Group I secreted PLA2 and arachidonic acid metabolites in the maintenance of cat LES tone

Spontaneous tone of in vitro lower esophageal sphincter (LES) circular muscle is associated with elevated levels of arachidonic acid (AA), PGF(2 alpha), and increased [S-35]guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S) binding to G(q)-, G(i3)-, and G(i1/i2)-like G proteins. Tone and AA levels were reduced by inhibitors of a pancreatic-like (group I) secreted phospholipase A(2) (sPLA(2)), by the cyclooxygenase inhibitor indomethacin, and by the thromboxane A(2) antagonist SQ-29548. In addition, pertussis toxin (PTX) reduced LES tone, confirming a role of PTX-sensitive G proteins in maintenance of LES tone. PGF(2 alpha) contracted LES smooth muscle (strips and cells) and increased [S-35] GTP gamma S binding to G(q) and G(i3) in solubilized LES circular muscle membranes. PGF(2 alpha)-induced contraction of LES permeable muscle cells was inhibited by G(q) and G(i3) but not by G(i1/i2) and G(0) antibodies. The thromboxane A(2) analog U-46619 contracted LES smooth muscle and increased G(q) binding. U-46619-induced contraction was inhibited by G(q) but not by G(i3), G(i1/i2), and G(0) antibodies. LES tone and [S-35] GTP gamma S binding were significantly reduced by indomethacin. We conclude that group I sPLA(2) may mediate "spontaneous" LES tone by producing AA, which is metabolized to PGF(2 alpha) and thromboxane A(2). These AA metabolites activate receptors linked to G(i3) and G(q) to maintain LES contraction.