The partitioning of nitrogen into urea or ammonia in chronic acidosis reflects the flow of gln to either the splanchnic bed or kidneys. The direction of gln flow determines the rate of urea production and as well renal base and glucose production. That this system is under regulatory control is obvious from the profound shift in urinary nitrogen excretion from less than 2 percent to almost 40 percent as ammonia at the expense of urea during chronic acidosis. However in chronic renal disease, trauma and diabetes mellitus this control is lost. The question therefore is at what point is urea genesis affected and how is gln flow regulated in acidosis. To answer this question 2 hypotheses are tested in vivo: I. intraorganal and II. interorganal control. The former localizes the control point to the liver with acidosis (H+) decreasing glutaminase flux and (HCO-3) unreagenesis; the net effect is a shifting of nitrogen to gln and hence renal ammoniagenesis at the expense of ureagenesis. In contrast interorgan control reflects a concerted action of muscle and liver to supply glutamine at the expense of unreagenesis while under the influence of renal gln consumption. The quantitative participation of I and II to balancing the renal gln deficit and their roles in modulating unreagenesis will be evaluated in vivo. Organ gln balance, hindquarters, gut, liver and kidneys will be obtained from simultaneously determined blood flows and A-V gln concentration differences; nitrogen deposition into urea or ammonia is quantitated by the use of C-14 paraminohippurate and the dilution principle, hepatic and portal flow, and the Fick principle, kidney, and the appropriate A-V concentration differences. According to I the decline in urea-genesis should be matched by the increment in hepatic gln release. According to II decrement in ureagenesis should be matched by the increment in muscle plus hepatic net gln release. Hepatic unidirectional gln fluxes using labeled C-14 gln will be measured as an index of in situ glutaminase flux to I and II. Orchestrating influences on I and II will be the effect of acidosis, chronic vs acute, ammonia and glucgon. This proposal should therefore determine: (1) the relative roles of intraorganal and interorganal control in gln flow, and nitrogen partitioning (2) the role of unidirectional hepatic glutaminase flux in [I] and [II] and (3) the orchestration of gln flow and regulation of nitrogen deposition by pH, ammonia (portal and renal venous release) and glucagon.
