ACE-INHIBITION PREVENTS AND REVERSES L-NAME-EXACERBATED NEPHROSCLEROSIS IN SPONTANEOUSLY HYPERTENSIVE RATS

Chronic nitric oxide inhibition exacerbates hypertension and nephroscl erosis in spontaneously hypertensive rats (SHRs). In this study, we de termined whether angiotensin-converting enzyme (ACE) inhibition could prevent or reverse the systemic, renal, and glomerular hemodynamic alt erations and the pathological changes of nephrosclerosis. Four groups of 20-week-old SHRs were studied: group 1, untreated controls; group 2 , treated with N-omega-nitro-L-arginlne methyl ester (L-NAME, 50 mg/L for 3 weeks); group 3, L-NAME cotreated with quinapril (3 mg . kg(-1). d(-1) for 3 weeks). and group 4, L-NAME for 3 weeks followed by quina pril for 3 weeks (same doses). The results of this study demonstrated that both cotreatment (group 3) and posttreatment (group 4) with quina pril reduced mean arterial pressure (186+/-9 and 192+/-9 mm Hg, respec tively, compared with group 2 SHRs, 221+/-5 mm Hg) and total periphera l resistance index associated with significant reductions in afferent and efferent arteriolar resistances; nephrosclerosis pathological scor es; and urinary protein excretion (all at least P<.01). ACE inhibition also significantly increased stroke index, single-nephron glomerular filtration rare, and ultrafiltration coefficient compared with the L-N AME SHRs. Most notable were the findings that cotreatment with quinapr il completely prevented the renal glomerular hemodynamic alterations w ith reduced glomerular capillary hydrostatic pressure and efferent art eriolar resistance compared with both the untreated and the L-NAME-tre ated SHRs (all at least P<.01). Posttreatment with quinapril also reve rsed the glomerular injury (subcapsular, -83%; juxtamedullary, -56%) a nd arteriolar (-87%) injury scores obtained from renal biopsy specimen s (P<.005 and P<.0001, respectively). These changes were associated wi th decreased periarteriolar fibronectin and increased afferent arterio lar oc-smooth muscle actin deposition (immunohistochemistry). These da ta, therefore, demonstrate that ACE inhibition not only prevents but a lso reverses L-NAME-exacerbated severe nephrosclerosis in SHRs, as ind icated by improved systemic, renal, and glomerular hemodynamic changes , proteinuria, and histological alterations.