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

Abstract

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 eect on renal parameters, relative to the systemic eects. 2 Renal eects: intravenous infusion of captopril ± lysozyme for 6 h resulted in a more pronounced increment of renal blood¯ow (31+2% vs 17+4% at 0.5 mg kg 71 6h 71 , P50.01) and an approximately 5 fold enhanced natriuresis (167+17% vs 36+7% at 1 mg kg 71 6 h 71 , P50.001) in comparison with equimolar amounts of captopril as a free drug. In correspondence with these ®ndings, renal ACE inhibition was potentiated approximately 5 fold (750+4% vs 722+3% at 1 mg kg 71 6 h 71 , P50.001). 3 Systemic eects: conjugated captopril did not aect blood pressure in dosages up to 5 mg kg 71 6 h 71. This eect coincided with a less pronounced inhibition of the pressor response to intravenously administered angiotensin I (712+3% vs 766+5% at 1 mg kg 71 6 h 71 , P50.001), and a markedly attenuated plasma ACE inhibition (719+2% vs 737+3% at 1 mg kg 71 6 h 71 , P50.001) 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 (767+5% vs 715+7% at 4 mg kg 71 24 h 71 , P50.001) 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 eects as well as less systemic eects compared to captopril itself.

Regulation of cardiac and renal mineralocorticoid receptor expression by captopril following myocardial infarction in rats

“…Our results showed that captopril treatment increased left ventricular systolic performance, as assessed by maximal +sdP / dt (Mill et al, 2003). ACE-induced natriuresis may also contribute to the observed effects (Hensen et al, 1991;Haverdings et al, 2002). This effect, however, was not tested in this study.…”

Everything we always wanted to know about furosemide but were afraid to ask

“…In a chronic setting, ACEi seems to enhance the natriuretic response to furosemide in heart failure (53). It would be an interesting option to specifically target the renal RAS [e.g., by using lysozyme-modified captopril (61)] to prevent the acute BP effects of ACEi. Altogether, there is uncertainty about the regulation of systemic and renal RAS in response to furosemide and, conversely, about the renal response to furosemide in the presence and absence of an intact RAS.…”

Review: Preventing End-Stage Renal Disease in Diabetic Patients — Dual Blockade of the Renin-Angiotensin System (Part II)

“…Finding ways of transporting inactive forms of the drugs to renal compartments where they will be activated is an elegant strategy. Haverdings et al 127 developed a method, by which the ACE-I, captopril, is conjugated to low-molecular-weight protein, lysozyme, which accumulates specifically in proximal tubule cells. When administered to rats, renal haemodynamic effects were more pronounced compared with captopril as a free drug, without systemic effects.…”

“…When administered to rats, renal haemodynamic effects were more pronounced compared with captopril as a free drug, without systemic effects. 127 More importantly, rats with renal disease had a more extensive antialbuminuric response to captopril-lysozyme than to free captopril. 127,128…”

“…127 More importantly, rats with renal disease had a more extensive antialbuminuric response to captopril-lysozyme than to free captopril. 127,128…”