Gekle M, Silbernagl S
Department of Physiology, University of Würzburg, Germany.
J Pharmacol Exp Ther. 1993 Oct;267(1):316-21.
The nephrotoxin ochratoxin A (OTA) causes a reduction of glomerular filtration rate (GFR) and of para-aminohippuric acid (PAH) clearance. We determined renal plasma flow (RPF), filtration fraction (FF) and total renal vascular resistance (TRVR). Using furosemide, we investigated the role of tubuloglomerular feedback (TGF) for GFR reduction. Using enalapril and the angiotensin II antagonist DUP 753 we investigated the role of angiotensin II for GFR reduction. Six days' application of 0.5 mg/kg b.wt. of OTA i.p. to male Wistar rats leads to RPF reduction from 3.98 +/- 0.18 to 1.97 +/- 0.18 ml/(min.g kidney wet weight) and GFR reduction from 1.08 +/- 0.06 to 0.69 +/- 0.04 ml/(min.g kidney wet weight) (n = 6, P < .05 for both). FF increased to 130% of control and TRVR to 202% of control (n = 6, P < .05 for both). The application of furosemide (30 mg/(h.kg b.wt.) after pretreatment with OTA had no effect on the reduction of GFR indicating that TGF is not involved. Pretreatment with OTA and enalapril [0.5 mg/(d.kg) b.wt.] blunted the effect of OTA alone significantly (GFR only dropped to 88% of control). Pretreatment with OTA and DUP 753 [20 mg/(d.kg) b.wt.] blunted the effect of OTA alone significantly: GFR and RPF only dropped to 89 and 91% of control, respectively. FF and TRVR were no longer different from control. Acute application of DUP 753 (2 mg/kg b.wt. i.v.) after pretreatment with OTA blunted the effect of OTA to a lesser extend. Our conclusions are: 1) Reduction of PAH clearance and of GFR is in part due to reduced RPF. 2) The increase in TRVR is at least in part caused by an increase of the efferent resistance. 3) Activation of the TGF is not involved in GFR reduction. 4) The increase in TRVR and the decrease of GFR are mainly mediated by angiotensin II.
肾毒素赭曲霉毒素A（OTA）可导致肾小球滤过率（GFR）和对氨基马尿酸（PAH）清除率降低。我们测定了肾血浆流量（RPF）、滤过分数（FF）和总肾血管阻力（TRVR）。使用呋塞米，我们研究了球管反馈（TGF）对GFR降低的作用。使用依那普利和血管紧张素II拮抗剂DUP 753，我们研究了血管紧张素II对GFR降低的作用。对雄性Wistar大鼠腹腔注射0.5mg/kg体重的OTA，连续6天，导致RPF从3.98±0.18降至1.97±0.18ml/（min·g肾湿重），GFR从1.08±0.06降至0.69±0.04ml/（min·g肾湿重）（n = 6，两者P均<0.05）。FF增加至对照的130%，TRVR增加至对照的202%（n = 6，两者P均<0.05）。在OTA预处理后应用呋塞米（30mg/（h·kg体重））对GFR的降低没有影响，表明TGF未参与其中。用OTA和依那普利[0.5mg/（d·kg）体重]预处理可显著减弱OTA单独作用的效果（GFR仅降至对照的88%）。用OTA和DUP 753[20mg/（d·kg）体重]预处理可显著减弱OTA单独作用的效果：GFR和RPF仅分别降至对照的89%和91%。FF和TRVR与对照不再有差异。在OTA预处理后静脉注射DUP 753（2mg/kg体重）急性给药，对OTA作用的减弱程度较小。我们的结论是：1）PAH清除率和GFR的降低部分归因于RPF的降低。2）TRVR的增加至少部分是由出球阻力增加引起的。3）TGF的激活不参与GFR的降低。4）TRVR的增加和GFR的降低主要由血管紧张素II介导。
