Yarger W E, Schocken D D, Harris R H
J Clin Invest. 1980 Feb;65(2):400-12. doi: 10.1172/JCI109683.
Relief of unilateral ureteral obstruction (UUO) of 24 h duration in rats is followed by severe renal vasoconstriction in the postobstructive kidney (POK). The present study examined possible roles of renal prostaglandins (PG) and thromboxanes (TX), as well as the renin-angiotensin system, in this vasoconstriction. Administration of the cyclooxygenase inhibitor indomethacin, which blocks both PG and TX production, failed to improve POK hemodynamics in UUO rats. To explore the possible role of the TX compounds, which include the potent vasoconstrictor thromboxane A2 (TXA2), UUO rats were infused with imidazole, an agent that blocks synthesis of TX, but not of PG. Imidiazole led to two- to threefold increases in the clearance of both inulin and rho-aminohippuric acid by the POK. This effect of imidazole was abolished by indomethacin, suggesting that the amelioration of POK vasoconstriction by imidazole was a result of inhibition of vasoconstrictor TX synthesis (e.g. TXA2), with PG vasodilators (e.g. PGE2 or PG12) still active. Urea, infused in a solution whose osmolality and volume were identical to the imidazole infusion, failed to improve hemodynamics in the POK, making it unlikely that nonspecific effects of volume expansion or osmotic diuresis mediated the beneficial effect of imidazole. Further studies examined the possible role of the renin-angiotensin systems in the vasoconstriction of the POK. UUO rats infused with the angiotensin II antagonist, Saralasin, exhibited no significant improvement in POK function, a finding that might be at least partly attributable to agonist/vasoconstrictor properties of Saralasin. In other experiments, treatment of UUO rats with the angiotensin-converting enzyme blocker SQ 14225 (Captopril), in order to inhibit angiotensin II formation, led to at least twofold increases in the clearance of both inulin and rho-aminohippuric acid in the POK. It is unlikely that Captopril exerted this beneficial effect by potentiating the vasodilator kinins, because the effect was not diminished by administration of either carboxypeptidase B (which destroys the kinins) or Trasylol (which blocks kinin synthesis). Thus, these results suggest that both angiotensin II, as well as metabolites of the PG-TX system, may be important determinants of postobstructive renal hemodynamics in the rat.
大鼠单侧输尿管梗阻（UUO）24小时后解除梗阻，梗阻后肾（POK）会出现严重的肾血管收缩。本研究探讨了肾前列腺素（PG）和血栓素（TX）以及肾素 - 血管紧张素系统在这种血管收缩中的可能作用。给予环氧化酶抑制剂吲哚美辛，其可阻断PG和TX的生成，但未能改善UUO大鼠的POK血流动力学。为了探究TX化合物（包括强效血管收缩剂血栓素A2（TXA2））的可能作用，给UUO大鼠输注咪唑，该药物可阻断TX的合成，但不影响PG的合成。咪唑使POK对菊粉和对氨基马尿酸的清除率提高了两到三倍。吲哚美辛消除了咪唑的这种作用，这表明咪唑改善POK血管收缩是抑制血管收缩剂TX合成（如TXA2）的结果，而PG血管舒张剂（如前列腺素E2或前列环素）仍然具有活性。以与咪唑输注溶液渗透压和体积相同的溶液输注尿素，未能改善POK的血流动力学，这表明血容量扩张或渗透性利尿的非特异性作用不太可能介导咪唑的有益作用。进一步的研究探讨了肾素 - 血管紧张素系统在POK血管收缩中的可能作用。给UUO大鼠输注血管紧张素II拮抗剂沙拉新，POK功能无显著改善，这一发现可能至少部分归因于沙拉新的激动剂/血管收缩特性。在其他实验中，用血管紧张素转换酶阻滞剂SQ 14225（卡托普利）治疗UUO大鼠以抑制血管紧张素II的形成，导致POK对菊粉和对氨基马尿酸的清除率至少提高了两倍。卡托普利不太可能通过增强血管舒张激肽发挥这种有益作用，因为给予羧肽酶B（可破坏激肽）或抑肽酶（可阻断激肽合成）均未减弱该作用。因此，这些结果表明血管紧张素II以及PG - TX系统的代谢产物可能是大鼠梗阻后肾血流动力学的重要决定因素。
