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HORMONES AND SIGNALING

Role of phospholipase A₂ (group I secreted) in the genesis of basal tone in the internal anal sphincter smooth muscle

Department of Medicine, Division of Gastroenterology and Hepatology, Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania

Submitted 10 July 2007 ; accepted in final form 22 August 2007

The role of phospholipase A₂ (PLA₂) in the genesis of basal tone in the internal anal sphincter (IAS) is not known. We determined the effects of PLA₂ and inhibitors on the basal tone and intraluminal pressures (IASP) in the rat IAS vs. rectal smooth muscles (RSM). In addition, we determined the correlations between the IAS tone, PLA₂ levels, and the actual enzymatic activity. Inhibition of PLA₂ by 4-bromophenacyl bromide (universal inhibitor of PLA₂) and MJ33 [selective inhibitor of secreted isoform of PLA₂ (sPLA₂)] caused concentration-dependent decrease in the IAS tone and in the IASP. Maximal decreases in the IAS tone and IASP by 4-bromophenacyl bromide and MJ33 were 58.8 ± 6.9 and 51.5 ± 6.3%, and 66.7 ± 5.1 and 79.8 ± 8.2%, respectively. The sPLA₂ inhibitors were 100 times more potent in decreasing the IASP than the mean blood pressure. Conversely, the selective inhibitors of the cytosolic and calcium-independent PLA₂ arachidonyl trifluoromethyl ketone and bromoenol lactone, respectively, produced no significant effect. The IAS had characteristically higher levels of sPLA₂ activity (26.5 ± 4.9 µmol·min^–1·ml^–1) vs. the RSM (3.2 ± 0.4 µmol·min^–1·ml^–1), and higher levels of sPLA₂ as shown by Western blot and RT-PCR. Interestingly, administration of sPLA₂ transformed RSM into the tonic smooth muscle like that of the IAS: it developed basal tone and relaxed in response to the electrical field stimulation. From the present data, we conclude that sPLA₂ plays a critical role in the genesis of tone in the IAS. PLA₂ inhibitors may provide potential therapeutic target for treating anorectal motility disorders.

smooth muscle tone; rectoanal incontinence