Angiotensin II plays a pivotal role in the development of diabetic nephropathy, but it remains controversial as to the best approach to effectively block the actions of this hormone in the kidney. The aim of the present study was to explore the effects of long-term treatment (8 months) with a combination of an angiotensin type 1 (AT1) receptor antagonist, irbesartan (15 mg/kg per day), and an angiotensin-converting enzyme (ACE) inhibitor, captopril (100 mg/kg per day), in diabetic spontaneously hypertensive rats. Captopril treatment reduced blood pressure (163+/-3 mmHg versus diabetic 201+/-3 mmHg), but not albumin excretion rate (43.8x//1.3 mg/day versus diabetic 46.8x//1.4 mg/day). Irbesartan treatment was associated with a similar reduction in blood pressure (173+/-3 mmHg) to captopril, and albumin excretion rate was reduced (14x//1.5 mg/day). The combination of irbesartan and captopril induced further reductions in blood pressure (140+/-3 mmHg) and albumin excretion rates (4.0x//1.5 mg/day). Gene expression of transforming growth factor beta-1 was reduced by all treatments to a similar level as assessed by in situ hybridization. These results demonstrate the additive hypotensive and anti-albuminuric effects of an ACE inhibitor and an AT1 receptor, suggesting that combination therapy is an approach not only more effective at reducing blood pressure, but also at retarding the development of diabetic nephropathy.