ARGININE VASOPRESSIN-STIMULATED INSULIN-SECRETION AND ELEVATION OF INTRACELLULAR CA- INFLUENCES OF A PHOSPHOLIPASE-C INHIBITOR (10)-TRIEN-17-YL]AMINO]HEXYL]-1H-PYRROLE-2,5-DIONE (U-73122) AND A PHOSPHOLIPASE A(2) INHIBITOR N-(P-AMYLCINNAMOYL)ANTHRANILIC ACID(+ CONCENTRATION IN RAT INSULINOMA CELLS )

The present study investigated the mechanism by which arginine vasopre ssin (AVP) increases insulin secretion in rat insulinoma (RINm5F) cell s by using a specific phospholipase C (PLC) inhibitor, 1-[6-[[17 (10)- trien-17-yl]amino]hexyl]-1H-pyrrole-2,5-dione (U-73122), and a phospho lipase A(2) (PLA(2)) inhibitor, N-(p-amylcinnamoyl)anthranilic acid (A CA). AVP (0.1-100 nM) increased insulin secretion and cytosolic free C a++ concentration ([Ca++](i)) dose-dependently. AVP-induced increases in the intracellular concentration of inositol 1,4,5-trisphosphate (IP 3) and [Ca++](i) were dose-dependently inhibited by U-73122 (2-8 mu M) . At 8 mu M, U-73122 abolished AVP's effect on IP3 and [Ca++](i), but AVP-induced increases in insulin secretion were only reduced by 35%. I n contrast, 8 mu M U-73122 did not reduce the ionomycin (a Ca++ ionoph ore, 100 nM)-induced increase in [Ca++](i). The discrepancy between th e results of [Ca++](i) and insulin secretion in U-73122 experiments is indicative of the multiple signal transduction pathways associated wi th the activation of AVP receptors, specifically the Ca++-independent pathway. The phospholipase A(2) inhibitor ACA (100 mu M) did not antag onize AVP (10 nM)-induced increases in insulin secretion. These result s suggested: 1) U-73122 blocks FLC activities but fails to block other signal transduction pathways that trigger insulin secretion in these cells and 2) AVP increases insulin release from RINm5F cells through b oth the FLC-mediated Ca++-dependent and Ca++-independent pathways.