We studied the potential renoprotective properties of a calcium channel blocker in moderately hyperglycemic diabetic rats both in the early phase of the disease and in the very long term, and compared such an effect with that of an angiotensin-I-converting enzyme (ACE) inhibitor. Three groups of diabetic rats, one receiving no therapy except insulin and the remaining two receiving insulin and the ACE inhibitor enalapril or the calcium blocker lacidipine and one group of nondiabetic control rats were followed for 4-6 weeks. Both antihypertensive drugs lowered systolic blood pressure comparably. At the end of the observation period, untreated diabetic rats exhibited elevation of glomerular filtration rate and renal plasma flow. Both enalapril and lacidipine treatment completely prevented whole-kidney hyperfiltration and hyperperfusion. Four additional groups of rats, similarly treated, were followed for 1 year. A comparable control of systolic blood pressure and blood glucose level was achieved with the two antihypertensive regimens throughout the whole study period. At 12 months, the average kidney weight was elevated to similar values in all diabetic groups relative to control rats. Untreated diabetic rats had progressive proteinuria and developed glomerulosclerosis. Enalapril markedly limited the development of proteinuria. By contrast, urinary protein excretion in diabetic rats given lacidipine markedly increased with time, and values were as high as those in untreated diabetic animals. Similarly, only enalapril was effective in limiting glomerular injury. These results indicate that ACE inhibition but not calcium channel blockade has a favorable effect in preventing renal disease progression in diabetic rats and suggest that the various antihypertensive regimens are not equally beneficial in protecting against diabetic glomerulopathy.