Differential efficacy of perindopril and enalapril in experimental diabetic nephropathy

1. Treatment with angiotensin converting enzyme (ACE) inhibitors ameliorates human and experimental diabetic nephropathy, possibly as a result of changes in angiotensin II (AngII) and/or bradykinin concentrations. However, ACE is an indiscriminate enzyme, which hydrolyses numerous vasoactive peptides at two catalytic sites that are thought to be substrate specific. AngI is cleaved at the C-terminal site, bradykinin at both the C- and N-terminal sites, while other substrates may be preferentially cleaved at the N-terminal site. Of the various ACE inhibitors, 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 concentrations of C-terminal related substrates. 2. Diabetes was induced by tail vein injection of streptozotocin (60 mg/kg) in 14 week old SHR. Blood glucose was maintained at 4-8 mmol/L by daily ultralente insulin injection and rats were randomized to control, enalapril (10 mg/kg per day) or perindopril (4 mg/kg per day) groups. Blood pressure, creatinine 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 higher in the perindopril group than the enalapril group, although this difference was significant only in the second month (P < 0.025). Creatinine 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). Proteinuria was also lower in this group (4.3 +/- 0.9 mg/24h) than in the enalapril-treated (11.3 +/- 5.8 mg/24h; P < 0.05) or control groups (32.1 +/- 4.5 mg/24h; P < 0.0005). 4. The difference in efficacy between perindopril and enalapril that we have observed suggests that the benefits of ACE inhibition derive from changes in the concentrations of peptides catalysed by the C-terminal rather than the N-terminal site.