Skip to main content
SpringerLink
Log in

The cholinomimetic agent bethanechol activates IK(ACh) in feline atrial myocytes

  • Original Article
  • Published:
Naunyn-Schmiedeberg's Archives of Pharmacology Aims and scope Submit manuscript

Abstract

The effect of the cholinomimetic agent, bethanechol on macroscopic membrane currents was studied in dispersed cat atrial myocytes, using the whole-cell patch-clamp technique. Bethanechol activated an inward rectifying potassium current similar to IK(ACh), and a delayed rectifying-like outward current, similar to IKM3 activated by pilocarpine, choline, and tetramethylammonium, and IKM4 activated by 4-aminopyridine. The relatively specific muscarinic receptors subtype antagonists methoctramine (M2), and tropicamide (M4) inhibited both current components induced by bethanechol, suggesting a lack of specificity of these antagonists on cat atrial myocytes. The specific antagonist of M3 receptors, para-fluoro-hexahydro-siladifenidol did not significantly inhibit the bethanechol-induced currents. In addition, pretreatment with PTX prevented activation of the bethanechol-induced inward and outward currents, suggesting that M3 receptors are probably not involved in the bethanechol action. The IK(ACh) specific blocker tertiapin inhibited both inward rectifying- and delayed rectifying-like currents. These results suggest that both current components result from activation of a single channel type, likely IK(ACh).

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1A–C.
Fig. 2.
Fig. 3A–C.
Fig. 4A–C.
Fig. 5A–C.
Fig. 6A–C.
Fig. 7A–F.
Fig. 8A–D.

Similar content being viewed by others

References

  • Bonner TI (1989) The molecular basis of muscarinic receptor diversity. Trends Neurosci 12:148–151

    CAS  PubMed  Google Scholar 

  • Bonner TI, Buckley NJ, Young AC, Brann MR (1987) Identification of a family of muscarinic acetylcholine receptor genes. Science 237:527–532

    Google Scholar 

  • Breitwieser GE, Szabo G (1985) Uncoupling of cardiac muscarinic and β-adrenergic receptors from ion channels by a guanine nucleotide analogue. Nature 317:538–540

    CAS  PubMed  Google Scholar 

  • Brown JH, Taylor P (2001) Muscarinic receptor agonists and antagonists. In: Hardman JG, Limbird LE (eds) Goodman and Gilman's the pharmacological basis of therapeutics. McGraw-Hill, New York, pp 155–173

  • Caulfield MP, Birdsall NJM (1998) International Union of Pharmacology. XVII. Classification of muscarinic acetylcholine receptors. Pharmacol Rev 50:279–290

    CAS  PubMed  Google Scholar 

  • Dei S, Bellucci C, Ghelardini C, Romanelli NM, Spampinato S (1996) Synthesis, characterization and pharmacological profile of tropicamide enantiomers. Life Sci 58:2147–2153

    Article  CAS  PubMed  Google Scholar 

  • Dhein S, van Koppen CJ, Brodde OE (2001) Muscarinic receptors in the mammalian heart. Pharmacol Res 44:161–182

    Article  CAS  PubMed  Google Scholar 

  • Drici MD, Diochot S, Terrenoire C, Romey G, Lazdunski M (2000) The bee venom peptide tertiapin underlines the role of I(KACh) un acetylcholine-induced atrioventricular blocks. Br J Pharmacol 131:569–577

    CAS  PubMed  Google Scholar 

  • Eglen RM, Whiting RL (1990) Heterogeneity of vascular muscarinic receptors. J Auton Pharmacol 10:233–245

    CAS  PubMed  Google Scholar 

  • Eglen RM, Hegde S, Watson N (1996) Muscarinic receptor subtypes and smooth muscle function. Pharmacol Rev 48:531–565

    CAS  PubMed  Google Scholar 

  • Fermini B, Nattel S (1994) Choline chloride activates time-dependent and time-independent K+ currents in dog atrial myocytes. Am J Physiol 266:C42–C51

    CAS  PubMed  Google Scholar 

  • Hulme EC, Birdsall NJ, Buckley NJ (1990) Muscarinic receptor subtypes. Annu Rev Pharmacol Toxicol 30:633–673

    CAS  PubMed  Google Scholar 

  • Isenberg G, Klöckner U (1982) Calcium tolerant ventricular myocytes prepared by pre-incubation in a KB-medium. Pflügers Arch 395:6–18

    Google Scholar 

  • Kitamura H, Yokoyama M, Akita H, Matsushita K, Kurachi Y, Yamada M (2000) Tertiapin potently and selectively blocks muscarinic K+ channels in rabbit cardiac myocytes. J Pharmacol Exp Ther 293:196–205

    CAS  PubMed  Google Scholar 

  • Krejcic A, Tucek S (2002) Quantitation of mRNAs for M(1) to M(5) subtypes of muscarinic receptors in rat heart and brain cortex. Mol Pharmacol 61:1267–1272

    Article  CAS  PubMed  Google Scholar 

  • Kurachi Y (1985) Voltage-dependent activation of the inward-rectifier potassium channel in the ventricular cell membrane of guinea-pig heart. J Physiol 366:365–385

    CAS  PubMed  Google Scholar 

  • Kurachi Y (1995) G protein regulation of cardiac muscarinic potassium channel. Am J Physiol 269:C821–C830

    CAS  PubMed  Google Scholar 

  • Lazareno S, Birdsall NJ (1993) Pharmacological characterization of acetylcholine-stimulated [35S]-GTPγS binding mediated by human muscarinic m1-m4 receptors: antagonist studies. Br J Pharmacol 109:1120–1127

    CAS  PubMed  Google Scholar 

  • Lazareno S, Roberts FF (1989) Functional and binding studies with muscarinic M2-subtype selective antagonists. Br J Pharmacol 98:309–317

    CAS  PubMed  Google Scholar 

  • Lazareno S, Buckley NJ, Roberts FF (1990) Characterization of muscarinic M4 binding sites in rabbit lung, chicken heart, and NG108–15 cells. Mol Pharmacol 38:805–815

    CAS  PubMed  Google Scholar 

  • Loffelholz K, Pappano AJ (1985) The parasympathetic neuroeffector junction of the heart. Pharmacol Rev 37:1–24

    PubMed  Google Scholar 

  • Meyer T, Wellner-Kienitz M-C, Biewald A, Bender K, Eickel A, Pott L (2001) Depletion of phosphatidylinositol 4,5-biphosphate by activation of phospholipase C-coupled receptors causes slow inhibition but not desensitization of G protein-gated inward rectifier K+ current in atrial myocytes. J Biol Chem 276:5650–5658

    Article  CAS  PubMed  Google Scholar 

  • Mutschler E, Moser U, Wess J, Lambrecht G (1995) Muscarinic receptor subtypes—pharmacological, molecular biological and therapeutical aspects. Pharm Acta Helv 69:243–258

    Article  CAS  PubMed  Google Scholar 

  • Navarro-Polanco RA, Sánchez-Chapula JA (1997) 4-Aminopyridine activates potassium currents by activation of a muscarinic receptor in feline atrial myocytes. J Physiol 498:663–678

    CAS  PubMed  Google Scholar 

  • Okamoto H, Prestwich SA, Asai S, Unno T, Bolton TB, Komori S (2002) Muscarinic agonist potencies at three different effector systems linked to the M2 or M3 receptor in longitudinal smooth muscle of guinea-pig small intestine. Br J Pharmacol 135:1765–1775

    CAS  PubMed  Google Scholar 

  • Sakmann B, Trube G (1984) Voltage-dependent inactivation of inward-rectifying single-channel currents in the guinea-pig heart cell membrane. J Physiol 347:659–683

    CAS  PubMed  Google Scholar 

  • Sánchez-Chapula JA (1988) Effects of bupivacaine on membrane currents of guinea-pig ventricular myocytes. Eur J Pharmacol 156:303–308

    Article  PubMed  Google Scholar 

  • Sanguinetti MC, Jurkiewicz NK (1990) Two components of cardiac delayed rectifier K+ current. Differential sensitivity to block by class III antiarrhythmic agents. J Gen Physiol 96:195–215

    CAS  PubMed  Google Scholar 

  • Shi H, Wang H, Wang Z (1999a) Identification and characterization of multiple subtypes of muscarinic acetylcholine receptors and their physiological functions in canine hearts. Mol Pharmacol 55:497–507

    CAS  PubMed  Google Scholar 

  • Shi H, Wang H, Wang Z (1999b) M3 muscarinic receptor activation of a delayed rectifier potassium current in canine atrial myocytes. Life Sci 65:PL143–149

    Article  PubMed  Google Scholar 

  • Shi H, Wang H, Lu Y, Yang B, Wang Z (1999c) Choline modulates cardiac membrane repolarization by activating an M3 muscarinic receptor and its coupled K+ channel. J Membr Biol 169:55–64

    CAS  PubMed  Google Scholar 

  • Soejima M, Noma A (1984) Mode of regulation of the ACh-sensitive K-channel by the muscarinic receptor in rabbit atrial cells. Pflügers Arch 400:424–431

    Google Scholar 

  • Van Zwiten PA, Doods HN (1995) Muscarinic receptors and drugs in cardiovascular medicine. Cardiovasc Drugs Ther 9:159–167

    PubMed  Google Scholar 

  • Wang H, Shi H, Lu Y, Yang B, Wang Z (1999) Pilocarpine modulates the cellular electrical properties of mammalian hearts by activating a cardiac M3 receptor and a K+ current. Br J Pharmacol 126:1725–1734

    CAS  PubMed  Google Scholar 

  • Yamada M, Inanobe A, Kurachi Y (1998) G protein regulation of potassium ion channels. Pharmacol Rev 50:723–757

    CAS  PubMed  Google Scholar 

  • Zang WJ, Yu XJ, Boyett MR (1995) Barium block of the muscarinic potassium current in guinea-pig atrial cells. Pflügers Arch 430:348–357

    Google Scholar 

Download references

Acknowledgements

We thank Dr. Michael Sanguinetti for critical reading of the manuscript. This work was supported by Consejo Nacionl de Ciencia y Tecnologia (CONACyT, México) grant 35136-N (to RANP) and grant 41536-M (to JASCh). These experiments were approved by the Ethics Committee of the University of Colima, Colima, Col., México.

Author information

Authors and Affiliations

  1. Facultad de Medicina Humana y Ciencias de la Salud, Universidad Autónoma de Zacatecas, Zacatecas, México

    Dora E. Benavides-Haro

  2. Unidad de Investigación "Carlos Méndez" del Centro de Investigaciones Biomédicas de la Universidad de Colima, Colima, México

    Ricardo A. Navarro-Polanco & José A. Sánchez-Chapula

Authors
  1. Dora E. Benavides-Haro
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ricardo A. Navarro-Polanco
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. José A. Sánchez-Chapula
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to José A. Sánchez-Chapula.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Benavides-Haro, D.E., Navarro-Polanco, R.A. & Sánchez-Chapula, J.A. The cholinomimetic agent bethanechol activates IK(ACh) in feline atrial myocytes. Naunyn-Schmiedeberg's Arch Pharmacol 368, 309–315 (2003). https://doi.org/10.1007/s00210-003-0789-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00210-003-0789-1

Keywords

Search

Navigation