EFFECTS OF PARATHYROID-HORMONE ON HEPATOCYTE PH(I) AND NA-H+ EXCHANGER ACTIVITY()

Parathyroid hormone (PTH) induces a rise in cytosolic calcium - [Ca2+] (i) - in many cells. A rise in [Ca2+](i) activates the Na+-H+ antiport , but PTH inhibits the Na+-H+ exchanger in kidney cells. Since PTH ind uces a rise in [Ca2+](i) of hepatocytes, we examined the effect of PTH on their Na+-H+ antiport and intracellular pH (pH(i)). PTH caused an initial activation of Na+-H+ exchanger, and this stimulation is amilor ide sensitive. The activation of the Na+-H+ exchanger was followed by progressive inhibition. This inhibitory effect was dose dependent and occurred over a wide range of external sodium concentrations. PTH also caused a progressive rise in hepatocyte pH(i) which became apparent a fter the initial activation of the Na+-H+ antiport. This alkalinizatio n of hepatocytes occurred when the cells were placed in sodium or pota ssium media. These actions of PTH were mimicked by dibutyryl cyclic AM P and 12-o-tetradecanoylphorbol-13-acetate (TPA) and were abolished by H-89 (an inhibitor of protein kinase A), staurosporine (an inhibitor of protein kinase C), and the calcium channel blockers verapamil or ni fedipine. The data are consistent with the formulation that PTH, throu gh the activation of the cAMP-protein kinase A pathway, protein kinase C, and calcium channels inhibitable by verapamil or nifedipine, induc es a rise in [Ca2+](i) of hepatocytes. The latter event causes an init ial activation of Na+-H+ antiport which is followed by a rise in pH(i) . Also, PTH may facilitate a Ca2+/2H(+) exchange across the hepatocyte membrane and causes an initial and persistent rise in pH(i), since th e rise in pH(i) occurred under conditions where Na+-H+ antiport is ina ctive (potassium media). In addition, PTH either directly or through a ctivation of second messenger(s) leads to an increased ammonia content of hepatocytes which could maintain a high pH(i). Consequently, the N a+-H+ antiport is inhibited in an effort to restore the pH(i) back to normal.