8 pg/mL). ANP-dependent cGMP accumulation by isolated inner medullary collecting duct (IMCD) cells from both Sham and CBDL rat kidneys was dose-dependent; however, at higher concentrations of ANP (> 10(-8) M), accumulation by cells from CBDL rats was significantly blunted, indicating resistance to ANP. Binding of 125I-ANP to IMCD cells was not different in CBDL rats compared with Sham control rats. Renal denervation improved but did not completely reverse the blunted natriuresis, and ANP resistance persisted in IMCD cells from denervated kidneys of CBDL rats. Incubation of IMCD cells with the phosphodiesterase inhibitors isomethylbutylxanthine or Zaprinast (each at 10(-3) M) restored ANP responsiveness in both innervated and denervated kidneys from CBDL rats, and intrarenal infusion of Zaprinast (10 micrograms/min) corrected the blunted increase in UNaV and UcGMPV after VE in rats with CBDL. These results suggest that ANP resistance in a model of abnormal sodium metabolism devoid of intrinsic renal disease may be related to increased activity of phosphodiesterase in renal target cells for ANP as well as to heightened renal nerve activity.
容量扩张性（VE）利钠反应减弱以及肾脏对心房利钠肽（ANP）的抵抗是病理性钠潴留状态的特征。本研究检测了胆总管结扎（CBDL）后1至3周的大鼠，此时它们存在高胆红素血症和低白蛋白血症。假手术的正常大鼠（假手术组）在急性容量扩张（静脉注射生理盐水，2 mL/100 g体重，持续5分钟）后，钠排泄率（UNaV）从1.0±0.1增加至16.3±3.9 μEq/分钟，而CBDL大鼠的反应减弱，在1周后明显，在2周和3周时达到最大（3周时为0.3±0.1至3.2±0.4 μEq/分钟，与假手术组反应相比，P<0.01）。尽管血浆ANP浓度增加得更多（假手术组，低血容量时为9.6±0.4 pg/mL，容量扩张后为22.8±2.6 pg/mL；CBDL组，15.3±2.3至41.8±6.8 pg/mL），但尿cGMP排泄率峰值（UcGMPV）也减弱了（37.9±3.6对87.5±8.3 pmol/分钟，P<0.01）。来自假手术组和CBDL大鼠肾脏的分离的肾内髓集合管（IMCD）细胞对ANP依赖性cGMP的积累呈剂量依赖性；然而，在较高浓度的ANP（>10⁻⁸ M）时，CBDL大鼠细胞的积累明显减弱，表明对ANP有抵抗。与假手术对照组大鼠相比，CBDL大鼠中125I-ANP与IMCD细胞的结合没有差异。肾去神经支配改善但未完全逆转减弱的利钠反应，并且CBDL大鼠去神经支配肾脏的IMCD细胞中ANP抵抗仍然存在。用磷酸二酯酶抑制剂异丁基甲基黄嘌呤或扎普司特（均为10⁻³ M）孵育IMCD细胞可恢复CBDL大鼠支配和去神经支配肾脏中ANP的反应性，并且肾内输注扎普司特（10 μg/分钟）可纠正CBDL大鼠容量扩张后UNaV和UcGMPV减弱的增加。这些结果表明，在没有内在肾脏疾病的异常钠代谢模型中，ANP抵抗可能与ANP肾靶细胞中磷酸二酯酶活性增加以及肾神经活动增强有关。
