Submitted on July 10, 2007
Accepted on August 22, 2007
Role of Phospholipase A2 (Group I Secreted) in the Genesis of Basal Tone in the Internal Anal Sphincter Smooth Muscle
Marcio AF de Godoy1 and Satish Rattan2*
1 Medicine, Division of Gastroenterology and Hepatology, Thomas Jefferson University, United States
2 Division of Gastroenterology, Thomas Jefferson University, Philadelphia, Pennsylvania, United States
* To whom correspondence should be addressed. E-mail: satish.rattan{at}jefferson.edu.
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 inhibitors on the basal tone and intraluminal pressures (IASP) in the rat IAS vs. rectal (RSM) smooth muscles. In addition, we determined the correlations between the IAS tone, PLA2 levels and the actual enzymatic activity. Inhibition of PLA2 by BPB (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 BPB 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 (cPLA2) and calcium-independent PLA2 (iPLA2) AACOCF3 and BEL respectively, produced no significant effect. The IAS had characteristically higher levels of sPLA2 activity (26.5 ± 4.9 µmol/min/ml) vs. the RSM (3.2 ± 0.4 µmol/min/ml), 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 EFS. 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.
