Relationship between delta-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 (PtdIns4,5P2). In the present study, delta-9-tetrahydrocannabinol (THC) was utilized to raise endogenous levels of arachidonic acid. In acinar cells simultaneously prelabeled with [3H]arachidonic acid and [32P]Pi, THC (1-20 microM) produced a concentration-dependent increase in free [3H]arachidonic acid release and a reduction in the steady state levels of [32P]Ptd-Ins4,5P2. THC (1-20 microM) also caused a concentration-dependent inhibition of myo-[3H]inositol trisphosphate accumulation, cytoplasmic Ca2+ level, and amylase secretion elicited by 0.1 microM caerulein. The findings that THC (20 microM) 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.
Chaudhry
A
A
Department of Pharmacology, Medical College of Virginia, Richmond 23298-0001.
Thompson
R H
RH
Rubin
R P
RP
Laychock
S G
SG
D000681:Amylases / Q000378:metabolism*; D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D002108:Ceruletide / Q000494:pharmacology; D013759:Dronabinol / Q000494:pharmacology*; D066298:In Vitro Techniques; D007295:Inositol Phosphates / Q000378:metabolism; D008555:Melitten / Q000494:pharmacology; D010179:Pancreas / Q000502:physiology*; D019269:Phosphatidylinositol 4,5-Diphosphate; D010716:Phosphatidylinositols / Q000378:metabolism*; D051381:Rats; D012636:Secretory Rate / Q000187:drug effects
D001095:Arachidonic Acids; D007295:Inositol Phosphates; D019269:Phosphatidylinositol 4,5-Diphosphate; D010716:Phosphatidylinositols; D008555:Melitten; D016718:Arachidonic Acid; D013759:Dronabinol; D002108:Ceruletide; D000681:Amylases; D002118:Calcium