Skip to main content
NCBI home page
British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 1993 Jan;108(1):111–115. doi: 10.1111/j.1476-5381.1993.tb13448.x

Antiarrhythmic agents act differently on the activation phase of the ACh-response in guinea-pig atrial myocytes.

N Inomata 1, T Ohno 1, T Ishihara 1, N Akaike 1
PMCID: PMC1907710  PMID: 8428201

Abstract

1. Anti-acetylcholine effects of pilsicainide, flecainide, disopyramide and propafenone on the acetylcholine (ACh)-induced K+ current (IK.ACh) were examined in dissociated guinea-pig atrial myocytes under whole-cell voltage clamp by the use of the 'concentration-clamp' technique. 2. The IK.ACh was activated with a latency of about 100 ms after 1 microM ACh application and desensitized to a steady-state level. The latent period and the time to peak response were shortened with increasing ACh concentration. 3. The values of half-maximal inhibition (IC50) on the peak and steady state responses were 25 and 25 microM for pilsicainide, 1.7 and 2.0 microM for disopyramide, 19 and 2.0 microM for flecainide and 0.7 and 0.2 microM for propafenone, respectively. 4. Pilsicainide and disopyramide increased the latent period and the time to peak of IK.ACh in a concentration-dependent manner. Flecainide and propafenone did not change the latent period, but shortened the time to peak and hastened the decay of IK.ACh in a voltage-independent manner. 5. The results suggest that the mechanisms underlying the anti-acetylcholine effect of antiarrhythmic drugs are different among these drugs: i.e., pilsicainide and disopyramide mainly block the muscarinic ACh receptors while flecainide and propafenone inhibit the K+ channel itself as open channel blockers.

Full text

PDF
111

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Akaike N., Inoue M., Krishtal O. A. 'Concentration-clamp' study of gamma-aminobutyric-acid-induced chloride current kinetics in frog sensory neurones. J Physiol. 1986 Oct;379:171–185. doi: 10.1113/jphysiol.1986.sp016246. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Akaike N., Lee K. S., Brown A. M. The calcium current of Helix neuron. J Gen Physiol. 1978 May;71(5):509–531. doi: 10.1085/jgp.71.5.509. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Armstrong C. M. Ionic pores, gates, and gating currents. Q Rev Biophys. 1974 May;7(2):179–210. doi: 10.1017/s0033583500001402. [DOI] [PubMed] [Google Scholar]
  4. Birkhead J. S., Vaughan Williams E. M. Dual effect of disopyramide on atrial and atrioventricular conduction and refractory periods. Br Heart J. 1977 Jun;39(6):657–660. doi: 10.1136/hrt.39.6.657. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Breitwieser G. E., Szabo G. Uncoupling of cardiac muscarinic and beta-adrenergic receptors from ion channels by a guanine nucleotide analogue. Nature. 1985 Oct 10;317(6037):538–540. doi: 10.1038/317538a0. [DOI] [PubMed] [Google Scholar]
  6. Endou M., Gando S., Hattori Y., Kanno M. Binding profiles of class I antiarrhythmic agents to cardiac muscarinic receptors: competitive and allosteric interactions with the receptors and their pharmacological significance. J Pharmacol Exp Ther. 1991 Sep;258(3):992–998. [PubMed] [Google Scholar]
  7. Follmer C. H., Colatsky T. J. Block of delayed rectifier potassium current, IK, by flecainide and E-4031 in cat ventricular myocytes. Circulation. 1990 Jul;82(1):289–293. doi: 10.1161/01.cir.82.1.289. [DOI] [PubMed] [Google Scholar]
  8. Hashimoto K., Ishii M., Komori S., Mitsuhashi H. Canine digitalis arrhythmia as a model for detecting Na-channel blocking antiarrhythmic drugs: a comparative study using other canine arrhythmia models and the new antiarrhythmic drugs, propafenone, tocainide, and SUN 1165. Heart Vessels. 1985 Feb;1(1):29–35. doi: 10.1007/BF02066484. [DOI] [PubMed] [Google Scholar]
  9. Hattori Y., Inomata N., Aisaka K., Ishihara T. Electrophysiological actions of N-(2,6-dimethylphenyl)-8-pyrrolizidine-acetamide hydrochloride hemihydrate (SUN 1165), a new antiarrhythmic agent. J Cardiovasc Pharmacol. 1986 Sep-Oct;8(5):998–1002. doi: 10.1097/00005344-198609000-00017. [DOI] [PubMed] [Google Scholar]
  10. Honjo H., Watanabe T., Kamiya K., Kodama I., Toyama J. Effects of propafenone on electrical and mechanical activities of single ventricular myocytes isolated from guinea-pig hearts. Br J Pharmacol. 1989 Jul;97(3):731–738. doi: 10.1111/j.1476-5381.1989.tb12010.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Imaizumi Y., Giles W. R. Quinidine-induced inhibition of transient outward current in cardiac muscle. Am J Physiol. 1987 Sep;253(3 Pt 2):H704–H708. doi: 10.1152/ajpheart.1987.253.3.H704. [DOI] [PubMed] [Google Scholar]
  12. Inomata N., Ishihara T., Akaike N. Activation kinetics of the acetylcholine-gated potassium current in isolated atrial cells. Am J Physiol. 1989 Oct;257(4 Pt 1):C646–C650. doi: 10.1152/ajpcell.1989.257.4.C646. [DOI] [PubMed] [Google Scholar]
  13. Inomata N., Ishihara T., Akaike N. Mechanisms of the anticholinergic effect of SUN 1165 in comparison with flecainide, disopyramide and quinidine in single atrial myocytes isolated from guinea-pig. Br J Pharmacol. 1991 Dec;104(4):1007–1011. doi: 10.1111/j.1476-5381.1991.tb12541.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Inomata N., Ishihara T., Akaike N. SUN 1165: a new antiarrhythmic Na current blocker in ventricular myocytes of guinea-pig. Comp Biochem Physiol C. 1987;87(2):237–243. doi: 10.1016/0742-8413(87)90003-x. [DOI] [PubMed] [Google Scholar]
  15. Kurachi Y., Nakajima T., Sugimoto T. Acetylcholine activation of K+ channels in cell-free membrane of atrial cells. Am J Physiol. 1986 Sep;251(3 Pt 2):H681–H684. doi: 10.1152/ajpheart.1986.251.3.H681. [DOI] [PubMed] [Google Scholar]
  16. Kurachi Y., Nakajima T., Sugimoto T. On the mechanism of activation of muscarinic K+ channels by adenosine in isolated atrial cells: involvement of GTP-binding proteins. Pflugers Arch. 1986 Sep;407(3):264–274. doi: 10.1007/BF00585301. [DOI] [PubMed] [Google Scholar]
  17. Mirro M. J., Manalan A. S., Bailey J. C., Watanabe A. M. Anticholinergic effects of disopyramide and quinidine on guinea pig myocardium. Mediation by direct muscarinic receptor blockade. Circ Res. 1980 Dec;47(6):855–865. doi: 10.1161/01.res.47.6.855. [DOI] [PubMed] [Google Scholar]
  18. Nakajima T., Kurachi Y., Ito H., Takikawa R., Sugimoto T. Anti-cholinergic effects of quinidine, disopyramide, and procainamide in isolated atrial myocytes: mediation by different molecular mechanisms. Circ Res. 1989 Feb;64(2):297–303. doi: 10.1161/01.res.64.2.297. [DOI] [PubMed] [Google Scholar]
  19. Osterrieder W., Yang Q. F., Trautwein W. The time course of the muscarinic response to ionophoretic acetylcholine application to the S-A node of the rabbit heart. Pflugers Arch. 1981 Mar;389(3):283–291. doi: 10.1007/BF00584791. [DOI] [PubMed] [Google Scholar]
  20. Pfaffinger P. J., Martin J. M., Hunter D. D., Nathanson N. M., Hille B. GTP-binding proteins couple cardiac muscarinic receptors to a K channel. Nature. 1985 Oct 10;317(6037):536–538. doi: 10.1038/317536a0. [DOI] [PubMed] [Google Scholar]
  21. Pott L., Pusch H. A kinetic model for the muscarinic action of acetylcholine. Pflugers Arch. 1979 Dec;383(1):75–77. doi: 10.1007/BF00584478. [DOI] [PubMed] [Google Scholar]
  22. Yatani A., Codina J., Brown A. M., Birnbaumer L. Direct activation of mammalian atrial muscarinic potassium channels by GTP regulatory protein Gk. Science. 1987 Jan 9;235(4785):207–211. doi: 10.1126/science.2432660. [DOI] [PubMed] [Google Scholar]
  23. Yeh J. Z., Narahashi T. Kinetic analysis of pancuronium interaction with sodium channels in squid axon membranes. J Gen Physiol. 1977 Mar;69(3):293–323. doi: 10.1085/jgp.69.3.293. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from British Journal of Pharmacology are provided here courtesy of The British Pharmacological Society

RESOURCES