In a long-term multiple-catheter sheep model (n = 5), organ clearance of the dipeptide tyrosyl-arginine (TyrArg) and its effects on interorgan amino acid metabolism were investigated. Clearance by hindlimb and splanchnic tissues was measured during infusion into the external iliac artery and superior mesenteric artery, respectively. The hindlimb, intestine, and total splanchnic region removed 32% +/- 9.2% (mean +/- SE), 23% +/- 15%, and 33% +/- 24%, respectively, of the amount of TyrArg infused. There was a large release of tyrosine and arginine when TyrArg was infused into either the hindlimb or intestine, which was quantitatively similar to the TyrArg taken up by these organs. However, across the total splanchnic region, the baseline influx of tyrosine and arginine was not altered by infusion of TyrArg. During either clearance study, only trace amounts of TyrArg or its constituent amino acids were excreted in urine. Infusion of TyrArg produced the following effects on interorgan amino acid metabolism: (1) a reduction in the initial efflux of phenylalanine, leucine, isoleucine, and valine from the hindlimb; (2) a reduction in net efflux of citrulline by the intestine and total splanchnic tissues; and (3) a reduction in efflux of arginine and uptake of citrulline from the kidney. In conclusion, we have shown that TyrArg is cleared from the bloodstream by hindlimb (predominantly muscle) and splanchnic tissues. These results indicate that TyrArg taken up by the hindlimb and intestine was hydrolyzed to its constituent amino acids, which were released quantitatively into the circulation. Of the tissues studied, only the liver appeared to use the amino acids liberated from hydrolysis of TyrArg.(ABSTRACT TRUNCATED AT 250 WORDS)