A metabonomic study of biochemical changes characteristic of genetically hypertensive rats based on ~1H NMR spectroscopic urinalysis

摘要

Spontaneously hypertensive rats (SHR) provide a simple model for studying essential hypertension. Their genetic and metabolic features are of great interest because they may provide insights into the pathophysiological processes underlying essential hypertension. We have thus investigated the metabolic characteristics of SHR at various ages, covering the prehypertensive stage and the developmental phase of hypertension, using a ~1H nuclear magnetic resonance (NMR)-based metabonomic approach. Twenty-four-hour urine samples from the SHR and their age-matched normotensive control, Wistar-Kyoto rats, were analyzed using ~1H NMR spectroscopy, and the spectral data were subjected to principal components analysis (PCA) to find metabolic differences between the two strains. Consequently, it was possible to separate the urine samples between the two strains at any age ranging from 4 to 20 weeks in the principal component scores plots. The major spectral regions and signals (metabolites) contributing to the separation were picked up based on the loadings. Subsequently, the urinary excreted levels of metabolites highlighted by the PCA were compared based on the signal intensities corrected by urine volume and body weight. These investigations revealed the major metabolic changes characteristic of the SHR, which included differences in citrate, alpha-ketoglutarate, succinate, hippurate, phenylacetylglycine, p-cresol glucuronide, creatine, taurine, medium-chain dicarboxylates (tentative), unknown (d 3.11), and the regions at 3.60, 3.64, 3.68 and 3.88 p.p.m. The results supported the occurrence of metabolic acidosis in the SHR in the period of prehypertension as well as rapidly rising blood pressure. In addition, the intestinal microfloral populations in the SHR were suggested to be altered in the developmental phase of hypertension.