Renal targeting of captopril selectively enhances the intrarenal over the systemic effects of ACE inhibition in rats (Retracted Article.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)

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.