To investigate abnormalities of metabolism in spontaneously hypertensive rats (SHR) that might be related to the pathogenesis of hypertension, we measured concentrations of free amino acids in plasma and in homogenates of skeletal muscle from SHR and age-matched normotensive Wistar-Kyoto (WKY) rats. These pools were evaluated in rats aged 3.5, 6, 8 and 28 wk, corresponding to time points before, during and after onset of hypertension. Amino acid content of aortic tissue also was examined at 3.5 and 6 wk. In plasma, amino acid concentrations were relatively unchanged throughout the study. Free amino acid content of muscle, on the other hand, decreased markedly with age in both strains. The most consistent and quantitatively important difference between strains was the much smaller muscle pool of lysine in SHR at 3.5, 6 and 8 wk of age compared with WKY controls. The arginine pool was also smaller in SHR but only at 3.5 and 6 wk. Other urea cycle amino acids were also lower in muscle of SHR at 3.5 wk. These alterations in the muscle amino acid pool were mirrored in plasma and were also found in aortic tissue. Glutamine was higher in muscle and plasma of SHR at 6 wk and thereafter. At 28 wk, however, many amino acids, including the branched-chain amino acids and tyrosine and glutamine, were present at higher concentrations in muscle and plasma of SHR than in those of WKY rats. These differences, because they occur most strikingly in SHR during the prehypertensive state, may be related to the development of hypertension.