Attenuation of Gastrointestinal Tract Propulsion in Rats by Zinc Acetate: Investigation into Serotonergic and Dopaminergic Mechanisms
This study evaluated the influence of orally administered zinc acetate on gastrointestinal tract propulsion of rats. It also evaluated the effects of the salt on faecal output and gastrointestinal transit time in the rats. The effects of zinc acetate on feeding as well as water intake were determined. The dose of zinc acetate which produced the maximal effect was used to investigate the receptors involved in the alteration of gastrointestinal motility by the salts. All the three doses of zinc acetate (50 mg/kg, 80 mg/kg and 110 mg/kg) produced a significant reduction in the number of total faecal pellets produced in eight hours of study (2.67 ± 0.67, 10.75 ± 0.60, 5 ± 0.52) respectively when compared with the control group (15.67 ± 0.52). Also, the three doses of zinc acetate produced a dose-dependent significant reduction in the faecal mass (1.23 ± 0.08g, 0.96 ± 0.07g, 0.59 ± 0.07g) respectively when compared with control group (3.39 ± 0.25g).The total transit time in rats treated with 50 mg/kg of zinc acetate (746.2 ± 5.95 minutes) increased significantly compared to the control group (251.2 ± 5.48 minutes). The three doses of zinc acetate produced a dose-dependent reduction (p < 0.05) in food intake (9.67 ± 0.61, 9.17 ± 0.62 and 5.00 ± 0.39) respectively compared to the control group (18.33 ± 0.67). Pre-treatment with metoclopramide (5HT3 & D2 blocker/5HT4 serotonergic agonist) significantly increased faecal pellet output in zinc acetate treated rats (4.80 ± 0.20) when compared with rats treated with zinc acetate alone (2.67 ± 0.67).The study concluded that zinc acetate reduced gastrointestinal tract propulsion in rats evidenced as increased intestinal transit time of rats and reduced faecal pellet output via stimulation of 5HT3 and 5HT4 serotonergic and dopaminergic receptors.
Rufus Ojo Akomolafe,
Olusoji Adeola Adalumo,
Kayode Dominion Samuel Bamitale,
Attenuation of Gastrointestinal Tract Propulsion in Rats by Zinc Acetate: Investigation into Serotonergic and Dopaminergic Mechanisms, American Journal of Life Sciences.
Vol. 2, No. 6,
2014, pp. 406-412.
Huizinga J.D and Lammers W.J (2009). Gut peristalsis is governed by a multitude of cooperating mechanisms. American Journal of Physiology 296:G1–G8
Rao S.S, Camilleri M and Hasler W.L (2011). Evaluation of gastrointestinal transit in clinical practice: position paper of the American and European Neurogastroenterology and Motility Societies. Journal of Neurogastroenterology and Motility 23: 8–23.
Szarka L.A and Camilleri M (2009). Methods for measurement of gastric motility. American Journal of Physiology, 296:G461–G475.
Medici V, Sturniolo G.C, Santon A, D'Incà R, Bortolami M, Cardin R, Basso D, Albergoni V, Irato P (2005). Efficacy of zinc supplementation in preventing acute hepatitis in Long-Evans Cinnamon rats; Liver International. Aug; 25(4):888-95.
Marona Hérida R. N. and Lucchesi M. B. B. (2004). Protocol to refine intestinal motility test in mice Laboratory Animals Ltd. Laboratory Animals 38, 257–260.
McKee K.K, Tan C.P, Palyha O.C, Liu J, Feighner S.D, Hreniuk D.L, Smith R.G, Howard A.D, Van der Ploeg L.H (1997). Cloning and characterization of two human G protein-coupled receptor genes (GPR38 and GPR39) related to the growth hormone secretagogue and neurotensin receptors. Genomics, 46:426-434.
Moechars D, Depoortere I, Moreaux B, de Smet B, Goris I, Hoskens L, Daneels G, Kass S, Ver Donck L, Peeters T, Coulie B (2006). Altered gastrointestinal and metabolic function in the GPR39- obestatin receptor-knockout mouse. Gastroenterology, 131:1131-1141.
Jackson VR, Nothacker HP, Civelli O (2006). GPR39 receptor expression in the mouse brain. Neuroreport, 17:813-816.
Zhang J.V, Ren P.G, Avsian-Kretchmer O et al., (2005). “Medicine: obestatin, a peptide encoded by the ghrelin gene, opposes ghrelin’s effects on food intake,” Science, vol. 310, no. 5750, pp. 996–999.
Holst B, Egerod K.L, Schild E, Vickers S.P, Cheetham S, Gerlach L.O, Storjohann L, Stidsen C.E, Jones R, Beck-Sickinger A.G, Schwartz T.W (2007). GPR39 signaling is stimulated by zinc ions but not by obestatin. Endocrinology, 148:13-20.
Nogueiras R.P, Pfluger S. Tovar et al., (2007). “Effects of obestatin on energy balance and growth hormone secretion in rodents,” Endocrinology, vol. 148, no. 1, pp. 21–26.
Depoortere Inge (2012). GI functions of GPR39: novel biology. Current Opinion in Pharmacology 12:647–652.
Mantzoros C.S, Prasad A.S, Beck F.W.J, Grabowski S, Kaplan J, Adair C and Brewer G.J (1998). Zinc May Regulate Serum Leptin Concentrations in Humans. Journal of the American College of Nutrition, Vol. 17, No. 3, 270–275.
Casimiro-Lopes G, de Oliveira-Junior A.V, Portella E.S, Lisboa P.C, Donangelo C.M, de Moura E.G, Koury J.C (2009). Plasma Leptin, Plasma Zinc, and Plasma Copper Are Associated in Elite Female and Male Judo Athletes. Biological Trace Element Research 127:109-115.
Grunfeld C, Zhao C and Fuller J et al., (1996). Endotoxin and cytokines induce expression of leptin, the ob gene product, in hamsters. Journal of Clinical Investigation 97:2152–2157.
Chen MD, Lin PY (2000). Zinc-induced hyperleptinemia relates to the amelioration of sucrose-induced obesity with zinc repletion. Obesity Research; 8:525-9.
Chen MD, Yang VC, Alexander PS, Lin PY, Song YM (2001). Effects of selected minerals on leptin secretion in streptozotocin-induced hyperglycemic mice. Experimental Biology and Medicine (Maywood); 226:836-40.
Wynne K, Stanley S, McGowan B and Bloom S (2005). Appetite control. Journal of Endocrinology 184, 291–318.
Grill H.J and Kaplan J.M (2002). The neuroanatomical axis for control of energy balance. Frontiers in Neuroendocrinology 23 2–40.
Elmquist J.K, Ahima R.S, Maratos-Flier E, Flier J.S and Saper C.B (1997). Leptin activates neurons in ventrobasal hypothalamus and brainstem. Endocrinology 138 839–842.
Hosoi T, Kawagishi T, Okuma Y, Tanaka J and Nomura Y (2002). Brainstem is a direct target for leptin’s action in the central nervous system. Endocrinology 143 3498–3504.
Robertson RP, Zhou H and Slucca M (2011). A role for zinc in pancreatic islet β-cell cross-talk with the α-cell during hypoglycaemia. Diabetes Obesity and Metabolism; 13 Suppl 1:S106-11
Jing M.Y, Sun J.Y and Wang J.F (2008). The effect of peripheral administration of zinc on food intake in rats fed Zn-adequate or Zn-deficient diets. Biological and Trace Elements Research; 124:144-56.
McKinley MJ, Denton DA, Oldfield BJ, et al (2006).Water intake and the neural correlates of the consciousness of thirst. Journal of Seminar in Nephrology. 26:249–257.
Fregoneze JB, Souza C, Cunha M, Ferreira H, De-Oliveira I, Barros L, Malbouisson M & De-Castro-e-Silva E (1994). Acute effects of intra-cerebroventricular administration of zinc on the drinking behavior of rats induced by dehydration or central cholinergic and angiotensinergic stimulation. Brazilian Journal of Medical and Biological Research, 27: 2623-2633.
Fregoneze J.B, Luz C.P, Castro L, Oliveira P, Lima A.K.S, Souza F, Maldonado I, Macêdo D.F, Ferreira M.G, Bandeira I.P.V, Rocha Jr. M.A, Carvalho F.L.Q. and De-Castro-e-Silva E (1999). Zinc and Water Intake in Rats: Investigation of Adrenergic and Opiatergic Central Mechanisms. Brazilian Journal of Medical and Biological Research 32: 1217-1222.
Antunes-Rodrigues J, McCann S.M, Rogers L.C, and Samson W.K (1985). Atrial natriuretic factor inhibits dehydration- and angiotensin II-induced water intake in the conscious, unrestrained rat. Proceedings of National Academy of Science USA 82: 8720-8723.
Burrell L.M, Lambert H.J and Bayliss P.H (1992). Atrial natriuretic peptide inhibits fluid intake in hyperosmolar subjects. Journal of Clinical Science (London) 83: 35-39.
McKinley M.J and Johnson A.K (2004). The Physiological Regulation of Thirst and Fluid Intake. News in Physiological Sciences 19: 1-6.
Turton M.D, O’Shea D, Gunn I, Beak S.A, Edwards C.M, Meeran K, Choi S.J, Taylor G.M, Heath M.M, Lambert P.D et al., (1996). A role for glucagon-like peptide-1 in the central regulation of feeding. Nature 379 69–72.
DeCastro-e-Silva E, Marinho CA, Soares T, Castro L, Sarmento C, Cunha M, Gonzalez V, Oliveira P, Nascimento T, Luz CP, Santana Jr P, DeOliveira IR and Fregoneze JB (1996). Calcium channel blockers inhibit the antidipsogenic effect of central injections of zinc in rats. Brazilian Journal of Medical and Biological Research, 29: 1651-1655.
Stengaard-Pedersen K (1982). Inhibition of enkephalin binding to opiate receptors by zinc ions: possible physiological importance in the brain. Acta Pharmacologica et Toxicologica, 50: 213-220.
Johnson A.K and Thunhorst R.L (1997). The neuroendocrinology of thirst and salt appetite: Visceral sensory signals and mechanisms of central integration. Frontiers in Neuroendocrinology, 18: 292-353.
Furness J.B and Costa M (1987). The Enteric Nervous System. Churchill Livingstone, Edingburgh.
Olsson C and Holmgren S (2001). The control of gut motility. Journal of Comparative Biochemistry and Physiology. A Molecular and Integrative Physiology. 128: 481–503
Hansen M.B (2003). Neurohumoral control of gastrointestinal motility. Physiological Research: 52, 1–30.
Maqbool S, Parkman H.P and Friedenberg F.K (2009). Wireless capsule motility: comparison of the Smart Pill GI monitoring system with scintigraphy for measuring whole gut transit. Digestive Diseases and Sciences. 2009; 54:2167–2174.
Elinder F. and Arhem P. (2003). Metal ion effects on ion channel gating. Quarterly Review of Biophysics. 36: 373-427.
Norgaard-Nielsen, K. and Gether, U. (2006). Zn2+ modulation of neurotransmitter transporters. Handbook of Experimental Pharmacology: 1–22.
Egerod K.L, Holst B, Petersen P.S, Hansen J.B, Mulder J, Hokfelt T, Schwartz T.W (2007). GPR39 splice variants versus antisense gene LYPD1: expression and regulation in gastrointestinal tract endocrine pancreas, liver, and white adipose tissue. Journal of Molecular Endocrinology 21:1685-1698.
Lauwers E, Landuyt B, Arckens L, Schoofs L and Luyten W (2006). Obestatin does not activate orphan g protein-coupled receptor GPR39. Biochemical and Biophysical Research Communication, 351:21-25.
Yasuda S, Miyazaki T, Munechika K, Yamashita M, Ikeda Y and Kamizono A (2007). Isolation of Zn2+ as an endogenous agonist of GPR39 from fetal bovine serum. Journal of Receptor Signal Transduction Research, 27:235-246.
Storjohann L, Holst B and Schwartz TW (2008). Molecular mechanism of Zn2+ agonism in the extracellular domain of GPR39. Federation of European Biochemical Societies Letters, 582:2583-2588.
Chan Lingtak-Neander (2008). Opioid Analgesics and the Gastrointestinal Tract. Practical Gastroenterology Nutrition Issues in Gastroenterology, Series #65 Carol Rees Parrish, R.D., M.S., Series Editor: 37-50.
DeSchepper H.U, Cremonini F, Park M-I, et al., (2004). Opioids and the gut: pharmacology and current clinical experience. Journal of Neurogastroenterology and Motility; 16:383-394.
De Luca A, Coupar I.M (1996). Insights into opioid action in the intestinal tract. Pharmacology and Therapeutics; 2:103-115.
Schetz J.A. Chu A and Sibley D.R (1999). Zinc modulates antagonist interactions with D2-like dopamine receptors through distinct molecular mechanisms 4. Journal of. Pharmacology and Experimental Therapeutics. 289: 956–964.
Fowler C.B, Pogozheva I.D, LeVine H and Mosberg H.I (2004). Refinement of a homology model of the µ-opioid receptor using distance constraints from intrinsic and engineered zinc binding sites. Biochemistry 43: 8700–8710.
Liu Y, Teeter M.M, DuRand C.J and Neve K.A (2006). Identification of a Zn2+-binding site on the dopamine D2 receptor. Biochemical and Biophysical Research Communication. 339, 873–879