<b><i>Background/Aims:</i></b> NSAID-induced enteropathy has been the focus of recent basic and clinical research subsequent to the development of the capsule endoscope and double-balloon endoscope. We review the possible pathogenic mechanisms underlying NSAID-induced enteropathy and discuss the role of the inhibition of COX-1/COX-2 and the influences of food as well as various prophylactic treatments on these lesions. <b><i>Methods:</i></b> Studies were performed in experimental animals. <b><i>Results:</i></b> Multiple factors, such as intestinal hypermotility, decreased mucus secretion, enterobacteria, and upregulation of iNOS/NO expression, are involved in the pathogenesis of NSAID-induced enteropathy, in addition to the decreased production of PGs due to the inhibition of COX. Enterobacterial invasion is the most important pathogenic event, and intestinal hypermotility, which was associated with this event, is essential for the development of these lesions. NSAIDs also upregulate the expression of COX-2, and the inhibition of both COX-1 and COX-2 is required for the intestinal ulcerogenic properties of NSAIDs to manifest. NSAID-induced enteropathy is prevented by PGE<sub>2</sub>, atropine, ampicillin, and aminoguanidine as well as soluble dietary fiber, and exacerbated by antisecretory drugs such as proton pump inhibitors. <b><i>Conclusion:</i></b> These findings on the pathogenesis of NSAID-induced enteropathy will be useful for the future development of intestinal-sparing alternatives to standard NSAIDs.
We examined the effects of stress on the indomethacin (IND)-induced gastric antral ulcer formation in refed mice. Male mice underwent refeeding of diet for 2 hours after a fast for 22 hours, followed by IND injection; the lesion index was measured 24 hours later. Mice also underwent a defined diet for 2 hours following a fast for 22 hours, and the stomachs were collected 1.5 hours later. We then measured the volume and the bile acid concentrations of the gastric contents. Mice underwent restraint stress (RS) in a cylindrical plastic tube for 60 minutes, or treatment with corticotropin-releasing factor (CRF), following refeeding of diet for 2 hours. We then examined the effects of RS and CRF on the lesion index, gastric emptying, and duodenogastric bile reflux. The effects of receptor antagonists for CRF2 (astressin-2B), CRF1, 5-hydroxytriptamine 3 (ondansetron), dopamine 2 (haloperidol), and cholecystokinin 1 (lorglumide) on the effects of RS or CRF were examined. IND (10 mg/kg, s.c.) induced pronounced lesions in the antrum. RS and CRF (30 μg/kg, i.p.) increased the severity of the antral lesions accompanied by an increase in gastric volume and concentration of bile acids. These effects of RS and peripheral CRF were significantly inhibited by pretreatment with astressin-2B, ondansetron, haloperidol, and lorglumide, but not by the CRF1 receptor antagonist. This study suggests that RS increases the severity of IND-induced gastric antral ulcers associated with gastroparesis and enhanced bile reflux via activation of peripheral CRF2, 5-hydroxytriptamine 3, and cholecystokinin 1 receptors with central dopamine 2 receptor, but not by CRF1 receptor. SIGNIFICANCE STATEMENT: Restraint stress worsens nonsteroidal anti-inflammatory drugs-induced antral ulcers due to inhibition of gastric motility and increase in bile reflux via activation of peripheral corticotropin-releasing factor 2, 5-hydroxytriptamine 3, and cholecystokinin 1 receptors with central dopamine 2 receptor. Our study predicts that gastroparesis induced by antimotility drugs, stress, functional dyspepsia, Parkinson disease, diabetes mellitus, and other conditions worsens, and gastroprokinetic agents prevent the severity of nonsteroidal anti-inflammatory drugs-induced gastric antral ulcers.
The effect of EM-523 [de(N-methyl)-N-ethyl-8,9-anhydroerythromycin A 6,9-hemiacetal], an erythromycin derivative, on preparations of isolated intestine of rabbits, rats and guinea pigs was investigated and compared to the effects of motilin and prostaglandin F2 alpha (PGF2 alpha). EM-523 and motilin induced contractions in the rabbit intestinal preparations but not in the rat or guinea pig preparations. In contrast, PGF2 alpha induced contractions in all three intestinal preparations. The rabbit duodenum and jejunum were more sensitive than the ileum to EM-523 and motilin, but no selectivity was observed with PGF2 alpha. The contractile responses induced by EM-523 and by motilin were not influenced by pretreatment with tetrodotoxin, atropine, naloxone or mepyramine but were greatly suppressed by pretreatment with verapamil or removal of calcium ions from the medium, suggesting that both agents induce intestinal contractions by acting directly on smooth muscle and that their actions depend largely on extracellular calcium. The contractile response to EM-523 or motilin was reduced markedly after treatment of the preparation with a high concentration of either agent, and cross-tachyphylaxis between EM-523 and motilin was also observed. These findings indicate that the contractile activity of EM-523 is very similar to that of motilin and that EM-523 and motilin may share the same site of action.
The dose of calcineurin inhibitors in renal transplantation has been adjusted, based on the therapeutic drug monitoring data. However, the data do not always correlate with clinical drug efficacy. In vitro response of peripheral-blood mononuclear cells to immunosuppressive drugs is reported to correlate with the recipient-response to therapeutic efficacy of the drug. We report, here, usefulness of a lymphocyte immunosuppressant sensitivity test for the estimation of individual drug sensitivity in renal transplant recipients. The LIST we have developed includes MTT assay procedures without the use of radioisotope-labeled compounds, which is convenient for general hospital use. Utilizing this procedure, we compared the pharmacological efficacy between cyclosporine A and tacrolimus in 41 renal transplant recipients.
To clarify the mechanisms underlying the positive inotropic action of endothelin‐1 (ET‐1), we investigated the effect of ET‐1 on twitch cell shortening and the Ca 2+ transient in rat isolated ventricular myocytes loaded with a fluorescent Ca 2+ indicator indo‐1. There was a cell‐to‐cell heterogeneity in response to ET‐1. ET‐1 (100 n m ) increased twitch cell shortening in only 6 of 14 cells (44 %) and the increase in twitch cell shortening was always accompanied by an increase in the amplitude of the Ca 2+ transient. The ET A ‐ and ET B ‐receptors antagonist TAK‐044 (100 n m ) almost reversed both the ET‐1‐induced increases in twitch cell shortening and in the Ca 2+ transient. In the ET‐1 non‐responding cells, the amplitude of the Ca 2+ transient never increased. Intracellular pH slightly increased (∼0.08 unit) after 30 min perfusion of ET‐1 in rat ventricular myocytes. However, ET‐1 did not change the myofilament responsiveness to Ca 2+ , which was assessed by (1) the relationship between the Ca 2+ transient amplitude and twitch cell shortening, and by (2) the Ca 2+ transient‐cell shortening phase plane diagram during negative staircase. We concluded that there was a cell‐to‐cell heterogeneity in the positive inotropic effect of ET‐1, and that the ET‐receptor‐mediated positive inotropic effect was mainly due to an increase in the Ca 2+ transient amplitude rather than to an increase in myofilament responsiveness to Ca 2+ . British Journal of Pharmacology (1998) 123 , 1343–1350; doi: 10.1038/sj.bjp.0701743
