Advertisement

Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 368, Issue 4, pp 309–315 | Cite as

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

  • Dora E. Benavides-Haro
  • Ricardo A. Navarro-Polanco
  • José A. Sánchez-ChapulaEmail author
Original Article

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).

Keywords

Bethanechol Feline atrial myocytes Muscarinic inward rectifying potassium current Muscarinic receptors 

Notes

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.

References

  1. Bonner TI (1989) The molecular basis of muscarinic receptor diversity. Trends Neurosci 12:148–151PubMedGoogle Scholar
  2. Bonner TI, Buckley NJ, Young AC, Brann MR (1987) Identification of a family of muscarinic acetylcholine receptor genes. Science 237:527–532Google Scholar
  3. Breitwieser GE, Szabo G (1985) Uncoupling of cardiac muscarinic and β-adrenergic receptors from ion channels by a guanine nucleotide analogue. Nature 317:538–540PubMedGoogle Scholar
  4. 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 155–173Google Scholar
  5. Caulfield MP, Birdsall NJM (1998) International Union of Pharmacology. XVII. Classification of muscarinic acetylcholine receptors. Pharmacol Rev 50:279–290PubMedGoogle Scholar
  6. Dei S, Bellucci C, Ghelardini C, Romanelli NM, Spampinato S (1996) Synthesis, characterization and pharmacological profile of tropicamide enantiomers. Life Sci 58:2147–2153CrossRefPubMedGoogle Scholar
  7. Dhein S, van Koppen CJ, Brodde OE (2001) Muscarinic receptors in the mammalian heart. Pharmacol Res 44:161–182CrossRefPubMedGoogle Scholar
  8. 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 131:569–577PubMedGoogle Scholar
  9. Eglen RM, Whiting RL (1990) Heterogeneity of vascular muscarinic receptors. J Auton Pharmacol 10:233–245PubMedGoogle Scholar
  10. Eglen RM, Hegde S, Watson N (1996) Muscarinic receptor subtypes and smooth muscle function. Pharmacol Rev 48:531–565PubMedGoogle Scholar
  11. Fermini B, Nattel S (1994) Choline chloride activates time-dependent and time-independent K+ currents in dog atrial myocytes. Am J Physiol 266:C42–C51PubMedGoogle Scholar
  12. Hulme EC, Birdsall NJ, Buckley NJ (1990) Muscarinic receptor subtypes. Annu Rev Pharmacol Toxicol 30:633–673PubMedGoogle Scholar
  13. Isenberg G, Klöckner U (1982) Calcium tolerant ventricular myocytes prepared by pre-incubation in a KB-medium. Pflügers Arch 395:6–18Google Scholar
  14. 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 293:196–205PubMedGoogle Scholar
  15. 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 61:1267–1272CrossRefPubMedGoogle Scholar
  16. Kurachi Y (1985) Voltage-dependent activation of the inward-rectifier potassium channel in the ventricular cell membrane of guinea-pig heart. J Physiol 366:365–385PubMedGoogle Scholar
  17. Kurachi Y (1995) G protein regulation of cardiac muscarinic potassium channel. Am J Physiol 269:C821–C830PubMedGoogle Scholar
  18. 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 109:1120–1127PubMedGoogle Scholar
  19. Lazareno S, Roberts FF (1989) Functional and binding studies with muscarinic M2-subtype selective antagonists. Br J Pharmacol 98:309–317PubMedGoogle Scholar
  20. Lazareno S, Buckley NJ, Roberts FF (1990) Characterization of muscarinic M4 binding sites in rabbit lung, chicken heart, and NG108–15 cells. Mol Pharmacol 38:805–815PubMedGoogle Scholar
  21. Loffelholz K, Pappano AJ (1985) The parasympathetic neuroeffector junction of the heart. Pharmacol Rev 37:1–24PubMedGoogle Scholar
  22. 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 276:5650–5658CrossRefPubMedGoogle Scholar
  23. Mutschler E, Moser U, Wess J, Lambrecht G (1995) Muscarinic receptor subtypes—pharmacological, molecular biological and therapeutical aspects. Pharm Acta Helv 69:243–258CrossRefPubMedGoogle Scholar
  24. Navarro-Polanco RA, Sánchez-Chapula JA (1997) 4-Aminopyridine activates potassium currents by activation of a muscarinic receptor in feline atrial myocytes. J Physiol 498:663–678PubMedGoogle Scholar
  25. 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 135:1765–1775PubMedGoogle Scholar
  26. Sakmann B, Trube G (1984) Voltage-dependent inactivation of inward-rectifying single-channel currents in the guinea-pig heart cell membrane. J Physiol 347:659–683PubMedGoogle Scholar
  27. Sánchez-Chapula JA (1988) Effects of bupivacaine on membrane currents of guinea-pig ventricular myocytes. Eur J Pharmacol 156:303–308CrossRefPubMedGoogle Scholar
  28. 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 96:195–215PubMedGoogle Scholar
  29. 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 55:497–507PubMedGoogle Scholar
  30. Shi H, Wang H, Wang Z (1999b) M3 muscarinic receptor activation of a delayed rectifier potassium current in canine atrial myocytes. Life Sci 65:PL143–149CrossRefPubMedGoogle Scholar
  31. 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 169:55–64PubMedGoogle Scholar
  32. Soejima M, Noma A (1984) Mode of regulation of the ACh-sensitive K-channel by the muscarinic receptor in rabbit atrial cells. Pflügers Arch 400:424–431Google Scholar
  33. Van Zwiten PA, Doods HN (1995) Muscarinic receptors and drugs in cardiovascular medicine. Cardiovasc Drugs Ther 9:159–167PubMedGoogle Scholar
  34. 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 126:1725–1734PubMedGoogle Scholar
  35. Yamada M, Inanobe A, Kurachi Y (1998) G protein regulation of potassium ion channels. Pharmacol Rev 50:723–757PubMedGoogle Scholar
  36. Zang WJ, Yu XJ, Boyett MR (1995) Barium block of the muscarinic potassium current in guinea-pig atrial cells. Pflügers Arch 430:348–357Google Scholar

Copyright information

© Springer-Verlag 2003

Authors and Affiliations

  • Dora E. Benavides-Haro
    • 1
  • Ricardo A. Navarro-Polanco
    • 2
  • José A. Sánchez-Chapula
    • 2
    Email author
  1. 1.Facultad de Medicina Humana y Ciencias de la SaludUniversidad Autónoma de ZacatecasZacatecasMéxico
  2. 2.Unidad de Investigación "Carlos Méndez" del Centro de Investigaciones Biomédicas de la Universidad de ColimaColimaMéxico

Personalised recommendations