Simultaneous blockade of endothelin A and B receptors in ischemic acute renal failure is detrimental to long-term kidney function

Background. There is growing evidence of long-term pathological consequence s following renal ischemia. Endothelin (ET) receptor antagonists have prove d beneficial in the treatment of ischemic acute renal failure (IARF); howev er, the long-term outcomes have not been assessed in this disease. Methods. Experimental IARF was induced in uninephrectomized female Sparague -Dawley rats (N = 8) by clamping of the renal pedicle. At 24-hours postisch emia, a once-only administration of drug or vehicle was given. One ischemic group received saline only (saline ischemic), and two other ischemic group s received either SE 234551 (ET, receptor antagonist, ETA group) or SE 2096 70 (ETA and ETB receptor antagonist, ETA/ETB group). A uninephrectomized co ntrol group was sham operated to simulate operative conditions without isch emia and was given a once-only saline infusion (sham ischemic). All groups were sacrificed at six-months postischemia. Serum creatinine was assessed d aily for one week and then every four weeks. Glomerular filtration rates (G FRs), systolic blood pressure, 24-hour urine collection, and creatinine cle arance were performed just prior to sacrifice. Immunohistochemistry for mon ocytes and macrophages (Mo and M phi), myofibroblasts (MF, a-SMA), collagen IV, and collagen III was also evaluated. Cell kinetics were studied by imm unostaining for proliferating cell nuclear antigen (PCNA) and by TUNEL. Results. Urinalysis revealed significant increases in urinary protein and a lbumin in the ETA/ETB group when compared with all other groups. GFRs and c reatinine clearance were also decreased significantly in the ET,IET, group. Urine albumin, protein, GFR, and creatinine clearance in the ET, group, ho wever, were not different from the sham ischemic and saline ischemic groups . Systolic blood pressure was increased in the saline ischemic group as com pared with all other groups. Kidney weights were increased in all ischemic groups, but no differences were observed between the saline ischemic group and ETR antagonist-treated groups. Immunohistochemistry revealed relationsh ips between Mo and M phi, MF, and tubulointerstitial collagen III, where th e saline ischemic and ETA/ETB groups were increased as compared with the sh am ischemic and ETA groups. There was no change observed in tubulointerstit ial collagen IV accumulation. The largest number of proliferating cells was demonstrated in the ETA/ETB group, whereas apoptotic cells were identified in small amounts in all groups, with the largest number being found in the saline ischemic group. Conclusions. Renal ischemia appears to have long-term functional and pathol ogical consequences that can be pre vented by treatment with ETA receptor a ntagonists. Blockade of both ETA and ETB receptors. however, appears to be detrimental to long-term kidney function.