Relationship between Δ-9-tetrahydrocannabinol-induced arachidonic acid release and secretagogue-evoked phosphoinositide breakdown and Ca²⁺ mobilization of exocrine pancreas

We have previously shown that addition of exogenous arachidonic acid to pancreatic acinar cells inhibits the incorporation of myo-[³H]inositol into membrane phosphoinositides and causes a reduction in the steady state levels of [³²P]phosphatidylinositol-4,5-bisphosphate (Ptdlns4,5P₂). In the present study, Δ-9-tetrahydrocannabinol (THC) was utilized to raise endogenous levels of arachidonic acid. In acinar cells simultaneously prelabeled with [³H]arachidonic acid and [³²P]P(i), THC (1-20 μM) produced a concentration-dependent increase in free [³H]arachidonic acid release and a reduction in the steady state levels of [³²P]Ptdlns4,5P₂. THC (1-20 μM) also caused a concentration-dependent inhibition of myo-[³H]inositol trisphosphate accumulation, cytoplasmic Ca²⁺ level, and amylase secretion elicited by 0.1 μM caerulein. The findings that THC (20 μM) was unable to inhibit either the rise in [Ca²⁺](i) elicited by ionomycin, or the secretory response to phorbol myristic acid or ionomycin, indicate that THC exerts a selective inhibitory effect on the phosphoinositide messenger system. These results support the postulate that endogenous arachidonic acid serves as a negative feedback regulator of phosphoinositide turnover in exocrine pancreas.