Su2039 Hydroxy-α-Sanshool Evokes Unique Colonic Migrating Motor Complex in Rat Proximal Colon by Blocking a Two-Pore Domain Potassium Channel, KCNK9, in Myenteric Neurons

to be normal in patients with uncomplicated diverticulosis, but it remains unclear whether this is the case in patients with more severe and/or complicated disease.OBJECTIVE: To test the hypothesis that inhibitory neurotransmission to sigmoid colon CSM is impaired in patients with complicated diverticulitis.METHODS: Standard intracellular recordings were performed from sigmoid colon CSM of patients who underwent sigmoid resection because of complications of diverticulitis (n=4) and compared to control tissue obtained from patients having resection for cancer.Tissue adjacent to recording sites was also examined histologically for muscle layer thickness and density of innervation using SNAP-25 immunohistochemistry. Quantitative analysis of electrophysiological recordings, histology and immunohistochemistry were performed by 'blinded' observers.Statistical significance was determined using t-tests with a p-value of <0.05 considered significant.RESULTS: Resting membrane potential was significantly more depolarized in CSM from diverticulitis patients vs controls (-39.0±0.9 vs -46.0±1.8 mV).In control tissue electrical stimulation (4 pulses, 0.5 ms) produced an inhibitory junction potential (IJP) of 11.0±1.3mV that was markedly inhibited (to 1.5±0.7 mV) by application of the selective P2Y1 receptor antagonist MRS-2500.The magnitude of the IJP was markedly attenuated in diverticulitis patients vs controls (0.7±0.7 vs 11.0±1.3mV).The CSM layer was on average 50% thicker in complicated diverticulitis patients versus controls (2.07 ± 0.65 mm vs 1.39 ± 0.23 mm) and this appeared to be due to muscular hypertrophy, as the average CSM cell number/length of tissue was significantly decreased in diverticulitis (0.84 ± 0.08 cells/100 μm in diverticulitis vs 1.6 ± 0.2 cells/100 μm in controls).Axon density was similar in the two groups (0.23 ± 0.06 axon intersections/CSM cell in controls vs 0.22 ± 0.03 axon intersections/CSM cell in diverticulitis).CONCLUSIONS: Purinergic inhibitory neurotransmission to sigmoid CSM appears markedly impaired in patients with complicated diverticulitis and resting membrane potential is also relatively depolarized.This is associated with hypertrophy of the CSM layer, but no apparent alteration in innervation density.Further studies are required to determine the mechanisms underlying this abnormality and how it may relate to the pathophysiology of diverticular disease.