Review article: a critical view on impaired accommodation as therapeutic target for functional dyspepsia
ABSTRACT Several important pathophysiological mechanisms have been identified in functional dyspepsia, however a complete understanding of these mechanisms and beneficial therapeutic strategies are still lacking. Based on the currently available literature we aimed at providing a critical view on one of these pathophysiological mechanisms, impaired accommodation. Although impaired gastric accommodation is identified as a major pathophysiological mechanism, the clinical evidence supporting its role as an important therapeutic target is currently still lacking. Treatment with fundic relaxant drugs has shown conflicting results and has been rather disappointing in general. These negative findings could be explained by the fact that impaired fundic accommodation is part of a more complex disorder involving other regions of the proximal gut or by the increasing insight that central mechanisms may play an important role. Future studies of impaired accommodation should take these considerations into account.
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- "In smooth muscle cells, NO or NO donors increase cGMP levels, resulting in the activation of several downstream signalling cascades which ultimately result in Ca 2+ removal from the myoplasm, membrane hyperpolarization and relaxation (Petkov & Boev, 1996; Cohen et al. 1999; Yu et al. 2003). In gastric motility disorders where enteric neuropathies are implicated, such as impaired gastric accommodation, directly targeting smooth muscle cGMP levels with NO donors or phosphodiesterase inhibitors improves symptoms and gastric smooth muscle function (Tack et al. 2002; Sarnelli et al. 2004; van den Elzen & Boeckxstaens, 2006). We previously reported that SNP increased cGMP-dependent PLB phosphorylation, and relaxed murine gastric fundus and antrum smooth muscles (Kim et al. 2006; Kim & Perrino, 2007). "
ABSTRACT: We investigated intracellular Ca(2+) waves, spontaneous transient outward currents (STOCs), and membrane potentials of gastric antrum smooth muscle cells from wild-type and phospholamban-knockout mice. The NO donor sodium nitroprusside (SNP) increased intracellular Ca(2+) wave activity in wild-type antrum smooth muscle cells, but had no effect on the constitutively elevated intracellular Ca(2+) wave activity of phospholamban-knockout cells. STOC activity was also constitutively elevated in phospholamban-knockout antrum smooth muscle cells relative to wild-type cells. SNP or 8-bromo-cGMP increased the STOC activity of wild-type antrum smooth muscle cells, but had no effect on STOC activity of phospholamban-knockout cells. Iberiotoxin, but not apamin, inhibited STOC activity in wild-type and phospholamban-knockout antrum smooth muscle cells. In the presence of SNP, STOC activity in wild-type and phospholamban-knockout antrum smooth muscle cells was inhibited by ryanodine, but not 2-APB. The cGMP-dependent protein kinase inhibitor KT5823 reversed the increase in STOC activity evoked by SNP in wild-type antrum smooth muscle cells, but had no effect on STOC activity in phospholamban-knockout cells. The resting membrane potential of phospholamban-knockout antrum smooth muscle cells was hyperpolarized by approximately -6 mV compared to wild-type cells. SNP hyperpolarized the resting membrane potential of wild-type antrum smooth muscle cells to a greater extent than phospholamban-knockout antrum smooth muscles. Despite the hyperpolarized membrane potential, slow wave activity was significantly increased in phospholamban-knockout antrum smooth muscles compared to wild-type smooth muscles. These results suggest that phospholamban is an important component of the mechanisms regulating the electrical properties of gastric antrum smooth muscles.The Journal of Physiology 09/2008; 586(Pt 20):4977-91. DOI:10.1113/jphysiol.2008.156836 · 4.54 Impact Factor
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ABSTRACT: In a randomized, placebo-controlled crossover design we studied the effect of gastric acidification on motilin-induced interdigestive antropyloroduodenal motility. Ten healthy volunteers participated in the study consisting of four experiments. Each experiment started after a spontaneous occurring phase III and consisted of intragastric infusion of either saline or acid (0.08 mol L(-1) HCl) for 90 min and intravenous infusion of either saline or motilin (4 pmol kg(-1) min(-1)) for 30 min. Antropyloroduodenal motility and pH were recorded continuously for 240 min. Reoccurrence of phase III was significantly (P < 0.05) earlier during intragastric saline-intravenous motilin infusion compared with control (intragastric saline-intravenous saline), 52 min (range 25-79) and 113 min (84-141) respectively. This effect was completely abolished during intragastric acid-intravenous motilin infusion, 112 min (82-142). The percentage of phase III of antral origin was significantly (P < 0.05) higher during intragastric saline-intravenous motilin infusion (90%) compared with control (30%). The mean area under the contraction (AUC) for phase II was significantly (P < 0.05) lower during intragastric saline-intravenous motilin infusion and intragastric acid-intravenous saline infusion compared with control. It is concluded that in humans intragastric acidification inhibits the effect of motilin on antroduodenal motility, decreases the AUC of antral phase II contractions and delays the occurrence of phase III of the migrating motor complex.Neurogastroenterology and Motility 08/2006; 18(8):637-46. DOI:10.1111/j.1365-2982.2006.00797.x · 3.42 Impact Factor
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ABSTRACT: Itopride, a dopamine D2 antagonist and acetylcholinesterase inhibitor, significantly improved symptoms in patients with functional dyspepsia in one phase II randomized trial. However, the mechanisms by which itopride may improve symptoms are unknown. We aimed to compare the effects of two doses of itopride and placebo on gastric volumes, gastric emptying, small bowel transit and satiation in female and male healthy volunteers. Randomized, double-blind, placebo-controlled study evaluated gastric function before and after 7 days of itopride 100 mg (n = 16) or 200 mg (n = 15) or placebo (n = 15) t.i.d. Validated methods were used to study gastric accommodation (single photon emission computed tomography), gastric emptying and orocecal transit and satiation postnutrient challenge. The three arms were comparable with regard to age, gender and body mass index. There were no statistically significant effects of itopride on gastric emptying, orocecal transit, fasting gastric volume, maximum tolerated volume or aggregate symptom score with nutrient drink challenge. Postprandial (PP) change in gastric volume differed in the three groups (P = 0.019): 625[+/-28 (SEM)], 555(+/-26) and 512(+/-33) in placebo, itopride 100 and 200 mg groups, respectively. In healthy subjects, itopride reduced total PP gastric volume without accelerating gastric emptying or significantly altering gastric motor and sensory function in healthy individuals.Neurogastroenterology and Motility 04/2007; 19(3):180-7. DOI:10.1111/j.1365-2982.2006.00869.x · 3.42 Impact Factor