Leupeptin inhibits adrenocorticotropic hormone-induced protein breakdown in the conscious dog

To elucidate the role of proteinase inhibitors in the regulation of protein breakdown in vivo, we measured the effect of leupeptin on the rate of appearance of leucine in the plasma compartment in overnight-fasted conscious dogs. Two groups of dogs were studied. The control group (I) received saline infusion, and the experimental group (II) was rendered hypercatabolic with daily administration of adrenocorticotropic hormone (ACTH) (500 U/d) for 4 d.ACTH treatment increased plasma cortisol from 2+/-0.4 to 17+/-2 mug/dl (P < 0.005). It raised plasma leucine levels (mumol/liter) from 123+/-6 in I to 206+/-5 in II (P < 0.01) and its rate of appearance into the plasma compartment (micromoles per kilogram per minute) from 3.1+/-0.1 in I to 4.6+/-0.3 in II (P < 0.01). Whole blood alanine concentration (micromoles per liter) increased by 50% (from 387+/-31 to 577+/-53, P < 0.01) and whole blood glutamine concentration (micromoles per liter) increased from 653+/-51 to 917+/-93 (P < 0.01). Leupeptin infusion in the ACTH-treated group significantly decreased both the concentration of plasma leucine and its rate of appearance. Blood glutamine declined by 30% (P < 0.05) after leupeptin, but no effect on blood alanine was observed. Leupeptin had no effect on the saline control group. These data indicate that leupeptin decreases the accelerated rate of protein breakdown induced by cortisol excess. The fact that it did not affect protein degradation in controls may indicate that control of protein breakdown in the postabsorptive state may differ from that during accelerated turnover. Thus, the antibiotic proteinase enzyme inhibitors may be potentially useful in treating conditions of inappropriate protein breakdown.