Muscarinic regulation of pacemaker frequency in murine gastric interstitial cells of Cajal

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Abstract
Peristaltic contractions in the stomach are regulated by the spread of electrical slow waves from the corpus to the pylorus. Gastric slow waves are generated and propagated by the interstitial cells of Cajal (ICC). All regions distal to the dominant pacemaker area in the corpus are capable of generating slow waves, but orderly gastric peristalsis depends upon a frequency gradient in which the corpus pacemaker frequency exceeds the antral frequency. Cholinergic, muscarinic stimulation enhances pacemaker frequency. We investigated this phenomenon using intact murine gastric muscles and cultured ICC. Acetylcholine (ACh) increased the frequency of slow waves in antrum and corpus muscles. The increase was significantly greater in the antrum. ACh and carbachol (CCh) increased the pacemaker currents in cultured ICC. At high doses of CCh, transient pacemaker currents fused into sustained inward currents that persisted for the duration of stimulation. The effects of CCh were blocked by low doses of the M3 receptor antagonist 1‐dimethyl‐4‐diphenylacetoxypiperidinium. Frequency enhancement by CCh was not affected by forskolin, but the phospholipase C inhibitor U‐73122 inhibited both the increase in frequency and the development of tonic inward currents. 2‐Aminoethyldiphenyl borate also blocked the chronotropic responses to CCh. Inhibitors of protein kinase C did not block responses to CCh. These studies show that mice are an excellent model for studying mechanisms that regulate gastric slow‐wave frequency. CCh, apparently via production of inositol 1,4,5‐trisphosphate, accelerates the frequency of pacemaker activity. High concentrations of CCh may block the entrainment of pacemaker currents, resulting in a tonic inward current.

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