P085. Direct smooth muscle stimulatory effect of nitrergic inhibition by L-NMMA on the migrating motor complex modulated by muscarinic and 5-HT3 receptor blockade
M.A. Halim1, S. Boghos1, L. Gillberg1, U. Karlbom2, M. Sundbom2, D.-L. Webb1, P.M. Hellström1, 1Uppsala University, Medical sciences, gastroenterology & hepatology, Uppsala, Sweden, 2Uppsala University, Surgical sciences, surgery, Uppsala, Sweden
Nitric oxide (NO) is elaborated in huge amounts in acute illness and exacerbations of inflammatory bowel disease. NO acts as an inhibitory neurotransmitter by relaxation of smooth muscle cells and suggested to be of major importance in toxic megacolon in ulcerative colitis. The migrating motor complex (MMC) is a cyclic motility pattern aiding absorption of nutrients and propulsion of intestinal contents. When MMC is dysregulated, it constitutes a cornerstone in the diagnosis of enteric dysmotility, which can cause small intestinal bacterial overgrowth. Little is known on how NO works in conjunction with other neurotransmitters to regulate the motor activity of the MMC.
Twenty-one healthy volunteers (22–38 years) underwent antroduodenojejunal manometry for 4h after a bolus injection of saline or the NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA, 10 mg/kg IV) with or without atropine (1 mg) or ondansetron (8 mg). Effects on the MMC pattern and the subsequent MMC were determined. Exhaled and rectal NO were monitored throughout experiments. Peptide hormones ghrelin, motilin and somatostatin with known effects on the MMC were measured. In vitro studies were done on human small bowel muscle strips with bethanechol (10−5M) in the presence of L-NMMA (10−4M) and tetrodotoxin (TTX, 10−6M).
L-NMMA elicited pre-mature duodeno-jejunal phase III in all subjects but one, irrespective of atropine or ondansetron. L-NMMA also shortened the MMC cycle length and shifted motility towards phase II with strong suppression of phase I of the subsequent MMC. This effect was not seen after pretreatment with atropine or ondansetron. Instead, atropine extended phase II activity of the MMC, whereas ondansetron had no effect. After administration of L-NMMA no increase of gut hormones was found. L-NMMA reduced exhaled NO levels in all subjects, while 12 of 17 had reduced rectal NO. Systemic blood pressure was consistently elevated for 2 hours after L-NMMA. In vitro, L-NMMA enhanced bethanechol-induced contractions that were insensitive to TTX.
NO exerts an inhibitory action on the MMC by suppressing the phase III activity independently of muscarinic and 5-HT3 receptor blockade. Furthermore, the motility intensity over the different phases of the MMC seems to be under influence of NO. Phase I of the MMC seems strongly dependent on NO, being counter-regulated by cholinergic and serotonergic mechanisms, whereas phase II is dependent on atropine-sensitive mechanisms for transition into the next phase III of MMC. The sensitization of motility by inhibition of NO is due to a direct effect on the smooth muscle cells, as neither gut peptide hormone release, nor neuronal mechanisms are related to the increased motor activity.
- Posted in: Poster presentations: Basic Science (2014)