Previous studies have demonstrated differences in the progression to glomerulosclerosis with the use of calcium channel blockers (CCB). The results with angiotensin-converting enzyme (ACE) inhibitors are more consistent. Moreover, only two studies have examined the combined effects of these drug classes on the development of glomerulosclerosis. The aim of the study presented here was to test the hypothesis that nonhypotensive doses of the combination (VT) of a nondihydropyridine CCB, verapamil (V), and an ACE-inhibitor, trandolapril (T), will slow the development of glomerulosclerosis better than either agent alone in stroke-prone spontaneously hypertensive rats (SHRSP). SHRSP were randomized to treatment in one of three groups with nonhypotensive doses of these agents; a fourth group served as control (C). The control rats developed significant increases in proteinuria compared with the other groups (C, 190 +/- 35 mg.kg-1.d-1 versus VT, 19 +/- 12 mg.kg-1.d-1; P < 0.05). This finding correlated with the degree of glomerulosclerosis (mean severity grading for C, 3.31 +/- 0.21 versus VT, 1.6 +/- 0.51; P < 0.05). Moreover, there was no significant reduction in arterial pressure between these groups (C, 282 +/- 5 versus VT, 259 +/- 13 mm Hg; P = 0.12). Despite persisting hypertension, the rise in proteinuria was also attenuated in both the V group (57 +/- 21 mg.kg-1.d-1) and the T group (43 +/- 24 mg.kg-1.d-1). However, compared with the control rats, kidney morphology was unchanged. Lastly, creatinine clearance was better preserved in the VT group compared with the control group (C, 0.57 +/- 0.01 versus VT, 0.74 +/- 0.06 mL.min-1.100 g-1; P < 0.05). It was concluded that the combination of nonhypotensive doses of VT attenuates the rise in proteinuria and progression to glomerulosclerosis. This study supports the concept that VT may have effects on the glomerulus that are independent of blood pressure reduction.