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ACE inhibition prevents and reverses L-NAME-exacerbated nephrosclerosis in spontaneously hypertensive rats
1Hypertension Research Laboratory, Alton Ochsner Medical Foundation, New Orleans, La. 70121, USA.
Insights
Angiotensin-converting enzyme (ACE) inhibition with quinapril prevents and reverses hypertension and nephrosclerosis in spontaneously hypertensive rats. This treatment improves systemic and renal hemodynamics, reducing kidney damage and proteinuria.
Area of Science:
- Nephrology
- Cardiovascular Research
- Pharmacology
Background:
- Chronic nitric oxide inhibition worsens hypertension and nephrosclerosis in spontaneously hypertensive rats (SHRs).
- Understanding the role of angiotensin-converting enzyme (ACE) in mitigating these effects is crucial for developing therapeutic strategies.
Purpose of the Study:
- To determine if ACE inhibition can prevent or reverse hemodynamic and pathological changes in L-NAME-induced nephrosclerosis in SHRs.
- To evaluate the effects of quinapril, an ACE inhibitor, on systemic, renal, and glomerular hemodynamics and kidney pathology.
Main Methods:
- Four groups of 20-week-old SHRs were studied: controls, L-NAME treated, L-NAME + quinapril cotreated, and L-NAME followed by quinapril posttreated.
- Measurements included mean arterial pressure, total peripheral resistance, arteriolar resistances, single-nephron glomerular filtration rate, and urinary protein excretion.
- Renal pathology, glomerular injury scores, and immunohistochemical analysis of fibronectin and alpha-smooth muscle actin were performed.
Main Results:
- Both cotreatment and posttreatment with quinapril significantly reduced mean arterial pressure and total peripheral resistance compared to L-NAME alone.
- ACE inhibition improved renal hemodynamic parameters, including glomerular filtration rate and ultrafiltration coefficient, and reduced nephrosclerosis and proteinuria.
- Quinapril completely prevented glomerular hemodynamic alterations and reversed existing glomerular and arteriolar injury, with associated changes in fibronectin and alpha-smooth muscle actin deposition.
Conclusions:
- ACE inhibition with quinapril effectively prevents and reverses L-NAME-induced severe nephrosclerosis in SHRs.
- The findings highlight the therapeutic potential of ACE inhibitors in managing hypertension-related kidney disease.
- Improved hemodynamic function and reduced pathological damage underscore the benefits of ACE inhibition in this model.
Abstract:
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 N omega-nitro-L-arginine 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 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 +/- 9 and 192 +/- 9 mm Hg, respectively, compared with group 2 SHRs, 221 +/- 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.