Chronic nitric oxide inhibition exacerbates hypertension and nephrosclerosis in spontaneously hypertensive rats (SHRs). In this study, we determined whether angiotensin-converting enzyme (ACE) inhibition could prevent or reverse the systemic, renal, and glomerular hemodynamic alterations and the pathological changes of nephrosclerosis. Four groups of 20-week-old SHRs were studied: group 1, untreated controls; group 2, treated with Nomega-nitro-L-arginine methyl ester (L-NAME, 50 mg/L for 3 weeks); group 3, L-NAME cotreated with quinapril (3 mg [centered dot] kg-1[centered dot] d-1for 3 weeks); and group 4, L-NAME for 3 weeks followed by quinapril for 3 weeks (same doses). The results of this study demonstrated that both cotreatment (group 3) and posttreatment (group 4) with quinapril reduced mean arterial pressure (186 plus/minus 9 and 192 plus/minus 9 mm Hg, respectively, compared with group 2 SHRs, 221 plus/minus 5 mm Hg) and total peripheral resistance index associated with significant reductions in afferent and efferent arteriolar resistances; nephrosclerosis pathological scores; and urinary protein excretion (all at least P < .01). ACE inhibition also significantly increased stroke index, single-nephron glomerular filtration rate, and ultrafiltration coefficient compared with the L-NAME SHRs. Most notable were the findings that cotreatment with quinapril completely prevented the renal glomerular hemodynamic alterations with reduced glomerular capillary hydrostatic pressure and efferent arteriolar resistance compared with both the untreated and the L-NAME-treated SHRs (all at least P < .01). Posttreatment with quinapril also reversed the glomerular injury (subcapsular, -83%; juxtamedullary, -56%) and arteriolar (-87%) injury scores obtained from renal biopsy specimens (P < .005 and P < .0001, respectively). These changes were associated with decreased periarteriolar fibronectin and increased afferent arteriolar alpha-smooth muscle actin deposition (immunohistochemistry). These data, therefore, demonstrate that ACE inhibition not only prevents but also reverses L-NAME-exacerbated severe nephrosclerosis in SHRs, as indicated by improved systemic, renal, and glomerular hemodynamic changes, proteinuria, and histological alterations. (Hypertension. 1996;27:176-183.)