Distinct time courses of renal protective action of angiotensin receptor antagonists and ACE inhibitors in chronic renal disease

Although the angiotensin receptor antagonist (ARB) shares the angiotensin-ll-blocking activity with the angiotensin-converting enzyme inhibitor (ACE-I), pharmacological mechanisms of action of these agents differ. We evaluated the temporal profiles of action of ACE-I and ARB on urinary protein excretion and nitrate/nitrate (NO_x) excretion in hypertensive (140 and/or 90mmHg) patients with chronic renal disease (serum creatinine <265 (range, 44-265)μmol/l or creatinine clearance > 30 (range, 30-121)ml/min). Patients with mild (<1 g/day; range, 0.4-1.0) and moderate proteinuria (>1 g/day; range, 1.1-6.9) were randomly assigned to ACE-I- and ARB-treated groups, and were treated with ACE-I (trandolapril or perindopril) or ARB(losartan or candesartan) for 48 weeks. In all groups, treatment with ACE-I or ARB decreased blood pressure to the same level, but had no effect on creatinine clearance. In patients with mild proteinuria, neither ACE-I nor ARB altered urinary protein excretion. In patients with moderate proteinuria, ACE-I caused 44 ± 6% reduction in proteinuria (from 2.7 ± 0.5 to 1.5 ± 0.4 g/day, n = 14) at 12 weeks, and this beneficial effect persisted throughout the protocol (48 weeks, 1.2 ± 0.2 g/day). In contrast, ARB did not produce a significant decrease in proteinuria at 12 weeks (23 ± 8%, n = 13), but a 41 ± 6% reduction in proteinuria was observed at 48 weeks. Similarly, although early (12 weeks) increases in urinary NO_x excretion were observed with ACE-I (from 257 ± 70 to 1111 ± 160 μmol/day) and ARB (from 280 ± 82 to 723 ± 86 μmol/day), the ARB-induced increase in NO_x excretion was smaller than that by ACE-I (P<0.05). In conclusion, although both ACE-I and ARB reduce blood pressure similarly, the effect of these agents on proteinuria differs in chronic renal disease with moderate proteinuria. Relatively early onset of the proteinuria-reducing effect was observed with ACE-I, which paralleled the increase in urinary NO_x excretion. Conversely, ARB decreased proteinuria and increased urinary NO_x excretion gradually. These time course-dependent changes in proteinuria and urinary NO_x may reflect the pharmacological property of ACE-I and ARB, with regard to the action on bradykinin.