• 1

    Eglen RM, Hegde SS, Watson N. Muscarinic receptor subtypes and smooth muscle function. Pharmacol Rev 1996;48:531565.

  • 2

    Wrzos HF, Tandon T, Ouyang A. Mechanisms mediating cholinergic antral circular smooth muscle contraction in rats. World J Gastroenterol 2004;10:32923298.

    • Search Google Scholar
    • Export Citation
  • 3

    Uchiyama T, Chess-Williams R. Muscarinic receptor subtypes of the bladder and gastrointestinal tract. J Smooth Muscle Res 2004;40:237247.

    • Search Google Scholar
    • Export Citation
  • 4

    Zhang LB, Horowitz B, Buxton IL. Muscarinic receptors in canine colonic circular smooth muscle. I. Coexistence of M2 and M3 subtypes. Mol Pharmacol 1991;40:943951.

    • Search Google Scholar
    • Export Citation
  • 5

    Marti M, Mevissen M, Althaus H, et al. In vitro effects of bethanechol on equine gastrointestinal contractility and functional characterization of involved muscarinic receptor subtypes. J Vet Pharmacol Ther 2005;28:565574.

    • Search Google Scholar
    • Export Citation
  • 6

    Steiner A. Modifiers of gastrointestinal motility of cattle. Vet Clin North Am Food Anim Pract 2003;19:647660.

  • 7

    Oyachi N, Lakshmanan J, Ahanya SN, et al. Development of ovine fetal ileal motility: role of muscarinic receptor subtypes. Am J Obstet Gynecol 2003;189:953957.

    • Search Google Scholar
    • Export Citation
  • 8

    Caulfield MP, Birdsall NJ. International Union of Pharmacology. XVII. Classification of muscarinic acetylcholine receptors. Pharmacol Rev 1998;50:279290.

    • Search Google Scholar
    • Export Citation
  • 9

    Eglen RM. Muscarinic receptor subtype pharmacology and physiology. Prog Med Chem 2005;43:105136.

  • 10

    Eglen RM. Muscarinic receptors and gastrointestinal tract smooth muscle function. Life Sci 2001;68:25732578.

  • 11

    Ehlert FJ, Sawyer GW, Esqueda EE. Contractile role of M2 and M3 muscarinic receptors in gastrointestinal smooth muscle. Life Sci 1999;64:387394.

    • Search Google Scholar
    • Export Citation
  • 12

    Matsui M, Motomura D, Karasawa H, et al. Multiple functional defects in peripheral autonomic organs in mice lacking muscarinic acetylcholine receptor gene for the M3 subtype. Proc Natl Acad Sci U S A 2000;97:95799584.

    • Search Google Scholar
    • Export Citation
  • 13

    Stengel PW, Gomeza J, Wess J, et al. M(2) and M(4) receptor knockout mice: muscarinic receptor function in cardiac and smooth muscle in vitro. J Pharmacol Exp Ther 2000;292:877885.

    • Search Google Scholar
    • Export Citation
  • 14

    Matsui M, Motomura D, Fujikawa T, et al. Mice lacking M2 and M3 muscarinic acetylcholine receptors are devoid of cholinergic smooth muscle contractions but still viable. J Neurosci 2002;22:1062710632.

    • Search Google Scholar
    • Export Citation
  • 15

    Caulfield MP. Muscarinic receptors—characterization, coupling and function. Pharmacol Ther 1993;58:319379.

  • 16

    Ehlert FJ, Ostrom RS, Sawyer GW. Subtypes of the muscarinic receptor in smooth muscle. Life Sci 1997;61:17291740.

  • 17

    Nelson DK, Pieramico O, Dahmen G, et al. M1-muscarinic mechanisms regulate interdigestive cycling of motor and secretory activity in human upper gut. Dig Dis Sci 1996;41:20062015.

    • Search Google Scholar
    • Export Citation
  • 18

    Akbulut H, Goren Z, Iskender E, et al. Subtypes of muscarinic receptors in rat duodenum: a comparison with rabbit vas deferens, rat atria, guinea-pig ileum and gallbladder by using imperialine. Gen Pharmacol 1999;32:505511.

    • Search Google Scholar
    • Export Citation
  • 19

    Stadelmann AM, Walgenbach-Telford S, Telford GL, et al. Distribution of muscarinic receptor subtypes in rat small intestine. J Surg Res 1998;80:320325.

    • Search Google Scholar
    • Export Citation
  • 20

    Wess J. Muscarinic acetylcholine receptor knockout mice: novel phenotypes and clinical implications. Annu Rev Pharmacol Toxicol 2004;44:423450.

    • Search Google Scholar
    • Export Citation
  • 21

    So I, Yang DK, Kim HJ, et al. Five subtypes of muscarinic receptors are expressed in gastric smooth muscles of guinea pig. Exp Mol Med 2003;35:4652.

    • Search Google Scholar
    • Export Citation
  • 22

    Dorje F, Levey AI, Brann MR. Immunological detection of muscarinic receptor subtype proteins (m1–m5) in rabbit peripheral tissues. Mol Pharmacol 1991;40:459462.

    • Search Google Scholar
    • Export Citation
  • 23

    Stoffel MH, Wicki Monnard C, Steiner A, et al. Distribution of muscarinic receptor subtypes and interstitial cells of Cajal in the gastrointestinal tract of healthy dairy cows. Am J Vet Res 2006;67:19921997.

    • Search Google Scholar
    • Export Citation
  • 24

    Radostits OM, Blood DC, et al. Manifestation of alimentary tract dysfunction. In: Radostits OM, Blood DC, Hinchcliff KW, ed.Veterinary medicine. 9th ed.London: WB Saunders Co, 2000;171176.

    • Search Google Scholar
    • Export Citation
  • 25

    Bauer AJ, Boeckxstaens GE. Mechanisms of postoperative ileus. Neurogastroenterol Motil 2004;16:5460.

  • 26

    Sattler D, Fecteau G, Girard C, et al. Description of 14 cases of bovine hypokalemia syndrome. Vet Rec 1998;143:503507.

  • 27

    Roussel AJ, Brumbaugh GW, Waldron RC, et al. Abomasal and duodenal motility in yearling cattle after administration of prokinetic drugs. Am J Vet Res 1994;55:111115.

    • Search Google Scholar
    • Export Citation
  • 28

    Eicher R, Audige L, Braun U, et al. Epidemiology and risk factors of cecal dilatation/dislocation and abomasal displacement in dairy cows. Schweiz Arch Tierheilkd 1999;141:423429.

    • Search Google Scholar
    • Export Citation
  • 29

    Kilbinger H, Weihrauch TR. Drugs increasing gastrointestinal motility. Pharmacology 1982;25:6172.

  • 30

    Megens AA, Awouters FH, Niemegeers CJ. General pharmacology of the four gastrointestinal motility stimulants bethanechol, metoclopramide, trimebutine, and cisapride. Arzneimittelforschung 1991;41:631634.

    • Search Google Scholar
    • Export Citation
  • 31

    Law NM, Bharucha AE, Undale AS, et al. Cholinergic stimulation enhances colonic motor activity, transit, and sensation in humans. Am J Physiol Gastrointest Liver Physiol 2001;281: G1228G1237.

    • Search Google Scholar
    • Export Citation
  • 32

    Ringger NC, Lester GD, Neuwirth L, et al. Effect of bethanechol or erythromycin on gastric emptying in horses. Am J Vet Res 1996;57:17711775.

    • Search Google Scholar
    • Export Citation
  • 33

    Lester GD, Merritt AM, Neuwirth L, et al. Effect of alpha 2-adrenergic, cholinergic, and nonsteroidal anti-inflammatory drugs on myoelectric activity of ileum, cecum, and right ventral colon and on cecal emptying of radiolabeled markers in clinically normal ponies. Am J Vet Res 1998;59:320327.

    • Search Google Scholar
    • Export Citation
  • 34

    Barahona MV, Sanchez-Fortun S, San Andres MD, et al. Acetylcholinesterase histochemistry and functional characterization of the muscarinic receptor mediating the contraction of the bovine oesophageal groove. J Auton Pharmacol 1997;17:7786.

    • Search Google Scholar
    • Export Citation
  • 35

    Michel A, Mevissen M, Burkhardt HW, et al. In vitro effects of cisapride, metoclopramide and bethanechol on smooth muscle preparations from abomasal antrum and duodenum of dairy cows. J Vet Pharmacol Ther 2003;26:413420.

    • Search Google Scholar
    • Export Citation
  • 36

    Steiner A, Denac M, Ballinari U. Effects of adrenaline, dopamine, serotonin, and different cholinergic agents on smooth muscle preparations from the ansa proximalis coli in cattle: studies in vitro. Zentralbl Veterinarmed [A] 1992;39:541547.

    • Search Google Scholar
    • Export Citation
  • 37

    Steiner A, Roussel AJ, Martig J. Effect of bethanechol, neostigmine, metoclopramide, and propranolol on myoelectric activity of the ileocecocolic area in cows. Am J Vet Res 1995;56:10811086.

    • Search Google Scholar
    • Export Citation
  • 38

    Steiner A, Meylan M, Eicher R. New aspects on the etiopathogenesis and treatment of cecal dilatation/dislocation in cows—a review. Schweiz Arch Tierheilkd 1999;141:419422.

    • Search Google Scholar
    • Export Citation
  • 39

    Hirsbrunner G, Knutti B, Liu I, et al. An in vitro study on spontaneous myometrial contractility in the cow during estrus and diestrus. Anim Reprod Sci 2002;70:171180.

    • Search Google Scholar
    • Export Citation
  • 40

    Portier C, Tritscher A, Kohn M, et al. Ligand/receptor binding for 2,3,7,8-TCDD: implications for risk assessment. Fundam Appl Toxicol 1993;20:4856.

    • Search Google Scholar
    • Export Citation
  • 41

    Dorje F, Wess J, Lambrecht G, et al. Antagonist binding profiles of five cloned human muscarinic receptor subtypes. J Pharmacol Exp Ther 1991;256:727733.

    • Search Google Scholar
    • Export Citation
  • 42

    Stengel PW, Cohen ML. Muscarinic receptor knockout mice: role of muscarinic acetylcholine receptors M(2), M(3), and M(4) in carbamylcholine-induced gallbladder contractility. J Pharmacol Exp Ther 2002;301:643650.

    • Search Google Scholar
    • Export Citation
  • 43

    Shi H, Wang H, Wang Z. Identification and characterization of multiple subtypes of muscarinic acetylcholine receptors and their physiological functions in canine hearts. Mol Pharmacol 1999;55:497507.

    • Search Google Scholar
    • Export Citation
  • 44

    Eglen RM, Harris GC. Selective inactivation of muscarinic M2 and M3 receptors in guinea-pig ileum and atria in vitro. Br J Pharmacol 1993;109:946952.

    • Search Google Scholar
    • Export Citation
  • 45

    Eglen RM, Reddy H, Watson N, et al. Muscarinic acetylcholine receptor subtypes in smooth muscle. Trends Pharmacol Sci 1994;15:114119.

  • 46

    Mansfield KJ, Mitchelson FJ, Moore KH, et al. Muscarinic receptor subtypes in the human colon: lack of evidence for atypical subtypes. Eur J Pharmacol 2003;482:101109.

    • Search Google Scholar
    • Export Citation
  • 47

    Grimm U, Fuder H, Moser U, et al. Characterization of the prejunctional muscarinic receptors mediating inhibition of evoked release of endogenous noradrenaline in rabbit isolated vas deferens. Naunyn Schmiedebergs Arch Pharmacol 1994;349:110.

    • Search Google Scholar
    • Export Citation
  • 48

    Hammer R, Giraldo E, Schiavi GB, et al. Binding profile of a novel cardioselective muscarine receptor antagonist, AF-DX 116, to membranes of peripheral tissues and brain in the rat. Life Sci 1986;38:16531662.

    • Search Google Scholar
    • Export Citation
  • 49

    Giraldo E, Monferini E, Ladinsky H, et al. Muscarinic receptor heterogeneity in guinea pig intestinal smooth muscle: binding studies with AF-DX 116. Eur J Pharmacol 1987;141:475477.

    • Search Google Scholar
    • Export Citation
  • 50

    Eltze M, Ullrich B, Mutschler E, et al. Characterization of muscarinic receptors mediating vasodilation in rat perfused kidney. Eur J Pharmacol 1993;238:343355.

    • Search Google Scholar
    • Export Citation
  • 51

    Hernandez M, Simonsen U, Prieto D, et al. Different muscarinic receptor subtypes mediating the phasic activity and basal tone of pig isolated intravesical ureter. Br J Pharmacol 1993;110:14131420.

    • Search Google Scholar
    • Export Citation
  • 52

    Lazareno S, Buckley NJ, Roberts FF. Characterization of muscarinic M4 binding sites in rabbit lung, chicken heart, and NG108-15 cells. Mol Pharmacol 1990;38:805815.

    • Search Google Scholar
    • Export Citation
  • 53

    Stengel PW, Yamada M, Wess J, et al. M(3)-receptor knockout mice: muscarinic receptor function in atria, stomach fundus, urinary bladder, and trachea. Am J Physiol Regul Integr Comp Physiol 2002;282:R1443R1449.

    • Search Google Scholar
    • Export Citation
  • 54

    Dietrich C, Kilbinger H. Prejunctional M1 and postjunctional M3 muscarinic receptors in the circular muscle of the guinea-pig ileum. Naunyn Schmiedebergs Arch Pharmacol 1995;351:237243.

    • Search Google Scholar
    • Export Citation
  • 55

    Sawyer GW, Ehlert FJ. Muscarinic M3 receptor inactivation reveals a pertussis toxin-sensitive contractile response in the guinea pig colon: evidence for M2/M3 receptor interactions. J Pharmacol Exp Ther 1999;289:464476.

    • Search Google Scholar
    • Export Citation
  • 56

    Peralta EG, Ashkenazi A, Winslow JW, et al. Differential regulation of PI hydrolysis and adenylyl cyclase by muscarinic receptor subtypes. Nature 1988;334:434437.

    • Search Google Scholar
    • Export Citation
  • 57

    Kaze C, Mevissen M, Hirsbrunner G, et al. Effect of endotoxins on contractility of smooth muscle preparations from the bovine abomasal antrum. Dtsch Tierarztl Wochenschr 2004;111:2835.

    • Search Google Scholar
    • Export Citation
  • 58

    Thomas EA, Baker SA, Ehlert FJ. Functional role for the M2 muscarinic receptor in smooth muscle of guinea pig ileum. Mol Pharmacol 1993;44:102110.

    • Search Google Scholar
    • Export Citation
  • 59

    Wess J. Molecular biology of muscarinic acetylcholine receptors. Crit Rev Neurobiol 1996;10:6999.

  • 60

    Maeda A, Kubo T, Mishina M, et al. Tissue distribution of mRNAs encoding muscarinic acetylcholine receptor subtypes. FEBS Lett 1988;239:339342.

    • Search Google Scholar
    • Export Citation
  • 61

    Eglen RM, Cornett CM, Whiting RL. Interaction of p-F-HHSiD (p-fluoro-hexahydrosila-difenidol) at muscarinic receptors in guinea-pig trachea. Naunyn Schmiedebergs Arch Pharmacol 1990;342:394399.

    • Search Google Scholar
    • Export Citation
  • 62

    Eglen RM, Michel AD, Montgomery WW, et al. The interaction of parafluorohexahydrosiladiphenidol at muscarinic receptors in vitro. Br J Pharmacol 1990;99:637642.

    • Search Google Scholar
    • Export Citation
  • 63

    Shi H, Wang H, Wang Z. M3 muscarinic receptor activation of a delayed rectifier potassium current in canine atrial myocytes. Life Sci 1999;64:PL251PL257.

    • Search Google Scholar
    • Export Citation

Advertisement

In vitro effects of bethanechol on specimens of intestinal smooth muscle obtained from the duodenum and jejunum of healthy dairy cows

Julia B. R. Pfeiffer Dr med vet1, Meike Mevissen Dr med vet, Dr habil2, Adrian Steiner Dr med vet, MS, Dr habil3, Christopher J. Portier PhD4, and Mireille Meylan Dr med vet, PhD, Dr habil5
View More View Less
  • 1 Clinic for Ruminants, Vetsuisse Faculty, University of Berne, 3012 Berne, Switzerland
  • | 2 Division of Veterinary Pharmacology and Toxicology, Vetsuisse Faculty, University of Berne, 3012 Berne, Switzerland
  • | 3 Clinic for Ruminants, Vetsuisse Faculty, University of Berne, 3012 Berne, Switzerland
  • | 4 Laboratory of Molecular Toxicology, Environmental Systems Biology and Risk Assessment, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709
  • | 5 Clinic for Ruminants, Vetsuisse Faculty, University of Berne, 3012 Berne, Switzerland

Abstract

Objective—To describe the in vitro effects of bethanechol on contractility of smooth muscle preparations from the small intestines of healthy cows and define the muscarinic receptor subtypes involved in mediating contraction.

Sample Population—Tissue samples from the duodenum and jejunum collected immediately after slaughter of 40 healthy cows.

Procedures—Cumulative concentration-response curves were determined for the muscarinic receptor agonist bethanechol with or without prior incubation with subtype-specific receptor antagonists in an organ bath. Effects of bethanechol and antagonists and the influence of intestinal location on basal tone, maximal amplitude (Amax), and area under the curve (AUC) were evaluated.

Results—Bethanechol induced a significant, concentration-dependent increase in all preparations and variables. The effect of bethanechol was more pronounced in jejunal than in duodenal samples and in circular than in longitudinal preparations. Significant inhibition of the effects of bethanechol was observed after prior incubation with muscarinic receptor subtype M3 antagonists (more commonly for basal tone than for Amax and AUC). The M2 receptor antagonists partly inhibited the response to bethanechol, especially for basal tone. The M3 receptor antagonists were generally more potent than the M2 receptor antagonists. In a protection experiment, an M3 receptor antagonist was less potent than when used in combination with an M2 receptor antagonist. Receptor antagonists for M1 and M4 did not affect contractility variables.

Conclusions and Clinical Relevance—Bethanechol acting on muscarinic receptor sub-types M2 and M3 may be of clinical use as a prokinetic drug for motility disorders of the duodenum and jejunum in dairy cows.

Abstract

Objective—To describe the in vitro effects of bethanechol on contractility of smooth muscle preparations from the small intestines of healthy cows and define the muscarinic receptor subtypes involved in mediating contraction.

Sample Population—Tissue samples from the duodenum and jejunum collected immediately after slaughter of 40 healthy cows.

Procedures—Cumulative concentration-response curves were determined for the muscarinic receptor agonist bethanechol with or without prior incubation with subtype-specific receptor antagonists in an organ bath. Effects of bethanechol and antagonists and the influence of intestinal location on basal tone, maximal amplitude (Amax), and area under the curve (AUC) were evaluated.

Results—Bethanechol induced a significant, concentration-dependent increase in all preparations and variables. The effect of bethanechol was more pronounced in jejunal than in duodenal samples and in circular than in longitudinal preparations. Significant inhibition of the effects of bethanechol was observed after prior incubation with muscarinic receptor subtype M3 antagonists (more commonly for basal tone than for Amax and AUC). The M2 receptor antagonists partly inhibited the response to bethanechol, especially for basal tone. The M3 receptor antagonists were generally more potent than the M2 receptor antagonists. In a protection experiment, an M3 receptor antagonist was less potent than when used in combination with an M2 receptor antagonist. Receptor antagonists for M1 and M4 did not affect contractility variables.

Conclusions and Clinical Relevance—Bethanechol acting on muscarinic receptor sub-types M2 and M3 may be of clinical use as a prokinetic drug for motility disorders of the duodenum and jejunum in dairy cows.

Contributor Notes

Dr. Pfeiffer's present address is Tierärztliche Hochschule Hannover, 30173 Hannover, Germany.

Supported by a grant from the Vetsuisse Faculty, Switzerland, and by Dr. E. Graeub AG, Berne, Switzerland.

Address correspondence to Dr. Meylan.