Ono H, Ono Y, Frohlich E D
Hypertension Research Laboratory, Alton Ochsner Medical Foundation, New Orleans, La. 70121, USA.
Hypertension. 1996 Feb;27(2):176-83. doi: 10.1161/01.hyp.27.2.176.
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.
慢性一氧化氮抑制会加剧自发性高血压大鼠（SHR）的高血压和肾硬化。在本研究中，我们确定血管紧张素转换酶（ACE）抑制是否能预防或逆转系统性、肾脏和肾小球血流动力学改变以及肾硬化的病理变化。对四组20周龄的SHR进行了研究：第1组，未治疗的对照组；第2组，用Nω-硝基-L-精氨酸甲酯（L-NAME，50 mg/L，持续3周）治疗；第3组，L-NAME与喹那普利联合治疗（3 mg·kg-1·d-1，持续3周）；第4组，L-NAME治疗3周后再用喹那普利治疗3周（相同剂量）。本研究结果表明，喹那普利联合治疗（第3组）和后续治疗（第4组）均降低了平均动脉压（与第2组SHR的221±5 mmHg相比，分别为186±9和192±9 mmHg）以及总外周阻力指数，同时显著降低了入球和出球小动脉阻力；肾硬化病理评分；以及尿蛋白排泄（均至少P<0.01）。与L-NAME处理的SHR相比，ACE抑制还显著增加了每搏输出指数、单肾单位肾小球滤过率和超滤系数。最值得注意的是，与未治疗和L-NAME处理的SHR相比，喹那普利联合治疗完全预防了肾小球血流动力学改变，肾小球毛细血管静水压和出球小动脉阻力降低（均至少P<0.01）。喹那普利后续治疗也逆转了肾活检标本中的肾小球损伤（被膜下，-83%；近髓质，-56%）和小动脉损伤评分（-87%）（分别为P<0.005和P<0.0001）。这些变化与动脉周围纤连蛋白减少和入球小动脉α-平滑肌肌动蛋白沉积增加有关（免疫组织化学）。因此，这些数据表明，ACE抑制不仅能预防，还能逆转L-NAME加剧的SHR严重肾硬化，表现为系统性、肾脏和肾小球血流动力学改变、蛋白尿和组织学改变的改善。
