RENAL TUBULAR PC02 AND ACID-BASE EQUILIBRIUM

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The proposed research is designed to gain insight into the process of CO2 transfer in the kidney cortex, and into the role of bicarbonate reabsorption in the early proximal tubule in the maintenance of acid-base equilibrium. Micropuncture and microelectrode measurements in rats will be coupled with mathematical modelling efforts to test specific hypotheses concerning: 1) the high PCO2 levels in the superficial renal cortex, 2) the influence of tubular bicarbonate and CO2 reabsorption on peritubular capillary PCO2, 3) the factors producing a transepithelial PCO2 gradient confined to the early proximal tubule, and 4) the factor influencing bicarbonate reabsorption along the proximal tubule. For each of these problems a mathematical model has been developed, based on physicochemical interactions between CO2, bicarbonate and hydrogen ions, and on the interaction of these species with-blood buffers. The models also consider the permeabilities and diffusivities of these species in their movement from one compartment to another. The assumptions used to develop the models will be tested by specific experimental maneuvers in Munich-Wistar rats designed to produce measurable changes in renal cortical PCO2. These experiments include acute plasma expansion, metabolic and respiratory acid-base disorders, carbonic anhydrase inhibition, inhibition or uncoupling of metabolic CO2 production, and diuretic administration. In these experiments, microelectrode PCO2 measurements as well as measurements of bicarbonate reabsorption will be carried out. Experimental PCO2 measurements will be compared with values calculated by the models for each setting to test specific hypotheses concerning CO2 and bicarbonate transfer from the tubular lumen to the peritubular capillaries. A separate group of experiments will focus on defining the factors influencing bircarbonate reabsorption in the first 1-2 mm of the proximal tubule. The effect of pH, filtered bicarbonate load, and transport inhibitors will be examined in micropuncture and microperfusion studies. Finally, we plan to measure Na+/H+ exchange activity in brush border membrane vesicles isolated from rat renal cortex. These studies should provide insight into the regulation of normal acid-base equilibrium, and ultimately into clinical disorders of acid-base equilibrium.