TCS 2510

Role of prostaglandins in spinal transmission of the exercise pressor reflex in decerebrated rats.[Pubmed:25003710]

Neuroscience. 2014 Sep 26;277:26-35.

Previous studies found that prostaglandins in skeletal muscle play a role in evoking the exercise pressor reflex; however the role played by prostaglandins in the spinal transmission of the reflex is not known. We determined, therefore, whether or not spinal blockade of cyclooxygenase (COX) activity and/or spinal blockade of endoperoxide (EP) 2 or 4 receptors attenuated the exercise pressor reflex in decerebrated rats. We first established that intrathecal doses of a non-specific COX inhibitor Ketorolac (100 mug in 10 mul), a COX-2-specific inhibitor Celecoxib (100 mug in 10 mul), an EP2 antagonist PF-04418948 (10 mug in 10 mul), and an EP4 antagonist L-161,982 (4 mug in 10 mul) effectively attenuated the pressor responses to intrathecal injections of arachidonic acid (100 mug in 10 mul), EP2 agonist Butaprost (4 ng in 10 mul), and EP4 agonist TCS 2510 (6.25 mug in 2.5 mul), respectively. Once effective doses were established, we statically contracted the hind limb before and after intrathecal injections of Ketorolac, Celecoxib, the EP2 antagonist and the EP4 antagonist. We found that Ketorolac significantly attenuated the pressor response to static contraction (before Ketorolac: 23 +/- 5 mmHg, after Ketorolac 14 +/- 5 mmHg; p<0.05) whereas Celecoxib had no effect. We also found that 8 mug of L-161,982, but not 4 mug of L-161,982, significantly attenuated the pressor response to static contraction (before L-161,982: 21 +/- 4 mmHg, after L-161,982 12 +/- 3 mmHg; p<0.05), whereas PF-04418948 (10 mug) had no effect. We conclude that spinal COX-1, but not COX-2, plays a role in evoking the exercise pressor reflex, and that the spinal prostaglandins produced by this enzyme are most likely activating spinal EP4 receptors, but not EP2 receptors.

Prostaglandin E(2) mediates proliferation and chloride secretion in ADPKD cystic renal epithelia.[Pubmed:22933297]

Am J Physiol Renal Physiol. 2012 Nov 15;303(10):F1425-34.

Prostaglandin E(2) (PGE(2)) contributes to cystogenesis in genetically nonorthologous models of autosomal dominant polycystic kidney disease (ADPKD). However, it remains unknown whether PGE(2) induces the classic features of cystic epithelia in genetically orthologous models of ADPKD. We hypothesized that, in ADPKD epithelia, PGE(2) induces proliferation and chloride (Cl(-)) secretion, two archetypal phenotypic features of ADPKD. To test this hypothesis, proliferation and Cl(-) secretion were measured in renal epithelial cells deficient in polycystin-1 (PC-1). PC-1-deficient cells increased in cell number (proliferated) faster than PC-1-replete cells, and this proliferative advantage was abrogated by cyclooxygenase inhibition, indicating a role for PGE(2) in cell proliferation. Exogenous administration of PGE(2) increased proliferation of PC-1-deficient cells by 38.8 +/- 5.2% (P < 0.05) but inhibited the growth of PC-1-replete control cells by 49.4 +/- 1.9% (P < 0.05). Next, we tested whether PGE(2)-specific E prostanoid (EP) receptor agonists induce intracellular cAMP and downstream beta-catenin activation. PGE(2) and EP4 receptor agonism (TCS 2510) increased intracellular cAMP concentration and the abundance of active beta-catenin in PC-1-deficient cells, suggesting a mechanism for PGE(2)-mediated proliferation. Consistent with this hypothesis, antagonizing EP4 receptors reverted the growth advantage of PC-1-deficient cells, implicating a central role for the EP4 receptor in proliferation. To test whether PGE(2)-dependent Cl(-) secretion is also enhanced in PC-1-deficient cells, we used an Ussing chamber to measure short-circuit current (I(sc)). Addition of PGE(2) induced a fivefold higher increase in I(sc) in PC-1-deficient cells compared with PC-1-replete cells. This PGE(2)-induced increase in I(sc) in PC-1-deficient cells was blocked by CFTR-172 and flufenamic acid, indicating that PGE(2) activates CFTR and calcium-activated Cl(-) channels. In conclusion, PGE(2) activates aberrant signaling pathways in PC-1-deficient epithelia that contribute to the proliferative and secretory phenotype characteristic of ADPKD and suggests a therapeutic role for PGE(2) inhibition and EP4 receptor antagonism.