The objective of this study was to test the hypothesis that the dietary dipeptide carnosine (beta-alanine-L-histidine) causes direct decreases in arterial tone. Isolated descending thoracic aortic rings from male Sprague-Dawley rats were used for all studies. Preconstriction of vessels was accomplished with phenylephrine. Carnosine (0.625-20 mM) produced dose-dependent vascular relaxation (P < 0.05) that was independent of endothelium. The constituent amino acid L-histidine did not produce any significant relaxation over the same dose range, whereas beta-alanine actually produced dose-dependent vasoconstriction (P < 0.05). The soluble guanylate cyclase inhibitor methylene blue (10(-5) M) significantly decreased the relaxation produced by carnosine (P < 0.05). Measurement of cyclic GMP in the presence and absence of methylene blue after carnosine and phenylephrine exposure was also done. Methylene blue 10(-5) M resulted in a decrease in cyclic GMP levels from 65.3 +/- 15.6 fmol/mg protein to 8.6 +/- 0.9 fmol/mg of protein (P = 0.001). We conclude that carnosine produces relaxation of isolated rat aorta independent of endothelium. The effect of carnosine is at least in part mediated via cyclic GMP production and is not reproduced by its constituent amino acids, L-histidine and beta-alanine.