Abstract
Lafutidine is a new type of antiulcer drug, possessing both an antisecretory effect, exerted via a blockade of the histamine H2 receptor, and gastroprotective activity, mediated by capsaicin-sensitive afferent nerves (CSN). In the present study, we examined the effect of lafutidine on gastric mucosal blood flow (GMBF) and duodenal HCO3 − secretion (DAS) under basal and acid-stimulated conditions in rats. Under urethane anesthesia, GMBF was measured using a laser Doppler flowmeter in a chambered stomach before and after exposure to 20 mM taurocholate (TC) plus 50 mM HCl, while DAS was measured in a proximal duodenal loop before and after mucosal acidification (10 mM HCl for 10 min) by titrating the perfusate at pH 7.0 using a pH-stat method and by adding 10 mM HCl. Lafutidine given intraperitoneally affected neither GMBF nor DAS under basal conditions, but augmented an increase in both GMBF and DAS induced by mucosal acidification. Although the acid-induced GMBF and DAS responses were significantly mitigated by both indomethacin and sensory deafferentation but not by ruthenium red (RT), the vanilloid receptor (VR)-1 antagonist, the responses were preserved in lafutidine-treated animals, even in the presence of indomethacin. Both GMBF and DAS were significantly increased by local application of capsaicin, the responses being attenuated by indomethacin and RT as well as sensory deafferentation. Lafutidine augmented the GMBF and DAS responses to capsaicin and preserved the responses, even in the presence of indomethacin. Capsaicin evoked an increase in [Ca2+]i in rat VR1-transfected HEK293 cells, while lafutidine had no effect by itself on [Ca2+]i in these cells and did not affect the increase in [Ca2+]i evoked by capsaicin. In conclusion, these results suggest that lafutidine mimics endogenous effects of prostaglandins to augment the GMBF and DAS responses to acid or capsaicin, probably by sensitizing CSN through an unknown site other than VR1. The luminal H+ itself is not a ligand for the RT-sensitive site of VR1 but plays a modulator role in the CSN-mediated physiological responses.
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REFERENCES
Holzer P. Capsaicin: Cellular targets, mechanisms of action, and selectivity for thin sensory neurons. Pharmacol Rev 43:143–195, 1991
Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D: The capsaicin receptor; a heat-activated ion channel in the pain pathway. Nature 389:816–824, 1997
Szallasi A, Blumbergm PM: Vanilloid (capsaicin) receptors and mechanisms. Pharmacol Rev 51:159–211, 1999
Nozawa Y, Nishihara K, Yamamoto A, Nakano M, Ajioka H, Matsuura N: Distribution and characterization of vanilloid receptors in the rat stomach. Neurosci Lett 309:33–36, 2001
Shibata M, Yamamura T, Inaba N, Onodera S, Chida Y, Ohnishi H: Gastric antisecretory effect of FRG-8813, a new histamine H2 receptor antagonist, in rats and dogs. Eur J Pharmacol 235:243–253, 1993
Onodera S, Shibata M, Tanaka M, Inaba N, Yamaura T, Ohnishi H: Gastroprotective activity of FRG-8813, a novel histamine H2-receptor antagonist, in rats. Jpn J Pharmacol 68:161–173, 1995
Kato S, Tanaka A, Kunikata T, Umeda M, Takeuchi K: Protective effect of lafutidine against indomethacin-induced intestinal ulceration in rats: relation to capsaicin-sensitive sensory neurons. Digestion 61:39–46, 2000
Umeda M, Nishiwaki H, Fujita A, Araki H, Takeuchi K. Effect of lafutidine, a novel histamine H2-receptor antagonist, on monochloramine-induced gastric lesions in rats: role of capsaicin-sensitive sensory neurons. J Gastroenterol Hepatol 14:859–865, 1999
Heylings JR, Garner A, Flemstrm G: Regulation of gastroduodenal HCO -3 transport by luminal acid in the frog in vitro. Am J Physiol 246:G235–G240, 1984
Takeuchi K, Tanaka H, Furukawa O, Okabe S: Gastroduodenal HCO -3 secretion in anesthetized rats: Effects of 16, 16-dimethyl PGE2, topical acid and acetazolamide. Jpn J Pharmacol 41:87–100, 1986
Holzer P, Livingston EH, Guth PH: Sensory neurons signal for an increase in rat gastric mucosal blood flow in the face of pending acid injury. Gastroenterology 101:416–423, 1991
Takeuchi K, Matsumoto J, Ueshima K, Okabe S: Role of capsaicin-sensitive afferent neurons in alkaline secretory response to luminal acid in the rat duodenum. Gastroenterology 101:954–961, 1991
Holzer P, Sametz W: Gastric mucosal protection against ulcerogenic factors in the rat mediated by capsaicin-sensitive afferent neurons. Gastroenterology 91:975–981, 1986
Takeuchi K, Niida H, Matsumoto J, Ueshima K, Okabe S: Gastric motility changes in capsaicin-induced cytoprotection in the rat stomach. Jpn J Pharmacol 55:147–155, 1991
Yamamoto H, Horie S, Uchida M, Tsuchiya S, Murayama T, Watanabe K: Effects of vanilloid receptor agonists and antagonists on gastric antral ulcers in rats. Eur J Pharmacol 432:203–210, 2001
Matsumoto J, Takeuchi K, Ueshima K, Okabe S: Role of capsaicin-sensitive afferent neurons in mucosal blood flow response of rat stomach induced by mild irritants. Dig Dis Sci 37:1336–1344, 1992
Tsutumi S, Tomioka A, Sudo M, Nakamura A, Shirakura K, Takagishi K, Kohama K: Propofol activates vanilloid receptor channels expressed in human embryonic kidney 293 cells. Neurosci Lett 312:45–49, 2001
Holzer P, Livingston EH, Saria A, Guth PH: Sensory neurons mediate protective vasodilatation in rat gastric mucosa. Am J Physiol 260:G363–G370, 1991
Takeuchi, K, Okabe S: Gastroduodenal bicarbonate secretion: Pharmacological regulation and contribution to mucosal protection. In Regulatory Mechanisms in Gastrointestinal Function. TS Gaginella (ed). CRC Press, Boca Raton, Florida, 1995, pp. 1–26
Hirata T, Ukawa H, Yamakuni H, Kato S, Takeuchi K: Cyclooxygenase isozymes in acute mucosal ulcerogenic and functional responses following barrier disruption in rat stomachs. Br J Pharmacol 122:447–454, 1997
Takeuchi K, Ohuchi T, Narita M, Okabe S: Capsaicin-sensitive sensory nerves in recovery of gastric mucosal integrity after damage by sodium taurocholate in rats. Jpn J Pharmacol 63:479–485, 1993
Tashima K, Korolkiewicz R, Kubomi M, Takeuchi K: Increased susceptibility of gastric mucosa to ulcerogenic stimulation in diabetic rats: role of capsaicin-sensitive sensory neurons. Br J Pharmacol 124:1395–1402, 1998
Tashima K, Nakashima M, Kagawa S, Kato S, Takeuchi K: Gastric hyperemic response induced by acid back-diffusion in rat stomachs following barrier disruption: relation to vanilloid type-1 receptors. Med Sci Monitor (in press)
Takeuchi K, Kato S, Ogawa Y, Komoike Y, Takeeda M, Matsumoto M: Facilitation by endogenous prostaglandins of capsaicin-induced cytoprotection in rat stomachs: involvement of EP2 and IP receptors. Br J Pharmacol (in press)
Boku K, Ohno T, Saeki T, Hayashi H, Hayashi I, Katori M, Murata T, Narumiya S, Saigenji K, Majima M: Adaptive cytoprotection mediated by prostaglandin I2 is attributable to sensitization of CRGP-containing sensory nerves. Gastroenterology 120:134–143, 2001
Sterinini C, Reeve JR, Brecha N: Distribution and characterization of calcitonin gene-related peptide immunoreactivity in the digestive system of normal and capsaicin-treated rats. Gastroenterology 93:852–862, 1987
Akiba Y, Guth PH, Engel E, Nastaskin I, Kaunitz JD: Acidsensing pathways of rat duodenum. Am J Physiol 277:G268–G274, 1999
Mclntyre P, McLatchie LM, Chambers A, Phillips E, Clarke M, Savidge J, Toms C, Peacock M, Shah K, Winter J, Weerasakera N, Webb M, Rang HP, Bevan S, Fames IF: Pharmacological differences between the human and rat vanilloid receptor 1 (VR1). Br J Pharmacol 132:1084–1094, 2001
Nishihara K, Nozawa Y, Nakano M, Ajioka H, Matsuura N: Sensitizing effects of lafutidine on CGRP-containing afferent nerves in the rat stomach. Br J Pharmacol 135:1487–1494, 2002
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Mimaki, H., Kagawa, S., Aoi, M. et al. Effect of Lafutidine, a Histamine H2-Receptor Antagonist, on Gastric Mucosal Blood Flow and Duodenal HCO3 − Secretion in Rats: Relation to Capsaicin-Sensitive Afferent Neurons. Dig Dis Sci 47, 2696–2703 (2002). https://doi.org/10.1023/A:1021021625569
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DOI: https://doi.org/10.1023/A:1021021625569