The amino acid L-arginine is a precursor of endothelium derived relaxing factor (EDRF). The pentapeptide 6A (Ala-Arg-Pro-Ala-Lys) released by plasmin degradation of fibrinogen also contains arginine and relaxes vascular smooth muscle by releasing EDRF (nitric oxide). To determine and compare the effects of L-arginine, peptide 6A and a combination of L-arginine and peptide 6A on femoral artery blood flow and vascular resistance, anesthetized mongrel dog were administered saline, L-arginine, D-arginine, peptide 6A and L-arginine + peptide 6A in a random order. L-arginine and peptide 6A both induced an immediate dose-dependent short-lasting increase in femoral blood flow and a decrease in vascular resistance. Peptide 6A exerted a much greater (P less than 0.01) vasodilatory effect than did L-arginine at the same molar concentration suggesting that properties besides the arginine content are important in the effect of the pentapeptide. D-arginine had much less effect than L-arginine, indicating that the effect of L-arginine may be related to its utilization for synthesis of EDRF. When the peptide 6A was given soon after L-arginine, its effect on blood flow was not greater than that of L-arginine alone suggesting that L-arginine in a large amount makes guanylate cyclase less available for the more active peptide.