Renal targeting of captopril selectively enhances the intrarenal over the systemic effects of ACE inhibition in rats (Retracted Article. See vol 138, pg 531, 2003)
Renal targeting of captopril selectively enhances the intrarenal over the systemic effects of ACE inhibition in rats (Retracted Article. See vol 138, pg 531, 2003)
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DOI：
10.1038/sj.bjp.0704814
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发表时间：
2002-08-01
影响因子：
7.3
通讯作者：
Moolenaar, F
中科院分区：
文献类型：
--
作者：
Haverdings, RFG;Haas, M;Moolenaar, F
1在先前关于ACE抑制剂Captopril的肾靶向研究中，我们证明了在与低分子量蛋白质溶菌酶缀合后，该药物在肾中的浓度可以增加6倍。在本研究中，我们在未受限制的大鼠中研究了与全身效应相比，全身给予卡托普利-溶菌酶是否也会导致对肾脏参数的增强效应。2肾脏效应：静脉输注卡托普利-溶菌酶6 h，肾血流量增加更明显（0.5 mg kg（-1）6 h（-1）时为31 +/- 2% vs 17 +/- 4%，P < 0.01），尿钠排泄增加约5倍（1 mg kg（-1）6 h（-1）时为167 +/- 17% vs 36 +/- 7%，P < 0.001）。与这些发现相一致，肾脏ACE抑制作用增强了约5倍（1 mg kg（-1）6 h（-1）时为-50 +/- 4% vs -22 +/- 3%，P < 0.001）。3全身效应：剂量高达5 mg kg（-1）6 h（-1）时，结合型卡托普利对血压没有影响。这种效应与静脉注射血管紧张素1对升压反应的抑制作用不太明显相一致（1 mg kg（-1）6 h（-1）时-12 +/- 3% vs -66 +/- 5%，P < 0.001），血浆ACE抑制明显减弱（-19 +2%vs-37 +3%at 1 mg kg（-1）6 h（-1）P < 0.001）与等效剂量的游离卡托普利相比。在肾病综合征中用溶菌酶处理7天证明该缀合物在肾病中也有活性：抗蛋白尿反应显著增强与游离药物相比（4 mg kg（-1）24 h（-1）时为-67 +/- 5% vs - 15 +/- 7%，P < 0.001），5这些数据表明，静脉内给予卡托普利-溶菌酶偶联物导致更有选择性的肾ACE抑制和增强的肾效应，以及与卡托普利本身相比更少的全身效应。
1 In previous studies on the renal targeting of the ACE inhibitor captopril, we demonstrated that a 6 fold increased concentration of this drug could be obtained in the kidney after conjugation to the low-molecular-weight protein lysozyme. In this study, we investigated in unrestrained rats whether systemic administration of captopril-lysozyme also 'results in an enhanced effect on renal parameters, relative to the systemic effects.2 Renal effects: intravenous infusion of captopril-lysozyme for 6 h resulted in a more pronounced increment of renal blood flow (31 +/- 2% vs 17 +/- 4% at 0.5 mg kg(-1) 6h(-1), P < 0.01) and an approximately 5 fold enhanced natriuresis (167 +/- 17% vs 36 +/- 7% at 1 mg kg(-1) 6 h(-1), P < 0.001) in comparison with equimolar amounts of captopril as a free drug. In correspondence with these findings, renal ACE inhibition was potentiated approximately 5 fold (-50 +/- 4% vs -22 +/- 3% at 1 mg kg(-1) 6 h(-1), P < 0.001).3 Systemic effects: conjugated captopril did not affect blood pressure in dosages up to 5 mg kg(-1) 6 h(-1). This effect coincided with a less pronounced inhibition of the pressor response to intravenously administered angiotensin 1 (-12 +/- 3% vs -66 +/- 5% at 1 mg kg(-1) 6 h(-1), P < 0.001), and a markedly attenuated plasma ACE inhibition (- 19 + 2% vs - 37 + 3% at 1 mg kg(-1) 6h(-1) P < 0.001) compared to an equivalent dose of free captopril.4 An experiment of continued intravenous administration of captopril-lysozyme for 7 days in nephrotic syndrome demonstrated that the conjugate is also active in renal disease: the antiproteinuric response was substantially augmented (-67 +/- 5% vs - 15 +/- 7% at 4 mg kg(-1) 24 h(-1), P < 0.001) compared to the free drug, in the absence of blood pressure reduction.5 These data demonstrate that intravenous administration of a captopril-lysozyme conjugate leads to more selective renal ACE inhibition and enhanced renal effects as well as less systemic effects compared to captopril itself.