Activation of arachidonoyl phospholipase A2 in prostaglandin-mediated action of sucralfate.
1. The mechanism of sucralfate-induced gastric mucosal prostaglandin generation was investigated using mucosal cells labeled with [14C]choline and [3H]arachidonic acid. 2. In comparison to the controls, the cells maintained in the presence of sucralfate showed a concentration dependent increase in lysophosphatidylcholine (LPC) synthesis and PGE2 generation. The maximal effect was attained at 25 microM sucralfate giving a 45.7% increase in LPC and 70% increase in PGE2. 3. Pretreatment with indomethacin prior to sucralfate, while causing inhibition in PGE2 generation, had no effect on LPC production and led to accumulation of free arachidonic acid. In the case of pretreatment with NDGA, the sucralfate caused increased LPC synthesis accompanied by enhanced PGE2 generation without free arachidonic acid accumulation. 4. The stimulatory effect of sucralfate on LPC synthesis and PGE2 generation was inhibited by phospholipase A2 inhibitors, mepacrine and BPB. The inhibitory effect was concentration dependent and attained maximum at 40 microM for BPB and 80 microM for mepacrine. 5. The results for the first time demonstrate that the enhancement in gastric mucosal prostaglandin generation by sucralfate results from the stimulation of mucosal phospholipase A2 for arachidonic acid release.
Slomiany
B L
BL
Research Center, University of Medicine and Dentistry of New Jersey, Newark, NJ 07103-2400.
Murty
V L
VL
Piotrowski
E
E
Morita
M
M
Piotrowski
J
J
Slomiany
A
A
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D002794:Choline / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000032:analysis / Q000096:biosynthesis; D004789:Enzyme Activation / Q000187:drug effects; D005753:Gastric Mucosa / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D066298:In Vitro Techniques; D050356:Lipid Metabolism; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008244:Lysophosphatidylcholines / Q000378:metabolism; D008297:Male; D010741:Phospholipases A / Q000037:antagonists & inhibitors / Q000378:metabolism*; D054467:Phospholipases A2; D010743:Phospholipids / Q000096:biosynthesis; D011453:Prostaglandins / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013392:Sucralfate / Q000494:pharmacology*
D016861:Cyclooxygenase Inhibitors; D016859:Lipoxygenase Inhibitors; D008244:Lysophosphatidylcholines; D010743:Phospholipids; D011453:Prostaglandins; D016718:Arachidonic Acid; D013392:Sucralfate; D010741:Phospholipases A; D054467:Phospholipases A2; D015232:Dinoprostone; D002794:Choline