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. 1988 Oct;404:613–635. doi: 10.1113/jphysiol.1988.sp017309

The negative inotropic effect of acetylcholine on ferret ventricular myocardium.

M R Boyett 1, M S Kirby 1, C H Orchard 1, A Roberts 1
PMCID: PMC1190845  PMID: 3253444

Abstract

1. The effects of acetylcholine (ACh) on developed tension and intracellular Ca2+ concentration (as measured with aequorin) were studied in ferret papillary muscles, and on twitch shortening, the action potential and membrane currents in ferret ventricular myocytes. 2. Addition of ACh to ferret papillary muscles resulted in decreases in developed tension and the intracellular Ca2+ transient, both of which then partially recovered in the continued presence of ACh ('fade' of the response). On wash-off of ACh both developed tension and the intracellular Ca2+ transient increased above control ('rebound') before returning to control values. 3. Addition of ACh to ferret ventricular myocytes resulted in a membrane hyperpolarization of 2 +/- 0.5 mV (mean +/- S.E.M.; n = 9), a decrease in action potential duration to 23 +/- 6% of control and a decrease in twitch shortening to 31 +/- 5% of control. In the continued presence of ACh these responses to ACh faded. Thirty seconds after the maximal effect of ACh, action potential duration had partially recovered to 34 +/- 6% of control and twitch shortening to 46 +/- 7% of control. 4. The effects of ACh on twitch shortening could be mimicked under voltage clamp by varying voltage clamp pulse duration to simulate the ACh-induced changes in action potential duration. 5. When ACh was applied during a train of voltage clamp pulses of constant duration, 81% of the cells showed less than a 20% decrease in Ca2+ current and twitch shortening. However in 19% of the cells twitch shortening and the apparent Ca2+ current decreased by more than 30%. 6. In the 81% of cells, the normal decrease in twitch shortening was wholly the result of the shortening of the action potential. This in turn was the result of an increase in an outward background current which increased the rate of repolarization during the action potential. The ACh-induced background current reversed at -89 +/- 2 mV and showed inward-going rectification; these properties suggest that it was carried by K+. 7. In the 19% of cells, the normal decrease in twitch shortening was only partly the result of the shortening of the action potential (due to both the increase in outward background current as well as the apparent decrease in Ca2+ current). In these cells the decrease in twitch shortening may also have been partly the direct result of the apparent decrease of Ca2+ current.

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Selected References

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

  1. Antoni H., Rotmann M. Zum Mechanismus der negative inotropen Acetylcholin-Wirkung auf das isolierte Froschmyokard. Pflugers Arch Gesamte Physiol Menschen Tiere. 1968;300(2):67–86. [PubMed] [Google Scholar]
  2. Beeler G. W., Jr, Reuter H. The relation between membrane potential, membrane currents and activation of contraction in ventricular myocardial fibres. J Physiol. 1970 Mar;207(1):211–229. doi: 10.1113/jphysiol.1970.sp009057. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Boyd N. D. Two distinct kinetic phases of desensitization of acetylcholine receptors of clonal rat PC12 cells. J Physiol. 1987 Aug;389:45–67. doi: 10.1113/jphysiol.1987.sp016646. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Boyett M. R., Fedida D. Changes in the electrical activity of dog cardiac Purkinje fibres at high heart rates. J Physiol. 1984 May;350:361–391. doi: 10.1113/jphysiol.1984.sp015206. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Boyett M. R., Hart G., Levi A. J., Roberts A. Effects of repetitive activity on developed force and intracellular sodium in isolated sheep and dog Purkinje fibres. J Physiol. 1987 Jul;388:295–322. doi: 10.1113/jphysiol.1987.sp016616. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Boyett M. R., Levi A. J. A simple electronic circuit for determining the twitch force and resting force of small heart muscle preparations. Pflugers Arch. 1987 Oct;410(3):340–341. doi: 10.1007/BF00580287. [DOI] [PubMed] [Google Scholar]
  7. Boyett M. R., Roberts A. The fade of the response to acetylcholine at the rabbit isolated sino-atrial node. J Physiol. 1987 Dec;393:171–194. doi: 10.1113/jphysiol.1987.sp016818. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Cannell M. B., Lederer W. J. A novel experimental chamber for single-cell voltage-clamp and patch-clamp applications with low electrical noise and excellent temperature and flow control. Pflugers Arch. 1986 May;406(5):536–539. doi: 10.1007/BF00583378. [DOI] [PubMed] [Google Scholar]
  9. Carmeliet E., Mubagwa K. Characterization of the acetylcholine-induced potassium current in rabbit cardiac Purkinje fibres. J Physiol. 1986 Feb;371:219–237. doi: 10.1113/jphysiol.1986.sp015970. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Carmeliet E., Mubagwa K. Desensitization of the acetylcholine-induced increase of potassium conductance in rabbit cardiac Purkinje fibres. J Physiol. 1986 Feb;371:239–255. doi: 10.1113/jphysiol.1986.sp015971. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Chapman R. A. Excitation-contraction coupling in cardiac muscle. Prog Biophys Mol Biol. 1979;35(1):1–52. doi: 10.1016/0079-6107(80)90002-4. [DOI] [PubMed] [Google Scholar]
  12. Chen B., MacLeod D. I., Stockman A. Improvement in human vision under bright light: grain or gain? J Physiol. 1987 Dec;394:41–66. doi: 10.1113/jphysiol.1987.sp016859. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Fabiato A. Simulated calcium current can both cause calcium loading in and trigger calcium release from the sarcoplasmic reticulum of a skinned canine cardiac Purkinje cell. J Gen Physiol. 1985 Feb;85(2):291–320. doi: 10.1085/jgp.85.2.291. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Farmer B. B., Mancina M., Williams E. S., Watanabe A. M. Isolation of calcium tolerant myocytes from adult rat hearts: review of the literature and description of a method. Life Sci. 1983 Jul 4;33(1):1–18. doi: 10.1016/0024-3205(83)90706-3. [DOI] [PubMed] [Google Scholar]
  15. Fischmeister R., Hartzell H. C. Cyclic guanosine 3',5'-monophosphate regulates the calcium current in single cells from frog ventricle. J Physiol. 1987 Jun;387:453–472. doi: 10.1113/jphysiol.1987.sp016584. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Garnier D., Nargeot J., Ojeda C., Rougier O. The action of acetylcholine on background conductance in frog atrial trabeculae. J Physiol. 1978 Jan;274:381–396. doi: 10.1113/jphysiol.1978.sp012154. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Gibbons W. R., Fozzard H. A. Relationships between voltage and tension in sheep cardiac Purkinje fibers. J Gen Physiol. 1975 Mar;65(3):345–365. doi: 10.1085/jgp.65.3.345. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Giles W., Noble S. J. Changes in membrane currents in bullfrog atrium produced by acetylcholine. J Physiol. 1976 Sep;261(1):103–123. doi: 10.1113/jphysiol.1976.sp011550. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Hancock J. C., Hoover D. B., Hougland M. W. Distribution of muscarinic receptors and acetylcholinesterase in the rat heart. J Auton Nerv Syst. 1987 Apr;19(1):59–66. doi: 10.1016/0165-1838(87)90145-7. [DOI] [PubMed] [Google Scholar]
  20. Hartzell H. C., Simmons M. A. Comparison of effects of acetylcholine on calcium and potassium currents in frog atrium and ventricle. J Physiol. 1987 Aug;389:411–422. doi: 10.1113/jphysiol.1987.sp016663. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Hescheler J., Rosenthal W., Trautwein W., Schultz G. The GTP-binding protein, Go, regulates neuronal calcium channels. 1987 Jan 29-Feb 4Nature. 325(6103):445–447. doi: 10.1038/325445a0. [DOI] [PubMed] [Google Scholar]
  22. Hino N., Ochi R. Effect of acetylcholine on membrane currents in guinea-pig papillary muscle. J Physiol. 1980 Oct;307:183–197. doi: 10.1113/jphysiol.1980.sp013430. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Iijima T., Irisawa H., Kameyama M. Membrane currents and their modification by acetylcholine in isolated single atrial cells of the guinea-pig. J Physiol. 1985 Feb;359:485–501. doi: 10.1113/jphysiol.1985.sp015598. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Josephson I., Sperelakis N. On the ionic mechanism underlying adrenergic-cholinergic antagonism in ventricular muscle. J Gen Physiol. 1982 Jan;79(1):69–86. doi: 10.1085/jgp.79.1.69. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Kentish J. C., Boyett M. R. A simple electronic circuit for monitoring changes in the duration of the action potential. Pflugers Arch. 1983 Aug;398(3):233–235. doi: 10.1007/BF00657157. [DOI] [PubMed] [Google Scholar]
  26. 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]
  27. 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]
  28. London B., Krueger J. W. Contraction in voltage-clamped, internally perfused single heart cells. J Gen Physiol. 1986 Oct;88(4):475–505. doi: 10.1085/jgp.88.4.475. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Löffelholz K., Pappano A. J. The parasympathetic neuroeffector junction of the heart. Pharmacol Rev. 1985 Mar;37(1):1–24. [PubMed] [Google Scholar]
  30. Noma A., Trautwein W. Relaxation of the ACh-induced potassium current in the rabbit sinoatrial node cell. Pflugers Arch. 1978 Nov 30;377(3):193–200. doi: 10.1007/BF00584272. [DOI] [PubMed] [Google Scholar]
  31. 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]
  32. Rardon D. P., Pappano A. J. Carbachol inhibits electrophysiological effects of cyclic AMP in ventricular myocytes. Am J Physiol. 1986 Sep;251(3 Pt 2):H601–H611. doi: 10.1152/ajpheart.1986.251.3.H601. [DOI] [PubMed] [Google Scholar]
  33. Soejima M., Noma A. Mode of regulation of the ACh-sensitive K-channel by the muscarinic receptor in rabbit atrial cells. Pflugers Arch. 1984 Apr;400(4):424–431. doi: 10.1007/BF00587544. [DOI] [PubMed] [Google Scholar]
  34. Sorota S., Tsuji Y., Tajima T., Pappano A. J. Pertussis toxin treatment blocks hyperpolarization by muscarinic agonists in chick atrium. Circ Res. 1985 Nov;57(5):748–758. doi: 10.1161/01.res.57.5.748. [DOI] [PubMed] [Google Scholar]
  35. Ten Eick R., Nawrath H., McDonald T. F., Trautwein W. On the mechanism of the negative inotropic effect of acetylcholine. Pflugers Arch. 1976 Feb 24;361(3):207–213. doi: 10.1007/BF00587284. [DOI] [PubMed] [Google Scholar]

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