Nitric Oxide Synthase Inhibition in Spontaneously Hypertensive Rats

The effects of the nitric oxide synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME) on cardiac index, renal micropuncture results, urinary excretion, and histology were obtained in 20-week-old male spontaneously hypertensive rats.

Abstract

Abstract To investigate the prolonged effects of nitric oxide inhibition on systemic, renal, and glomerular hemodynamics, the effects of the nitric oxide synthase inhibitor N ω -nitro- l -arginine methyl ester (L-NAME) on cardiac index, renal micropuncture results, urinary excretion, and histology were obtained in 20-week-old male spontaneously hypertensive rats (SHR) that were divided into two groups: untreated and L-NAME–treated (50 mg/L), each followed for 3 weeks. Cardiac index and effective renal plasma flow decreased ( P <.01) in L-NAME–treated SHR, exhibiting a positive correlation ( r =.816; P <.0001). Single-nephron plasma flow (123±8 versus 80±12 nL/min per gram; P <.01) and ultrafiltration coefficient ( P <.05) were also reduced in L-NAME–treated SHR versus controls. Most notably, the L-NAME–treated SHR had increased afferent (4.4±0.3 versus 9.5±1.3 U; P <.01) and efferent (1.4±0.1 versus 2.7±0.3 U; P <.01) glomerular arteriolar resistances versus controls. These functional changes were associated with significantly altered afferent arteriolar ( P <.001) and glomerular ( P <.005) histological injury scores accompanied by marked proteinuria ( P <.001). Because of the intense afferent glomerular artery constriction and lesser increase in efferent glomerular arteriolar resistance associated with reduced single-nephron plasma flow, glomerular capillary pressure did not increase in the L-NAME–treated SHR. Thus, L-NAME produced marked proteinuria and severe hypertensive nephrosclerosis manifested by afferent arteriolar fibrinoid necrosis, segmental glomerular hyalinosis and sclerosis, and myocardial fibrosis without any further increase in left ventricular mass, thereby providing a new model for severe hypertensive nephrosclerosis in young SHR without the necessity for surgical reduction of renal mass.