Submitted on December 18, 2008
Revised on February 5, 2009
Accepted on February 7, 2009
Arachidonic Acid Metabolites Follow the Preferential Course of Cyclooxygenase Pathway for the Basal Tone in the Internal Anal Sphincter
Marcio AF De Godoy1, Neeru Rattan2, and Satish Rattan1*
1 Thomas Jefferson University
2 Thomas jefferson University
* To whom correspondence should be addressed. E-mail: satish.rattan{at}jefferson.edu.
Present studies determined the roles of the cyclooxygenase (COX) vs. the lipoxygenase (LO) pathways in the metabolic pathway of arachidonic acid (AA) in the internal anal sphincter (IAS) tone. Studies were performed in the rat IAS vs. the non-tonic rectum smooth muscle (RSM). Indomethacin, the dual COX inhibitor, but not nordihydroguaiaretic acid (NDGA) the lipoxygenase (LO) inhibitor, produced precipitous decrease in the IAS tone. However, when added in the background of indomethacin, NDGA caused significant reversal of the IAS tone. These inhibitors had no significant effect on the RSM. To follow the significance of COX vs. LO pathways, we examined the effects of AA and its metabolites. In the IAS, AA caused an increase in the IAS tone (Emax of 38.8 ± 3.0%, pEC50 of 3.4 ± 0.1). In the RSM, AA was significantly less efficacious and potent (Emax = 11.3 ± 3.5%, pEC50 = 2.2 ± 0.3). The AA metabolites (via COXs) prostaglandin F2
and U-46619 (a stable analog of thromboxane A2) produced increases in the IAS tone and force in the RSM. Conversely, AA metabolites (via 5-LO) lipoxin A4, 5-hydroxyeicosatetraenoic acid, and leukotriene C4 decreased the IAS tone. Finally, the contractile effects of AA in the IAS were selectively attenuated by the COX-1 but not COX-2 inhibitor. Collectively, the specific effects of AA and the COX inhibitor, the Western blot and RT-PCR analyses showing specifically higher levels of COX-1, suggest a preferential role of COX (specifically COX-1) pathway vs. the LO in the regulation of the IAS tone.
