Malignant Alterations Following Early Blockade of Nitric Oxide Synthase in Hypertensive Rats

Yung Hsiang Hsu；Bang Gee Hsu；Hsing I Chen

arteriolar injury ； nitric oxide synthase ； stroke ； glomerular injury ； renal functions

The Chinese Journal of Physiology

50卷6期（2007 / 12 / 01）

283 - 293

英文

Nitric oxide (NO) is important for the homeostasis of organ functions. We studied the structural and functional changes in the cardiovascular (CV) and renal systems following early NO deprivation by various nonspecific and specific NO synthase (NOS) inhibitors: N-nitro-L-arginine methyl ester (L-NAME), N-nitro-L-arginine (L-NA), S-methyl-isothiourea (SMT), and L-N^6-(1-iminoethyl)-lysine (L-Nil). The aim is to elucidate the involvement of NO through endothelial or inducible NOS (eNOS and iNOS). Drugs were given to spontaneously hypertensive rats (SHR) and age-matched normotensive Wistar Kyoto rats (WKY) from a young age (5-wk-old). Physiological, biochemical, and pathological examinations were performed. L-NAME and L-NA treatment caused a rapid increase in tail cuff pressure (TCP). The TCP of SHR reached a malignant level within 30 days with signs of stroke, proteinurea, severe glomerular sclerosis, and moderate ventricular hypertrophy (VH). The plasma nitrite/nitrate was reduced, while creatinine, urea nitrogen and uric acid were elevated. The renal tissue cyclic guanosine monophosphate (cGMP) was decreased with an elevated collagen content. The numbers of sclerotic glomeruli, arteriolar and glomerular injury scores were markedly increased, accompanied by reduction in renal blood flow, filtration rate, and fraction. Plasma endothelin-1 was increased following L-NAME or L-NA treatment for 10 days. The expression of eNOS and iNOS mRNA was depressed by L-NAME and L-NA. The relevant iNOS inhibitors, SMT and L-Nil depressed the iNOS expression, but did not produce significant changes in CV and renal systems. The continuous release of NO via the eNOS system provides a compensatory mechanism to prevent the genetically hypertensive rats from rapid progression to malignant phase. Removal of this compensation results in VH, stroke, glomerular damage, renal function impairment, and sudden death.

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1. Yang, Yi-Ling,Liu, Demeral David,Hsieh, Nan-Kuang,Chen, Hsing-I(2008).Endothelin and Gelatinases in Renal Changes Following Blockade of Nitric Oxide Synthase in Hypertensive Rats.Chinese Journal of Physiology,51(3),186-195.