Windt Willemijn A K M, Tahara Atsua, Kluppel Alex C A, de Zeeuw Dick, Henning Robert H, van Dokkum Richard P E
Department of Clinical Pharmacology, Groningen Institute for Drug Evaluation (GUIDE), University Medical Center Groningen, Antonius Deusinglaan 1. NL-9713 AV Groningen NL-9713, The Netherlands.
J Renin Angiotensin Aldosterone Syst. 2006 Dec;7(4):217-24. doi: 10.3317/jraas.2006.041.
Vasopressin, mainly through the V1a-receptor, is thought to be a major player in the maintenance of hyperfiltration. Its inhibition could therefore lead to a decrease in progression of chronic renal failure. To this end, the effect of the vasopressin V1a-receptor-selective antagonist, YM218, was studied on proteinuria and focal glomerulosclerosis in early and late intervention after 5/6 nephrectomy in rats, and compared with an angiotensin-converting enzyme inhibitor (ACE-I).
After 5/6 nephrectomy, early intervention was performed between week 2 and 10 thereafter with the V1a-receptor-selective antagonist (VRA, 10 mg/kg/day, n=10), enalapril (ACE-I, 10 mg/kg/day, n=9), or vehicle (n=8). Late intervention was performed in another group between week 6 and 12 with VRA (10 mg/kg/day, n=7), lisinopril (ACE-I, 5 mg/kg/day, n=7), or vehicle (n=7).
In early intervention, proteinuria and focal glomerulosclerosis were significantly decreased by VRA compared to vehicle (44+7% and 59+8% respectively). ACE-I significantly decreased proteinuria (67+7%) and a trend towards a decrease in focal glomerulosclerosis was observed (30+18%). In late intervention, VRA did not decrease proteinuria and focal glomerulosclerosis compared to vehicle (21+20% and 0%, respectively), ACE-I significantly lowered proteinuria (92+2%) and a focal glomerulosclerosis (69+1%) lowering trend was observed.
These results indicate that VRA may protect against early progression of renal injury after 5/6 nephrectomy, whereas its effectiveness seems limited in established renal damage.
血管加压素主要通过V1a受体，被认为是维持超滤的主要因素。因此，抑制血管加压素可能会减缓慢性肾衰竭的进展。为此，研究了血管加压素V1a受体选择性拮抗剂YM218对大鼠5/6肾切除术后早期和晚期干预时蛋白尿和局灶性肾小球硬化的影响，并与血管紧张素转换酶抑制剂（ACE-I）进行比较。
5/6肾切除术后，在第2周至第10周进行早期干预，使用V1a受体选择性拮抗剂（VRA，10mg/kg/天，n = 10）、依那普利（ACE-I，10mg/kg/天，n = 9）或赋形剂（n = 8）。另一组在第6周至第12周进行晚期干预，使用VRA（10mg/kg/天，n = 7）、赖诺普利（ACE-I，5mg/kg/天，n = 7）或赋形剂（n = 7）。
在早期干预中，与赋形剂相比，VRA可使蛋白尿和局灶性肾小球硬化显著降低（分别为44 + 7%和59 + 8%）。ACE-I可显著降低蛋白尿（67 + 7%），并观察到局灶性肾小球硬化有下降趋势（30 + 18%）。在晚期干预中，与赋形剂相比，VRA未降低蛋白尿和局灶性肾小球硬化（分别为21 + 20%和0%），ACE-I可显著降低蛋白尿（92 + 2%），并观察到局灶性肾小球硬化有降低趋势（69 + 1%）。
这些结果表明，VRA可能预防5/6肾切除术后肾损伤的早期进展，而在已发生的肾损伤中其有效性似乎有限。
