Abstract
Prolonged exposure to gastric acid is a leading cause of gastroesophageal reflux disease (GERD) and esophagitis. With the ever increasing number of patients showing insensitivity to proton-pump-inhibitor (PPI) therapy with recurrence of symptoms over time, alternative treatment options remain an important issue. Previous studies from our laboratory have shown that a zinc sulfate salt can inhibit HCl generation at the cellular level of the parietal cell. In this paper, we examine the difference between two hydration forms of ZnSO4 (monohydrate H2O and heptahydrate 7H2O) in their entry characteristics into the parietal cell under several physiological conditions associated with acid secretion. Using the Zn sensitive fluorochrome Newport Green, we examined the rate of Zn entry in Δfluorescent units/second (ΔFU/second), at two different concentrations for both hydration states on both fasted and non-fasted animals. In a separate series of studies, we examined the effects of secretagogues on the entry rates and transport mechanisms. Exposure of the secretagogue carbachol transformed the resting parietal cell to an activated state and represents a stimulated condition through the neuronal pathway. The hormonal activation of the parietal cell was achieved by using histamine. Non-fasted conditions were considered to be a state between hormonal and neuronal activation. To demonstrate that ZnSO4 enters the parietal cell through the NKCC1 co-transporter, the inhibitor bumetanide was applied during secretagogue-stimulated acid secretion. Both salts, monohydrate and heptahydrate ZnSO4, show a concentration-dependent cell entry under all conditions studied. During stimulated acid secretion, induced through either the neuronal or the hormonal pathway, heptahydrate ZnSO4 enters the parietal cell significantly faster than monohydrate ZnSO4, whereas monohydrate ZnSO4 exhibits faster entry during resting conditions in fasted animals. At 30 μM following stimulation with histamine, heptahydrate ZnSO4 enters the cell faster than monohydrate ZnSO4 (ΔFU/second 30 μM ZnSO4*7H2O + histamine = 1.782, ΔFU/second 30 μM ZnSO4*H2O+histamine = 1.038, respectively). Three hundred micromolar, heptahydrate ZnSO4 shows a faster entry into the cells (ΔFU/second ZnSO4*7H2O300μM + carbachol = 4.02407) compared to monohydrate ZnSO4 (ΔFU/second ZnSO4*H2O300μM + carbachol = 3.225) following exposure to carbachol. The mechanism of entry of both salts was found to be predominantly via the basolateral NKCC1 transporter with the rate of zinc entry decreasing to minimal values (ΔFU/second = 0.275) after application of bumetanide during stimulated conditions.
Similar content being viewed by others
References
Ali T, Roberts DN, Tierney WM (2009) Long-term safety concerns with proton pump inhibitors. Am J Med 122:896–903. doi:10.1016/j.amjmed.2009.04.014
Bavishi C, Dupont HL (2011) Systematic review: the use of proton pump inhibitors and increased susceptibility to enteric infection. Aliment Pharmacol Ther 34:1269–1281. doi:10.1111/j.1365-2036.2011.04874.x
Bulbena O, Esplugues JV, Escolar G, Gil L, Navarro C, Esplugues J (1990) Zinc acexamate inhibits gastric acid and pepsinogen secretion in the rat. J Pharm Pharmacol 42:252–256
Cho CH, Ogle CW, Dai S (1976) Effects of zinc chloride on gastric secretion and ulcer formation in pylorus-occluded rats. Eur J Pharmacol 38:337–341
Cho CH, Ogle CW, Dai S (1978) Effects of zinc sulphate pretreatment on gastric acid secretion and lesion formation in rats infused intravenously with graded doses of methacholine. Pharmacology 17:32–38
Dent J, El-Serag HB, Wallander MA, Johansson S (2005) Epidemiology of gastro-oesophageal reflux disease: a systematic review. Gut 54:710–717. doi:10.1136/gut.2004.051821
Dial S, Delaney JA, Barkun AN, Suissa S (2005) Use of gastric acid-suppressive agents and the risk of community-acquired Clostridium difficile-associated disease. JAMA 294:2989–2995. doi:10.1001/jama.294.23.2989
Escolar G, Bulbena O (1989) Zinc compounds, a new treatment in peptic ulcer. Drugs Exp Clin Res 15:83–89
Farrell CP, Morgan M, Rudolph DS, Hwang A, Albert NE, Valenzano MC, Wang X, Mercogliano G, Mullin JM (2011) Proton pump inhibitors interfere with zinc absorption and zinc body stores. Gastroenterology Research 4:243–251
Fass R (2007) Proton-pump inhibitor therapy in patients with gastro-oesophageal reflux disease: putative mechanisms of failure. Drugs 67:1521–1530
Flemmer AW, Gimenez I, Dowd BF, Darman RB, Forbush B (2002) Activation of the Na-K-Cl cotransporter NKCC1 detected with a phospho-specific antibody. J Biol Chem 277:37551–37558. doi:10.1074/jbc.M206294200
Geibel JP, Wagner CA, Caroppo R, Qureshi I, Gloeckner J, Manuelidis L, Kirchhoff P, Radebold K (2001) The stomach divalent ion-sensing receptor scar is a modulator of gastric acid secretion. J Biol Chem 276:39549–39552
Ho PM, Maddox TM, Wang L, Fihn SD, Jesse RL, Peterson ED, Rumsfeld JS (2009) Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome. JAMA 301:937–944. doi:10.1001/jama.2009.261
Kirchhoff P, Socrates T, Sidani S, Duffy A, Breidthardt T, Grob C, Viehl CT, Beglinger C, Oertli D, Geibel JP (2011) Zinc salts provide a novel, prolonged and rapid inhibition of gastric acid secretion. Am J Gastroenterol 106:62–70. doi:10.1038/ajg.2010.327
Kopic S, Corradini S, Sidani S, Murek M, Vardanyan A, Foller M, Ritter M, Geibel JP (2010) Ethanol inhibits gastric acid secretion in rats through increased AMP-kinase activity. Cellular physiology and biochemistry: international journal of experimental cellular physiology, biochemistry, and pharmacology 25:195–202. doi:10.1159/000276553
Kopic S, Geibel JP (2013) Gastric acid, calcium absorption, and their impact on bone health. Physiol Rev 93:189–268. doi:10.1152/physrev.00015.2012
Kopic S, Murek M, Geibel JP (2010) Revisiting the parietal cell. American journal of physiology Cell physiology 298:C1–c10. doi:10.1152/ajpcell.00478.2009
Locke GR 3rd, Talley NJ, Fett SL, Zinsmeister AR, Melton LJ 3rd (1999) Risk factors associated with symptoms of gastroesophageal reflux. Am J Med 106:642–649
Madanick RD (2011) Proton pump inhibitor side effects and drug interactions: much ado about nothing? Cleve Clin J Med 78:39–49. doi:10.3949/ccjm.77a.10087
Malfertheiner P, Chan FK, McColl KE (2009) Peptic ulcer disease. Lancet (London, England) 374:1449–1461. doi:10.1016/s0140-6736(09)60938-7
McColl KE (2009) Effect of proton pump inhibitors on vitamins and iron. Am J Gastroenterol 104(Suppl 2):S5–S9. doi:10.1038/ajg.2009.45
Peghini PL, Katz PO, Bracy NA, Castell DO (1998) Nocturnal recovery of gastric acid secretion with twice-daily dosing of proton pump inhibitors. Am J Gastroenterol 93:763–767. doi:10.1111/j.1572-0241.1998.221_a.x
Prinz C, Kajimura M, Scott D, Helander H, Shin J, Besancon M, Bamberg K, Hersey S, Sachs G (1992) Acid secretion and the H,K ATPase of stomach. The Yale journal of biology and medicine 65:577–596
Puscas I, Sturzu L, Buzas G (1985) Effect of ZnSO4 upon gastric acid secretion and carbonic anhydrase. Int J Clin Pharmacol Ther Toxicol 23:609–612
Sachs G, Shin JM, Hunt R (2010) Novel approaches to inhibition of gastric acid secretion. Current Gastroenterology Reports 12:437–447. doi:10.1007/s11894-010-0149-5
Song Y, Leonard SW, Traber MG, Ho E (2009) Zinc deficiency affects DNA damage, oxidative stress, antioxidant defenses, and DNA repair in rats. J Nutr 139:1626–1631. doi:10.3945/jn.109.106369
Tutuian R, Castell DO (2004) Nocturnal acid breakthrough—approach to management. MedGenMed 6:11
Waisbren SJ, Geibel JP, Modlin IM, Boron WF (1994) Unusual permeability properties of gastric gland cells. Nature 368:332–335. doi:10.1038/368332a0
Yang YX, Lewis JD, Epstein S, Metz DC (2006) Long-term proton pump inhibitor therapy and risk of hip fracture. JAMA 296:2947–2953. doi:10.1001/jama.296.24.2947
Yousef MI, El-Hendy HA, El-Demerdash FM, Elagamy EI (2002) Dietary zinc deficiency induced-changes in the activity of enzymes and the levels of free radicals, lipids and protein electrophoretic behavior in growing rats. Toxicology 175:223–234
Acknowledgments
This work was supported by the Ohse Research Grant Department of Surgery.
Author information
Authors and Affiliations
Corresponding author
Additional information
Florentina Sophie Ferstl and Alice Miriam Kitay contributed equally to this work.
Rights and permissions
About this article
Cite this article
Ferstl, F.S., Kitay, A.M., Trattnig, R.M. et al. Secretagogue-dependent and -independent transport of zinc hydration forms in rat parietal cells. Pflugers Arch - Eur J Physiol 468, 1877–1883 (2016). https://doi.org/10.1007/s00424-016-1889-3
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00424-016-1889-3