Oppermann Mona, Hansen Pernille B, Castrop Hayo, Schnermann Jurgen
National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Am J Physiol Renal Physiol. 2007 Jul;293(1):F279-87. doi: 10.1152/ajprenal.00073.2007. Epub 2007 May 9.
Loop diuretics like furosemide have been shown to cause renal vasodilatation in dogs and humans, an effect thought to result from both a direct vascular dilator effect and from inhibition of tubuloglomerular feedback. In isolated perfused afferent arterioles preconstricted with angiotensin II or N(G)-nitro-L-arginine methyl ester, furosemide caused a dose-dependent increase of vascular diameter, but it was without effect in vessels from NKCC1-/- mice suggesting that inhibition of NKCC1 mediates dilatation in afferent arterioles. In the intact kidney, however, furosemide (2 mg/kg iv) caused a 50.5 +/- 3% reduction of total renal blood flow (RBF) and a 27% reduction of superficial blood flow (SBF) accompanied by a marked and immediate increase of tubular pressure and volume. At 10 mg/kg, furosemide reduced RBF by 60.4 +/- 2%. Similarly, NKCC1-/- mice responded to furosemide with a 45.4% decrease of RBF and a 29% decrease of SBF. Decreases in RBF and SBF and increases of tubular pressure by furosemide were ameliorated by renal decapsulation. In addition, pretreatment with candesartan (2 mg/kg) or indomethacin (5 mg/kg) attenuated the reduction of RBF and peak urine flows caused by furosemide. Our data indicate that furosemide, despite its direct vasodilator potential in isolated afferent arterioles, causes a marked increase in flow resistance of the vascular bed of the intact mouse kidney. We suggest that generation of angiotensin II and/or a vasoconstrictor prostaglandin combined with compression of peritubular capillaries by the expanding tubular compartment are responsible for the reduction of RBF in vivo.
像呋塞米这样的袢利尿剂已被证明可导致犬类和人类的肾血管扩张，这种效应被认为是由直接的血管扩张作用和对球管反馈的抑制共同导致的。在用血管紧张素II或N（G）-硝基-L-精氨酸甲酯预收缩的离体灌注入球小动脉中，呋塞米可引起血管直径的剂量依赖性增加，但对NKCC1基因敲除小鼠的血管没有影响，这表明对NKCC1的抑制介导了入球小动脉的扩张。然而，在完整肾脏中，呋塞米（静脉注射2mg/kg）可使总肾血流量（RBF）减少50.5±3%，浅表血流量（SBF）减少27%，同时伴有肾小管压力和容积的显著且即刻增加。在10mg/kg时，呋塞米使RBF减少60.4±2%。同样，NKCC1基因敲除小鼠对呋塞米的反应是RBF减少45.4%，SBF减少29%。呋塞米引起的RBF和SBF降低以及肾小管压力升高可通过肾被膜剥除得到改善。此外，用坎地沙坦（2mg/kg）或吲哚美辛（5mg/kg）预处理可减弱呋塞米引起的RBF降低和尿流峰值的减少。我们的数据表明，呋塞米尽管在离体入球小动脉中具有直接的血管扩张潜力，但却会导致完整小鼠肾脏血管床的血流阻力显著增加。我们认为，血管紧张素II和/或血管收缩性前列腺素的产生，以及扩张的肾小管腔对肾小管周围毛细血管的压迫，共同导致了体内RBF的降低。
