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Phosphatidylinositol Breakdown

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Phosphatidylinositol Breakdown Proc. Nati. Acad. Sci. USA Vol. 77, No. 6, pp. 3292-3296, June 1980 Biochemistry Evidence for a role in stimulus-secretion coupling of prostaglandins derived from release of arachidonoyl residues as a result of phosphatidylinositol breakdown (phospholipid effect/cyclooxygenase inhibitors/nonsteroidal anti-inflammatory drugs/phosphatidic acid/ pancreatic enzyme secretion) PAUL J. MARSHALL, JOHN F. DIXON, AND LOWELL E. HOKIN* Department of Pharmacology, University of Wisconsin Medical School, Madison, Wisconsin 53706 Communicated by David E. Green, March 20,1980 ABSTRACT That stimulation of secretion in exocrine and 5, 11, and 16). In recent years much attention has been paid to endocrine glands is associated with increased turnover of the role of prostaglandins (PGs) in modulating or regulating a phosphatidylinositol and phosphatidic acid has been known for many years. In the present work, mouse pancreases were pre- variety of physiological functions (17, 18). The formation of PGs labeled with [14C]arachidonic acid in the presence of the is controlled by the release of arachidonic acid from phospho- secretogogue carbamoylcholine. They were then incubated in lipids (19), and because PtdIns from brain, liver, and mouse media containing atropine and 1% albumin. The atropine pancreas consists largely of 1-stearoyl-2-arachidonoyl-sn-gly- causes the tissue to revert to the resting state, and the albumin cero-3-phosphoinositol (13, 20, 21), the release of arachidonic binds free [14C]arachidonic acid. The tissues were finally in- cubated in media containing no stimulant or the stimulant acid on stimulation of PtdIns breakdown followed by the for- caerulein, which is not blocked by atropine. Stimulation with mation of PGs, which would play a role in stimulus-secretion caerulein led to a 44% loss of [1-14C]arachidonic acid from coupling, is an attractive hypothesis. We have tested this hy- phosphatidylinositol. About half of this released arachidonic pothesis by studying the effects of: (i) nonsteroidal anti-in- acid ended up in phosphatidic acid. The remainder of the loss flammatory drugs (NSAID), which are cyclooxygenase inhib- could not be accounted for in any other lipid. No other phos- itors, in pholipids showed statistically significant changes on stimula- (ii) arachidonic acid the presence and absence of the tion. Several lines of evidence indicated that the missing ara- cyclooxygenase inhibitor indomethacin, and (iii) PGs on chidonic acid was converted to prostaglandins, which play a role secretogogue-stimulated amylase secretion in isolated mouse in stimulus-secretion coupling. Four nonsteroidal anti-in- pancreas incubated in vitro. We have also examined the change flammatory drugs inhibited secretogogue-induced amylase se- in steady-state level of [1-'4C]arachidonic acid in prelabeled cretion from pancreases, and their potencies paralleled their lipids on stimulation of pancreases with the secretogogue potencies in inhibiting cyclooxygenase, which converts ara- chidonic acid to prostaglandins. Amylase secretion was stimu- caerulein. The data indicate that arachidonic acid is released lated by arachidonic acid, and this stimulation was blocked by from Ptdlns on stimulation with caerulein and they suggest that the nonsteroidal anti-inflammatory drug indomethacin. Other part of this arachidonic acid forms a PG or PGs, which are in- fatty acids failed to elicit amylase secretion. At concentrations volved in stimulus-secretion coupling. of 3-10 nM, prostaglandins I2, E1, E2, D2, and F2. gave statisti- cally significant stimulations of secretion. Other prostaglandins tested gave no significant stimulation. MATERIALS AND METHODS Amylase Secretion. Adult male mice (25 g) from an inbred In 1953 Hokin and Hokin (1) reported that cholinergic stimu- Swiss-Webster strain were used. The pancreases were removed lation of amylase secretion, paralleled by the secretion of other and incubated as described by Hokin-Neaverson (12). The pancreatic enzymes from pigeon pancreas slices (2), was asso- pancreas tissue was preincubated for 15 min at 37°C before the ciated with an 8-fold increase in the incorporation of [32P]or- addition of any drugs. When NSAID were tested, the pancre- thophosphate into the total phospholipids. This "phospholipid ases were transferred to fresh media containing the drugs and effect" was subsequently found in a variety-of exocrine and incubated for an additional 15 min. This pretreatment was endocrine glands as well as synaptic tissue on stimulation with found necessary to maximize their inhibitory actions. The appropriate agonists (see reviews 8-6). The phospholipid effect NSAID, free fatty acids, and PGs were prepared immediately primarily involved increased turnover of phosphatidylinositol before use and added in dimethyl sulfoxide (Me2SO). An equal (PtdIns) and phosphatidic acid (PtdA) (7). The increased volume of Me2SO was added to control vessels. The volume of turnover of phosphate was associated with an increased turn- Me2SO was usually 0.25% of that of the incubation medium and over of glycerol and inositol (8), and it was confined to the en- never exceeded 0.5%. These concentrations of Me2SO had no doplasmic reticulum, as demonstrated by combined differential effect on amylase secretion. After the pretreatment period the centrifugation (9) and radioautography with [3H]myo-inositol tissues were transferred to fresh media containing the stimulant (10). The phospholipid effect involves a fall in steady-state level with or without inhibitory drugs. Unless otherwise indicated, of PtdIns and a rise in steady-state level of PtdA (11-15). the final incubation was 30 min. Aliquots of the incubation Although the phospholipid effect was reported over 25 years ago, its physiological significance is still not understood (see refs. Abbreviations: PtdIns, phosphatidylinositol; PtdA, phosphatidic acid; PtdSer, phosphatidylserine; PtdEtn, phosphatidylethanolamine; The publication costs of this article were defrayed in part by page PtdCho, phosphatidylcholine; Me2SO, dimethyl sulfoxide; NSAID, charge payment. This article must therefore be hereby marked "ad- nonsteroidal anti-inflammatory drugs; CbmCho, carbamoylcholine; vertisement" in accordance with 18 U. S. C. §1734 solely to indicate PG, prostaglandin; PZ, pancreozymin. this fact. * To whom reprint requests should be addressed. 3292 Biochemistry: Marshall et al. Proc. Natl. Acad. Sci. USA 77 (1980) 3293 media were then assayed for amylase by the method of Rick and Stegbauer (22). The activity of amylase in the medium was calculated as nmol of maltose released per mg wet weight of original pancreas per min at 250C. In the figures, the data are expressed either as percent inhibition of the secretogogue- stimulated secretion or percent of the control tissue incubated without any pharmacologically active compounds. All con- centrations of added substances are those in the final incubation 40 medium. [1-"4CArachidonic Acid Released from Prelabeled PtdIns. [1-14C}Arachidonic acid in toluene (Amersham) was dried 40 - under N2 and taken up in Me2SO, and 20-1. aliquots were An//~~~~ added to 2 ml of incubation medium. Each 2 ml of incubation medium contained 0.44 ,uCi (1 Ci = 3.7 X 1010 becquerels) of 20/ [1-14C]arachidonic acid (specific activity, 55.5 mci/mmol). The concentration of arachid6nic acid during incubation was 4 MAM. Pancreases were incubated and the radioactivity in lipids was 10 9 8 7 6 5 4 determined as described in Table 3. -log[indomethacin] (M) Materials. Pancreozymin (PZ), caerulein, and fatty acid-free FIG. 2. Log dose-response curves for indomethacin inhibition bovine serum albumin were obtained from Calbiochem, and of hormone-stimulated amylase release. The data points for PZ (0) Me2SO was obtained from Aldrich. Unless otherwise indicated, and caerulein (C) are averages of two experiments. all other chemicals were purchased from Sigma. PZ also stimulates pancreatic enzyme secretion by binding to a receptor different from that for muscarinic drugs, as evi- RESULTS denced by the lack of blockage by the muscarinic antagonist Effects of NSAID Cn Secretogogue-Stimulated Secretion atropine (24). However, indomethacin inhibited this secretion of Amylase. Carbamoylcholine (CbmCho), a muscarinic ago- and the secretion elicited by caerulein, which is a decapeptide nist, stimulates enzyme secretion in the exocrine pancreas; the analogue of PZ (Fig. 2). We used concentrations of PZ (100 concentration of CbmCho required to elicit maximal secretion ,gg/ml) or caerulein (0.5 Mg/ml) found to elicit maximal amy- was found to be approximately 1 uM (not shown). The mean lase secretion (not shown). Indomethacin appeared to maxi- and SD stimulation of amylase secretion in nine experiments mally block PZ- or caerulein-induced secretion at a concen- were 230 + 30% (range, 180-50%). Pretreatment of pancreases tration of 10 MM. with increasing concentrations of NSAID, which are cycloox- Effects of Arachidonic Acid on Amylase Secretion in the ygenase inhibitors, caused a marked decrease in CbmCho- Presence and Absence of Indomethacin. Arachidonic acid stimulated amylase secretion (Fig. 1). Indomethacin was the is the substrate in the synthesis of PGs, and this synthesis is most potent inhibitor tested and was followed by phenylbuta- blocked by cyclooxygenase inhibitors such as indomethacin (23). zone, aspirin, and salicylic acid in that order. At concentrations Amylase secretion was stimulated by arachidonic acid (Fig. 3). tested (10-10 to 10-3 M), CbmCho could not overcome the
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