Siragy H M, Jaffa A A, Margolius H S
Department of Internal Medicine, University of Virginia Health Sciences Center, Charlottesville 22908, USA.
Hypertension. 1997 Mar;29(3):757-62. doi: 10.1161/01.hyp.29.3.757.
Bradykinin and lys-bradykinin generated intrarenally appear to be important renal paracrine hormones. However, the renal effects of endogenously generated bradykinin are still not clearly defined. In this study, we measured acute changes in renal excretory and hemodynamic functions and renal cortical interstitial fluid levels of bradykinin, prostaglandin E2, and cGMP in response to an acute intrarenal arterial infusion of the bradykinin B2 receptor antagonist Hoe 140 (icatibant), cyclooxygenase inhibitor indomethacin, or nitric oxide synthase inhibitor N(G)-monomethyl-L-arginine (L-NMMA) given individually or combined in uninephrectomized, conscious dogs (n=10) in low sodium balance. Icatibant caused a significant decrease in urine flow, urinary sodium excretion, and renal plasma flow rate (each P<.001). Glomerular filtration rate did not change during icatibant administration. Icatibant produced an unexpected large increase in renal interstitial fluid bradykinin (P<.0001) while decreasing renal interstitial fluid prostaglandin E2 and cGMP (each P<.001). Both indomethacin and L-NMMA when given individually caused significant antidiuresis and antinatriuresis and decreased renal blood flow (each P<.001). Glomerular filtration rate decreased during L-NMMA administration (P<.001) and did not change during indomethacin administration. Combined administration of icatibant and indomethacin or L-NMMA caused significant decreases in renal excretory and hemodynamic functions, which were not different from changes observed with icatibant alone. The failure of icatibant to change renal function after inhibition of cyclooxygenase and nitric oxide synthase activity suggests that the effects of kinin B2 receptor are mediated by intrarenal prostaglandin E2 and nitric oxide generation. The increase in renal interstitial fluid bradykinin during icatibant requires further study of possible alterations in kinin synthesis, degradation, or clearance as a result of B2 receptor blockade.
肾内生成的缓激肽和赖氨酸缓激肽似乎是重要的肾旁分泌激素。然而，内源性生成的缓激肽对肾脏的影响仍未明确界定。在本研究中，我们在低钠平衡状态下，对10只单侧肾切除的清醒犬单独或联合给予缓激肽B2受体拮抗剂Hoe 140（依卡替班）、环氧化酶抑制剂吲哚美辛或一氧化氮合酶抑制剂N(G)-单甲基-L-精氨酸（L-NMMA），通过肾内动脉急性输注，测量肾脏排泄和血流动力学功能的急性变化以及肾脏皮质间质液中缓激肽、前列腺素E2和环鸟苷酸的水平。依卡替班导致尿流量、尿钠排泄和肾血浆流速显著降低（均P<0.001）。在给予依卡替班期间，肾小球滤过率未发生变化。依卡替班使肾间质液缓激肽意外大幅增加（P<0.0001），同时降低肾间质液前列腺素E2和环鸟苷酸（均P<0.001）。单独给予吲哚美辛和L-NMMA均引起显著的抗利尿和利钠作用，并降低肾血流量（均P<0.001）。在给予L-NMMA期间肾小球滤过率降低（P<0.001），而在给予吲哚美辛期间未发生变化。依卡替班与吲哚美辛或L-NMMA联合给药导致肾脏排泄和血流动力学功能显著降低，这与单独使用依卡替班时观察到的变化无差异。在抑制环氧化酶和一氧化氮合酶活性后依卡替班未能改变肾功能，提示激肽B2受体的作用是由肾内前列腺素E2和一氧化氮生成介导的。依卡替班给药期间肾间质液缓激肽的增加需要进一步研究B2受体阻断导致激肽合成、降解或清除可能发生的改变。
