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Regulation of pacemaker frequency in the murine gastric antrum

Tae Wan Kim, Elizabeth A. H. Beckett, Rhonda Hanna, Sang Don Koh, Tamás Ördög, Sean M. Ward and Kenton M. Sanders

PGE₂ has been linked to the production of gastric arrhythmias such as tachygastria. The interstitial cells of Cajal (ICC) generate electrical rhythmicity in gastrointestinal muscles, and may therefore be a target for PGE₂ in gastric muscles. We cultured ICC from the murine gastric antrum, verified that cells were Kit immunoreactive, and measured spontaneous slow waves. These events were caused by spontaneous inward (pacemaker) currents that were not blocked by nifedipine. Forskolin and 8-bromoadenosine 3':5'-cyclic monophosphate (8-Br-cAMP) reduced the frequency of pacemaker currents in ICC and of slow waves in intact antral muscles. The effects of forskolin and 8-Br-cAMP were not blocked by inhibitors of protein kinase A, suggesting that cAMP has direct effects on pacemaker activity. PGE₂ mimicked the effects of forskolin and 8-Br-cAMP on ICC, but increased slow-wave frequency in intact muscles. Therefore, the chronotropic effects of specific prostaglandin EP receptor agonists were examined. Butaprost and ONO-AE1-329, EP₂ and EP₄ receptor agonists, mimicked the effects of forskolin and 8-Br-cAMP on ICC and intact muscles. Sulprostone (EP₃>EP₁ agonist), GR63799, and ONO-AE-248 (EP₃ agonists) enhanced the frequencies of pacemaker currents in ICC and slow waves in intact muscles. The effects of sulprostone were not blocked by SC-19220, an EP₁ receptor antagonist. These observations suggest that the positive chronotropic effects of PGE₂ in intact muscles are mediated by EP₃ receptor stimulation. The effects of PGE₂ in intact muscles may be dependent upon the relative expression of EP receptors and/or proximity of receptors to sources of PGE₂.

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