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HORMONES AND SIGNALING

Arachidonic acid metabolites follow the preferential course of cyclooxygenase pathway for the basal tone in the internal anal sphincter

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

Submitted 18 December 2008 ; accepted in final form 7 February 2009

Present studies determined the roles of the cyclooxygenase (COX) versus 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 versus the nontonic rectal smooth muscle (RSM). Indomethacin, the dual COX inhibitor, but not nordihydroguaiaretic acid (NDGA), the LO inhibitor, produced a 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 versus LO pathways, we examined the effects of AA and its metabolites. In the IAS, AA caused an increase in the IAS tone (E_max = 38.8 ± 3.0% and pEC₅₀ = 3.4 ± 0.1). In the RSM, AA was significantly less efficacious and potent (E_max = 11.3 ± 3.5% and pEC₅₀ = 2.2 ± 0.3). The AA metabolites (via COXs) PGF₂ 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-HETE, 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 the 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 the COX (specifically COX-1) pathway versus the LO in the regulation of the IAS tone.

smooth muscle tone; thromboxanes; prostaglandin F₂