DIFFERENTIAL EFFICACY OF PERINDOPRIL AND ENALAPRIL IN EXPERIMENTAL DIABETIC NEPHROPATHY

1. Treatment with angiotensin converting enzyme (ACE) inhibitors ameli orates human and experimental diabetic nephropathy, possibly as a resu lt of changes in angiotensin II (AngII) and/or bradykinin concentratio ns, However, ACE is an indiscriminate enzyme, which hydrolyses numerou s vasoactive peptides at two catalytic sites that are thought to be su bstrate specific, AngI is cleaved at the C-terminal site, bradykinin a t both the C- and N-terminal sites, while other substrates may be pref erentially cleaved at the N-terminal site, Of the various ACE inhibito rs, some (e.g. perindopril) bind preferentially to the C-terminal site while others (e.g. enalapril) bind to both, We compared the efficacy of perindopril and enalapril in the diabetic SHR to determine whether all the benefits of ACE inhibition derive from changes in the concentr ations of C-terminal related substrates, 2. Diabetes was induced by ta il vein injection of streptozotocin (60 mg/kg) in 14 week old SHR, Blo od glucose was maintained at 4-8 mmol/L by daily ultralente insulin in jection and rats were randomized to control, enalapril (10 mg/kg per d ay) or perindopril (4 mg/kg per day) groups, Blood pressure, creatinin e clearance and urinary protein excretion were monitored for 3 months, 3. Blood pressure in both treatment groups was lower than in control (perindopril P<0.0001; enalapril P<0.0001). Levels were marginally hig her in the perindopril group than the enalapril group, although this d ifference was significant only in the second month (P<0.025). Creatini ne clearance was significantly lower in the perindopril group (0.44+/- 0.05 mL/min) than in either the control rats (0.85+/-0.11 mL/min; P<0. 001) or the enalapril-treated group (0.66+/-0.05 mL/min; P<0.005). Pro teinuria was also lower in this group (4.3+/-0.9 mg/24 h) than in the enalapril-treated (11.3+/-5.8 mg/24 h; P<0.05) or control groups (32.1 +/-4.5 mg/24 h; P<0.0005), 4. The difference in efficacy between perin dopril and enalapril that we have observed suggests that the benefits of ACE inhibition derive from changes in the concentrations of peptide s catalysed by the C-terminal rather than the N-terminal site.