Generic placeholder image

Current Pharmaceutical Design


ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

Review Article

Roles of Up-Regulated Expression of ASIC3 in Sex Difference of Acid-Induced Duodenal HCO3 - Responses

Author(s): Koji Takeuchi*, Yumi Ohashi and Kikuko Amagase

Volume 26 , Issue 25 , 2020

Page: [3001 - 3009] Pages: 9

DOI: 10.2174/1381612826666200417170319

Price: $65


Although the morbidity of ulcers is statistically higher in males than females, the mechanism of this difference remains unknown. Recent studies show that duodenal HCO3 - response to mucosal acidification is higher in females than males, and this may be a factor responsible for the sex difference in the mucosal protective mechanisms. In this article, we examined the duodenal HCO3 - responses to various stimuli in male and female rats, including estrogen, and reviewed the mechanisms responsible for the sex difference in the acid-induced HCO3 - secretion. Mucosal acidification was performed by exposing the duodenum to 10 mM HCl for 10 min. PGE2 was administered intravenously, while capsaicin was applied topically to the duodenum for 10 min. Tamoxifen was given s.c. 30 min before the acidification. Ovariectomy was performed 2 weeks before the experiments; half of the animals were given estrogen i.m. after the operation. Mucosal acidification increased duodenal HCO3 - secretion in male rats, and this response was inhibited by indomethacin and sensory deafferentation. Although no sex difference was found in HCO3 - responses to PGE2 and capsaicin, the response to acid was significantly greater in female than male rats. The different HCO3 - response to acid disappeared on ovariectomy, and this effect was totally reversed by the repeated administration of estrogen. The gene expression of ASIC3 in female rats was greater than in male rats and down-regulated by ovariectomy or tamoxifen treatment in an estradiol- dependent manner, while no sex difference was observed in TRPV1 and CFTR expressions. In conclusion, the acid-induced HCO3 - response is greater in female than male rats, and this phenomenon is not due to changes in PGE2 sensitivity or TRPV1/CFTR expressions but may be accounted for by increased expression of ASIC3 on sensory neurons, which is associated with the chronic influence of estrogen.

Keywords: Duodenal HCO3 - secretion, sex difference, mucosal acidification, estrogen, capsaicin-sensitive afferent neuron, ASIC3, rat.

Flemstrom G, Garner A. Gastroduodenal HCO3(-) transport: characteristics and proposed role in acidity regulation and mucosal protection. Am J Physiol 1982; 242(3): G183-93.
[PMID: 7039351]
Allen A, Flemström G, Garner A, Kivilaakso E. Gastroduodenal mucosal protection. Physiol Rev 1993; 73(4): 823-57.
[] [PMID: 8415927]
Takeuchi K, Okabe S. Gastroduodenal bicarbonate secretion: pharmacological modulation and contribution to mucosal protection Regulatory Mechanisms in Gastrointestinal Function. Boca Raton, FL: CRC 1995; pp. 1-26.
Takeuchi K, Magee D, Critchlow J, Matthews J, Silen W. Studies of the pH gradient and thickness of frog gastric mucus gel. Gastroenterology 1983; 84(2): 331-40.
[] [PMID: 6600224]
Bridén S, Flemström G, Kivilaakso E. Cysteamine and propionitrile inhibit the rise of duodenal mucosal alkaline secretion in response to luminal acid in rats. Gastroenterology 1985; 88(1 Pt 2): 295-302.
[] [PMID: 2981082]
Takeuchi K, Furukawa O, Tanaka H, Okabe S. A new model of duodenal ulcers induced in rats by indomethacin plus histamine. Gastroenterology 1986; 90(3): 636-45.
[] [PMID: 3943695]
Takeuchi K, Furukawa O, Okada M, Okabe S. Duodenal ulcers induced by indomethacin plus histamine in the dog. Involvement of the impaired duodenal alkaline secretion in their pathogenesis. Digestion 1988; 39(4): 230-40.
[] [PMID: 3220176]
Takeuchi K, Yagi K, Kato S, Ukawa H. Roles of prostaglandin E-receptor subtypes in gastric and duodenal bicarbonate secretion in rats. Gastroenterology 1997; 113(5): 1553-9.
[] [PMID: 9352857]
Sugamoto S, Kawauch S, Furukawa O, Mimaki TH, Takeuchi K. Role of endogenous nitric oxide and prostaglandin in duodenal bicarbonate response induced by mucosal acidification in rats. Dig Dis Sci 2001; 46(6): 1208-16.
[] [PMID: 11414296]
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 1991; 101(4): 954-61.
[] [PMID: 1889720]
Takeuchi K, Ueshima K, Matsumoto J, Okabe S. Role of capsaicin-sensitive sensory nerves in acid-induced bicarbonate secretion in rat stomach. Dig Dis Sci 1992; 37(5): 737-43.
[] [PMID: 1563317]
Takeuchi K, Kita K, Hayashi S, Aihara E. Regulatory mechanism of duodenal bicarbonate secretion: Roles of endogenous prostaglandins and nitric oxide. Pharmacol Ther 2011; 130(1): 59-70.
[] [PMID: 21185865]
Furukawa O, Kitamura M, Sugamoto S, Takeuchi K. Stimulatory effect of nitric oxide on bicarbonate secretion in bullfrog duodenums in vitro. Digestion 1999; 60(4): 324-31.
[] [PMID: 10394026]
Furukawa O, Kawauchi S, Mimaki H, Takeuchi K. Stimulation by nitric oxide of HCO3- secretion in bullfrog duodenum in vitro-roles of cyclooxygenase-1 and prostaglandins. Med Sci Monit 2000; 6(3): 454-9.
[PMID: 11208353]
Takeuchi K, Ukawa H, Kato S, et al. Impaired duodenal bicarbonate secretion and mucosal integrity in mice lacking prostaglandin E-receptor subtype EP(3). Gastroenterology 1999; 117(5): 1128-35.
[] [PMID: 10535876]
Takeuchi K, Ukawa H, Furukawa O, et al. Prostaglandin EP receptor subtypes involved in gastroduodenal bicarbonate secretion. J Physiol Pharmacol 1999; 50: 155-68.
[PMID: 10424714]
Aoi M, Aihara E, Nakashima M, Takeuchi K. Participation of prostaglandin E receptor EP4 subtype in duodenal bicarbonate secretion in rats. Am J Physiol Gastrointest Liver Physiol 2004; 287(1): G96-G103.
[] [PMID: 15194560]
Aihara E, Nomura Y, Sasaki Y, Ise F, Kita K, Takeuchi K. Involvement of prostaglandin E receptor EP3 subtype in duodenal bicarbonate secretion in rats. Life Sci 2007; 80(26): 2446-53.
[] [PMID: 17512019]
Takeuchi K, Kagawa S, Mimaki H, Kawauchi S. COX and NOS isozymes involved in duodenal bicarbonate response induced by mucosal acidification in rats. Dig Dis Sci 2002; 47: 2116-24.
[] [PMID: 12353866]
Takeuchi K, Kato S, Takeeda M, Ogawa Y, Nakashima M, Matsumoto M. Facilitation by endogenous prostaglandins of capsaicin-induced gastric protection in rodents through EP2 and IP receptors. J Pharmacol Exp Ther 2003; 304(3): 1055-62.
[] [PMID: 12604682]
Takeuchi K, Matsumoto J, Ueshima K, Ohuchi T, Okabe S. Induction of duodenal ulcers in sensory deafferented rats following histamine infusion. Digestion 1992; 51(4): 203-10.
[] [PMID: 1397737]
Kagawa S, Aoi M, Kubo Y, Kotani T, Takeuchi K. Stimulation by capsaicin of duodenal HCO3(-) secretion via afferent neurons and vanilloid receptors in rats: comparison with acid-induced HCO3(-) response. Dig Dis Sci 2003; 48(9): 1850-6.
[] [PMID: 14561013]
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 1997; 389(6653): 816-24.
[] [PMID: 9349813]
Szallasi A, Blumberg PM. Vanilloid (Capsaicin) receptors and mechanisms. Pharmacol Rev 1999; 51(2): 159-212.
[PMID: 10353985]
Gunthorpe MJ, Benham CD, Randall A, Davis JB. The diversity in the vanilloid (TRPV) receptor family of ion channels. Trends Pharmacol Sci 2002; 23(4): 183-91.
[] [PMID: 11931994]
Akiba Y, Guth PH, Engel E, Nastaskin I, Kaunitz JD. Acid-sensing pathways of rat duodenum. Am J Physiol 1999; 277(2): G268-74.
[PMID: 10444439]
Krishtal O. The ASICs: signaling molecules? Modulators? Trends Neurosci 2003; 26(9): 477-83.
[] [PMID: 12948658]
Chen CC, England S, Akopian AN, Wood JN. A sensory neuron-specific, proton-gated ion channel. Proc Natl Acad Sci USA 1998; 95: 10240-5.
[] [PMID: 9707631]
Waldmann R, Bassilana F, de Weille J, Champigny G, Heurteaux C, Lazdunski M. Molecular cloning of a non-inactivating proton-gated Na+ channel specific for sensory neurons. J Biol Chem 1997; 272(34): 20975-8.
[] [PMID: 9261094]
Deval E, Noël J, Lay N, et al. ASIC3, a sensor of acidic and primary inflammatory pain. EMBO J 2008; 27(22): 3047-55.
[] [PMID: 18923424]
Smith A, Contreras C, Ko KH, et al. Gender-specific protection of estrogen against gastric acid-induced duodenal injury: stimulation of duodenal mucosal bicarbonate secretion. Endocrinology 2008; 149(9): 4554-66.
[] [PMID: 18499763]
Tuo B, Wen G, Wei J, et al. Estrogen regulation of duodenal bicarbonate secretion and sex-specific protection of human duodenum. Gastroenterology 2011; 141(3): 854-63.
[] [PMID: 21699784]
Tuo B, Wen G, Wang X, et al. Estrogen potentiates prostaglandin E-stimulated duodenal mucosal HCO3− secretion in mice. Am J Physiol Endocrinol Metab 2012; 303(1): E111-21.
[] [PMID: 22535744]
Jin H, Wen G, Deng S, et al. Oestrogen upregulates the expression levels and functional activities of duodenal mucosal CFTR and SLC26A6. Exp Physiol 2016; 101(11): 1371-82.
[] [PMID: 27615377]
Takeuchi K, Ohashi Y, Kohmoto M, Oka H, Nomura Y, Aihara E. Gender difference in duodenal HCO3- response to mucosal acidification: Importance of up-regulation of ASIC3 by estradiol. Gastroenterology 2012; 142: S202-3.
Holzer P, Sametz W. Gastric mucosal protection against ulcerogenic factors in the rat mediated by capsaicin-sensitive afferent neurons. Gastroenterology 1986; 91(4): 975-81.
[] [PMID: 3527854]
Rosenstock SJ, Jørgensen T. Prevalence and incidence of peptic ulcer disease in a Danish County-a prospective cohort study. Gut 1995; 36(6): 819-24.
[] [PMID: 7615266]
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 Monit 2002; 8(5): BR157-63.
[PMID: 12011761]
McIntyre P, McLatchie LM, Chambers A, et al. Pharmacological differences between the human and rat vanilloid receptor 1 (VR1). Br J Pharmacol 2001; 132(5): 1084-94.
[] [PMID: 11226139]
Lingueglia E. Acid-sensing ion channels in sensory perception. J Biol Chem 2007; 282(24): 17325-9.
[] [PMID: 17430882]
Kaunitz JD, Akiba Y. Review article: duodenal bicarbonate - mucosal protection, luminal chemosensing and acid-base balance. Aliment Pharmacol Ther 2006; 24(Suppl. 4): 169-76.
[] [PMID: 17209861]
Dong X, Ko KH, Chow J, Tuo B, Barrett KE, Dong H. Expression of acid-sensing ion channels in intestinal epithelial cells and their role in the regulation of duodenal mucosal bicarbonate secretion. Acta Physiol (Oxf) 2011; 201(1): 97-107.
[] [PMID: 20969730]
Seidler U, Blumenstein I, Kretz A, et al. A functional CFTR protein is required for mouse intestinal cAMP-, cGMP- and Ca(2+)-dependent HCO3- secretion. J Physiol 1997; 505(Pt. 2): 411-23.
[] [PMID: 9423183]
Burnes LA, Kolker SJ, Danielson JF, Walder RY, Sluka KA. Enhanced muscle fatigue occurs in male but not female ASIC3-/- mice. Am J Physiol Regul Integr Comp Physiol 2008; 294(4): R1347-55.
[] [PMID: 18305024]
Staniland AA, McMahon SB. Mice lacking acid-sensing ion channels (ASIC) 1 or 2, but not ASIC3, show increased pain behaviour in the formalin test. Eur J Pain 2009; 13(6): 554-63.
[] [PMID: 18801682]

Rights & Permissions Print Export Cite as
© 2022 Bentham Science Publishers | Privacy Policy