OPPOSITE, PHASE-DEPENDENT EFFECTS OF 3,4,5-TRIMETHOXYBENZOIC ACID 8-(DIETHYLAMINO) OCTYL ESTER OR TETRACAINE ON ISLET FUNCTION DURING 3 PHASES OF GLUCOSE-STIMULATED INSULIN-SECRETION

The spontaneous decline of insulin secretion which occurs under a vari ety of secretory conditions is well documented and suggests a general desensitization of the secretory process distal to signal recognition. Accordingly, we have investigated the effects of agents thought to mo bilize intracellular Ca++ on insulin secretion over 24 h, which includ es periods of rising secretory activity (second phase) and desensitize d secretory activity (third phase). During the first 3 h of glucose st imulation of freshly isolated rat islets, insulin secretion was strong ly inhibited by 30 muM 3,4,5-trimethoxybenzoic acid 8-(diethylamino) o ctyl ester (TMB) or 300 muM tetracaine hydrochloride (TC). However, wh en either of these agents was added for the first time to islets at h 20 when insulin secretion was at a low steady rate (third phase), insu lin secretion was greatly enhanced. Both these inhibitory and stimulat ory effects declined with continued administration. Removal of TMB and rechallenge with high glucose plus forskolin uncovered a residual inh ibition in both chronically and acutely treated islets. Coadministrati on of forskolin with either TMB or TC blunted both inhibitory and stim ulatory effects. Pertussis toxin pretreatment, however, did not alter subsequent response of islets to either agent. Thus TMB or TC have opp osite, phase-dependent effects on glucose-stimulated insulin secretion . We postulate that potentiators of glucose-stimulated insulin secreti on, which are increased during second phase, are most sensitive to inh ibitory effects of TMB or TC, and that the low steady rate of third ph ase permits their stimulatory component(s) to become apparent.