Renal targeting of captopril selectively enhances the intrarenal over the systemic effects of ACE inhibition in rats

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. 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). 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 I (−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 6 h−1, P<0.001) compared to an equivalent dose of free captopril. 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. 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. British Journal of Pharmacology (2002) 136, 1107–1116. doi:10.1038/sj.bjp.0704814