Intracellular calcium–mediated activation of hepatic Na + /H + exchange by arginine vasopressin and phenylephrine

The effect of Ca + + mobilizing agonists arginine vasopressin and phenylephrine on Na + /H + exchange was studied in freshly isolated hepatocytes and isolated perfused rat livers. The activity of Na + /H + exchange was determined from the rate of H + efflux, 22 Na uptake and pH i recovery. Arginine vasopressin and phenylephrine stimulated H + efflux and 22 Na uptake in isolated rat hepatocytes and increased the rate of pH i recovery from acid‐loaded hepatocytes. These effects were inhibited by amiloride. Arginine vasopressin– and phenylephrine—induced increases in H + efflux were also dependent on extracellular Na + . Arginine vasopressin– and phenylephrine—induced increases in intracellular Ca + + concentration, H + efflux, 22 Na uptake and intracellular pH recovery were decreased in hepatocytes preloaded with the Ca + + ‐buffering agent [ bis ‐(2‐amino‐5‐methylphenoxy)‐ethane‐N,N,N′,N′‐tetraacetic acid] (MAPTA). Na + /H + exchange‐dependent intracellular pH recovery from cytosolic acidification was stimulated by thapsigargin, which increases intracellular calcium concentration by inhibiting endoplasmic reticulum Ca + + ATPase. Arginine vasopressin– and phenylephrine—induced increases in intracellular pH recovery were not dependent on extracellular Ca + + and were inhibited by calmidazolium, a calmodulin inhibitor. Arginine vasopressin and phenylephrine also increased H + efflux in the absence but not in the presence of amiloride in perfused rat livers without affecting biliary HCO   3 −excretion. These results indicate that arginine vasopressin and phenylephrine activate Na + /H + exchange in rat hepatocytes, an effect mediated in part by intracellular Ca + + and calmodulin kinase. Furthermore, sinusoidal Na + /H + exchange does not appear to be involved in biliary HCO   3 −excretion. (H EPATOLOGY 1992;15:134–143).