Skip to main content
SpringerLink
Log in

β-Adrenergic modulation of transient inward current in guinea-pig cardiac myocytes

Evidence for regulation of Ca2+-release from sarcoplasmic reticulum by a cyclic AMP dependent mechanism

  • Published:
Pflügers Archiv Aims and scope Submit manuscript

Abstract

Transient inward current (Iti) indicating Ca2+-release from the sarcoplasmic reticulum and L-type Ca2+-current(ICa) were studied in atrial and ventricular myocytes from hearts of adult guinea-pigs by means of whole-cell voltage-clamp. The increase of ICa caused by β-adrenergic stimulation using isoprenaline (ISO) or related experimental manoeuvres such as superfusion with forskoline (FORSK) was used as a qualitative monitor of an increase of intracellular cAMP. Changes of Iti were used to manifest changes of sarcoplasmic Ca2+-release. In myocytes dialysed with citrate-based (60 mM) pipette filling solution containing 100 μM EGTA spontaneous transient inward currents were recorded at a constant holding potential of −50 mV in the majority of myocytes. Superfusion with a solution containing ISO (≥5·10−8M) increased the amplitude of spontaneous Iti and reduced its time-to-peak. The effects of ISO on Iti developed in parallel to stimulation of ICa. In myocytes which did not show spontaneous cyclic Ca2+-release in the above condition, this could be evoked de novo by ISO. Spontaneous Iti was suppressed in the majority of cells by increasing the concentration of EGTA in the dialysing solution to 200 μM. Brief (50 ms) activation of ICa by voltage steps from −50 to +10 mV usually failed to trigger Ca2+-release from the SR. The increase of ICa-amplitude upon administration of ISO went ahead with the induction of Ca2+-release by brief activation of ICa. The effects of ISO could be mimicked by FORSK or intracellular dialysis with 3′5′-cyclic adenosine monophosphate. The effects on ICa and SR Ca2+-release were dependent on the concentration of the stimulating substance. In a given cell changing superfusion from a low to a high concentration of ISO or FORSK resulted in an increase of the number of Ca2+-release events per number of Ca2+-currents elicited and a shortening of time-to-peak of Iti's. The stimulating effects of ISO or FORSK on Ca2+-release were only partially due to an increase of the triggering ICa. Ca2+-currents too small to trigger Ca2+-release before β-adrenergic stimulation could evoke Ca2+-release after augmentation of intracellular cAMP. Whereas the effects of ISO and FORSK on ICa were reversible, the stimulatory effects on Ca2+-release persisted after washing out the substances. The results give support to the hypothesis that β-adrenoceptor-mediated positive inotropic and arrhythmogenic effects are, at least partly, due to a cyclic AMP-dependent regulatory mechanism modulating sarcoplasmic Ca2+-release.

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

Similar content being viewed by others

References

  • Allen DG, Kurihara S (1982) The effect of muscle length on intracellular calcium transients in mammalian cardiac muscle. J Physiol (Lond) 327:79–94

    Google Scholar 

  • Barcenas-Ruiz L, Beuckelmann DJ, Wier WG (1988) Sodium-calcium exchange in heart: currents and changes in [Ca2+]i. Science 238:1720–1722

    Google Scholar 

  • Barcenas-Ruiz L, Wier WG (1987) Voltage dependence of intracellular [Ca2+]i transients in guinea pig ventricular myocytes. Circ Res 613:148–154

    Google Scholar 

  • Bean BP, Nowycky MC, Tsien RW (1984) β-Adrenergic modulation of calcium channels in frog ventricular heart cells. Nature 307:371–375

    Google Scholar 

  • Bechem M, Pott L (1985) Removal of Ca current inactivation in dialysed guinea-pig atrial cardioballs by Ca chelators. Pflügers Arch 404:10–20

    Google Scholar 

  • Bechern M, Pott L, Rennebaum H (1983) Atrial muscle cells from hearts of adult guinea-pigs: a new preparation for cardiac cellular electrophysiology. Eur J Cell Biol 31:366–369

    Google Scholar 

  • Beuckelmann DJ, Pott L, Wier WG (1989) Transient inward current and intracellular calcium concentration in guinea-pig ventricular myocytes. J Physiol 314:110 P

    Google Scholar 

  • Beuckelmann DJ, Wier WG (1988) Mechanism of release of Calcium from sarcoplasmic reticulum of guinea-pig cardiac cells. J Physiol (Lond) 405:233–255

    Google Scholar 

  • Beuckelmann DJ, Wier WG (1989) Sodium-calcium exchange in guinea-pig cardic cells: exchange current and intracellular calcium. J Physiol (Lond) 414:499–520

    Google Scholar 

  • Blinks JR (1986) Intracellular [Ca2+] measurements. In: Fozzard HA, Haber E, Jennings RB, Katz AM, Morgan HE (eds) The Heart and Cardiovascular System. Raven New York, pp 671–701

    Google Scholar 

  • Brum G, Flockerzi V, Hofmann F, Osterrieder W, Trautwein W (1983) Injection of catalytic subunit of cAMP-dependent protein kinase into isolated cardiac myocytes. Pflügers Arch 398:147–154

    Google Scholar 

  • Brückner R, Mügge A, Scholz H (1985) Existence and functional role of α1-adrenoceptors in the mammalian heart. J Mol Cell Cardiol 17:639–645

    Google Scholar 

  • Cachelin AB, De Peyer JE, Kokubun S, Reuter H (1983) Calcium channel modulation by 8-bromo-cyclic AMP in cultured heart cells. Nature 304:462–464

    Google Scholar 

  • Callewaert G, Cleemann L, Morad M (1988) Epinephrine enhances Ca2+ current-regulated Ca2+ release and Ca2+ re-uptake in rat ventricular myocytes. Proc Natl Acad Sci 85:2009–2013

    Google Scholar 

  • Cannell MB, Berlin JR, Lederer WJ (1987) Effect of membrane potential changes on the calcium transient in single rat cardiac muscle cells. Science 238:1419–1423

    Google Scholar 

  • Capogrossi MC, Lakatta EG (1985) Frequency modulation and synchronization of spontaneous oscillations in cardiac cells. Am J Physiol 248:H412-H418

    Google Scholar 

  • Capogrossi MC, Suarez-Isla BA, Lakatta EG (1986) The interaction of electrically stimulated twitches and spontaneous contractile waves in single cardiac myocytes. J Gen Physiol 88:615–633

    Google Scholar 

  • Chapman RA (1983) Control of cardiac contractility at the cellular level. Am J Physiol 245:H535-H552

    Google Scholar 

  • Clusin WT, Fischmeister R, DeHaan G (1983) Caffeine-induced current in embryonic heart cells: time course and voltage-dependence. Am J Physiol 245:H528-H532

    Google Scholar 

  • Cranefield PF (1977) Action potentials, afterpotentials and arrhythmias. Circ Res 41:415–423

    Google Scholar 

  • DiFrancesco D, Noble D (1985) A model of cardiac electrical activity incorporating ionic pumps and concentration changes. Phil Trans Roy Soc B 307:353–398

    Google Scholar 

  • Endoh M, Blinks JR (1988) Actions of sympathetic amines on the Ca2+ transients and contractions of rabbit myocardium: Reciprocal changes in myofibrillar responsiveness to Ca2+ mediated through α- and β-adrenoceptors. Circ Res 62:247–265

    Google Scholar 

  • Fabiato A (1983) Calcium-induced release of calcium from the cardiac sarcoplasmic reticulum. Am J Physiol 245:H1-H14

    Google Scholar 

  • Fabiato A (1985a) Rapid ionic modifications during the aequorin-detected calcium transient in a skinned canine cardiac Purkinje cell. J Gen Physiol 85:189–246

    Google Scholar 

  • Fabiato A (1985b) Time and calcium dependence of activation of calcium-induced release of calcium from the sarcoplasmic reticulum of a skinned cardiac Purkinje cell. J Gen Physiol 85:247–289

    Google Scholar 

  • Fabiato A (1985c) 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 85:291–320

    Google Scholar 

  • Fabiato A, Fabiato F (1975) Relaxing and inotropic effects of cyclic AMP on skinned cardiac cells. Nature 253:556–558

    Google Scholar 

  • Fedida D, Noble D, Shimoni Y, Spindler AJ (1987) Inward current related to contraction in guinea-pig ventricular myocytes. J Physiol (Lond) 385:565–589

    Google Scholar 

  • Gasser J, Paganetti P, Carafoli E, Chiesi M (1988) Heterogeneous distribution of calmodulin and cAMP-dependent regulation of Ca2+ uptake in cardiac sarcoplasmic reticulum subfractions. Eur J Biochem 176:535–541

    Google Scholar 

  • Gibbons WR (1986) Cellular control of cardiac contraction. In: Fozzard HA, Haber E, Jennings RB, Katz AM, Morgan HE (eds) The Heart and Cardiovascular System. Raven New York, pp 747–778

    Google Scholar 

  • Gintant GA, Cohen IS (1988) Advances in cardiac cellular electrophysiology: implications for automaticity and therapeutics. Ann Rev Pharmacol Toxicol 28:61–81

    Google Scholar 

  • Hamill OP, Marty A, Neher E, Sakmann B, Sigworth FJ (1981) Improved patch clamp techniques for high-resolution current recording from cells and cell-free membrane patches. Pflügers Arch 391:85–100

    Google Scholar 

  • Hescheler J, Tang M, Jastorff B, Trautwein W (1987) On the mechanism of histamine induced enhancement of the cardiac Ca2+ current. Pflügers Arch 410:23–29

    Google Scholar 

  • January CT, Fozzard H (1988) Delayed afterdepolarizations in heart muscle: Mechanisms and relevance. Pharmacol Rev 40:219–227

    Google Scholar 

  • Kameyama M, Hofmann F, Trautwein W (1985) On the mechanism of β-adrenergic regulation of the Ca channel in guinea-pig heart. Pflügers Arch 405:285–293

    Google Scholar 

  • Katz AM, Takenaka H, Watras J (1986) The sarcoplasmic reticulum. In: Fozzard HA, Haber E, Jennings RB, Katz AM, Morgan HE (eds) The Heart and Cardiovascular System. Raven New York, pp 731–746

    Google Scholar 

  • Kovacs RJ, Nelson MT, Simmermann HKB, Jones LR (1988) Phospholamban forms Ca2+-selective channels in lipid bilayers. J Biol Chem 263:18364–18368

    Google Scholar 

  • Kranias EG, Steenaart NAE, Di Salvo J (1988) Purification and characterization of phospholamban phosphatase from cardiac muscle. J Biol Chem 263:15681–15687

    Google Scholar 

  • Kurihara S, Konishi M (1987) Effects of β-adrenoceptor stimulation on intracellular Ca transients and tension in rat ventricular muscle. Pflügers Arch 409:427–437

    Google Scholar 

  • Lindemann JP, Watanabe AM (1985) Muscarinic cholinergic inhibition of β-adrenergic stimulation of phospholamban phosphorylation and Ca2+ transport in guinea pig ventricles. J Biol Chem 280:13122–13129

    Google Scholar 

  • Lipp P, Mechmann S, Pott L (1987) Effects of Ca-release from sarcoplasmic reticulum on membrane currents in guinea-pig atrial cardioballs. Pflügers Arch 410:121–131

    Google Scholar 

  • Lipp P, Pott L (1988a) Transient inward current in guinea-pig atrial myocytes reflects of change of sodium-calcium exchange current. J Physiol (Lond) 397:601–630

    Google Scholar 

  • Lipp P, Pott L (1988b) Voltage-dependence of sodium-calcium exchange current in guinea-pig atrial myocytes determined by means of an inhibitor. J Physiol (Lond) 403:355–366

    Google Scholar 

  • Marban E, Wier WG (1985) Ryanodine as a tool to determine the contributions of calcium entry and calcium release to the calcium transient and contraction of cardiac Purkinje fibers. Circ Res 56:133–138

    Google Scholar 

  • Mechmann S, Pott L (1986) Identification of Na-Ca exchange current in single cardiac myocytes. Nature 319:597–599

    Google Scholar 

  • Meissner G (1984) Adenine nucleotide stimulation of Ca2+-induced Ca2+-release in sarcoplasmic reticulum. J Biol Chem 259:2365–2374

    Google Scholar 

  • Mitchell MR, Powell T, Terrar DA, Twist VW (1984) The effects of ryanodine, EGTA and low sodium on action potentials in rat and guinea-pig ventricular myocytes: evidence for two inward currents during the plateau. Br J Pharmacol 81:543–550

    Google Scholar 

  • Morad M, Cleemann L (1987) Role of Ca2+-channel in development of tension in heart muscle. J Mol Cell Cardiol 19:527–533

    Google Scholar 

  • Morgan JP, Blinks JR (1982) Intracellular Ca2+-transients in the cat papillary muscle. Can J Physiol Pharmacol 60:524–528

    Google Scholar 

  • Movsesian MA, Nishikawa M, Adelstein RS (1984) Phosphorylation of phospholamban by calcium-activated, phospholipiddependent protein kinase. J Biol Chem 259:8029–8032

    Google Scholar 

  • Noble D (1984) The surprising heart: a review of recent progress in cardiac electrophysiology. J Physiol (Lond) 353:1–50

    Google Scholar 

  • Opie LH, Muller C, Nathan D, Daries P, Lubbe WF (1980) Evidence for role of cyclic AMP as second messenger of arrhythmogenic effects of beta-stimulation. Adv Cycl Nucl Res 12:63–69

    Google Scholar 

  • Pott L (1988a) Ca2+-cycling causing arrhythmogenic transient inward current in guinea-pig atrial myocytes by stimulation of the cyclic AMP dependent regulatory pathway. Pflügers Arch 412 (Suppl. 1) R 24

    Google Scholar 

  • Pott L (1988b) β-Adrenergic stimulation facilitates Ca2+-induced Ca2+-release from sarcoplasmic reticulum in guinea-pig atrial myocytes. J Physiol (Lond) 407:127 P

    Google Scholar 

  • Pott L, Mechmann S (1986) Interaction of Ca-release and transmembrane Ca-current in guinea-pig atrial cardioballs. In: Lüttgau HC (ed) Membrane control of cellular activity. Fischer Stuttgart, New York, pp 99–109

    Google Scholar 

  • Reiter M (1988) Calcium mobilization and cardiac inotropic mechanisms. Pharmacol Rev 40:189–217

    Google Scholar 

  • Reuter H (1983) Calcium channel modulation by neurotransmitters enzymes and drungs. Nature 301:569–574

    Google Scholar 

  • Reuter H, Scholz H (1977) The regulation of the calcium conductance of cardiac muscle by adrenaline. J Physiol (Lond) 264:49–62

    Google Scholar 

  • Robinson-Steiner AM, Corbin JD (1986) Protein phosphorylation in the heart. In: Fozzard HA, Haber E, Jennings RB, Katz AM, Morgan HE (eds) The Heart and Cardiovascular System. Raven New York, pp 887–910

    Google Scholar 

  • Seamon KB, Padgett W, Daly JW (1981) Forskolin: unique diterpene activator of adenylate cyclase in membranes and intact cells. J Biol Chem 257:11591–11596

    Google Scholar 

  • Sheu S-S, Blaustein MP (1986) Sodium/calcium exchange and regulation of cell calcium and contractility in cardiac muscle, with a note about vascular smooth muscle. In: Fozzard HA, Haber E, Jennings RB, Katz AM, Morgan HE (eds) The Heart and Cardiovascular System. Raven New York, pp 509–535

    Google Scholar 

  • Stiles GL, Lefkowitz RJ (1984) β-adrenergic receptors: Biochemical mechanism of physiological regulation. Physiol Rev 64:661–743

    Google Scholar 

  • Tada M, Katz AM (1982) Phosphorylation of the sarcoplasmic reticulum and sarcolemma. Ann Rev Physiol 44:401–423

    Google Scholar 

  • Tada M, Kirchberger MA, Repke DI, Katz AM (1974) The stimulation of calcium transport in cardiac sarcoplasmic reticulum by adenosine 3′,5-monophosphate-dependent protein kinase. J Biol Chem 249:6174–6180

    Google Scholar 

  • Trautwein W, Kameyama M, Hescheler J, Hofmann F (1986) Cardiac calcium channels and their transmitter modulation. In: Lüttgau HC (ed) Membrane control of cellular activity. Fischer Stuttgart New York,pp 163–182

    Google Scholar 

  • Tsien RW (1977) Cyclic AMP and contractile activity in heart. Adv Cycl Nucl Res 8:363–420

    Google Scholar 

  • Wier WG (1980) Calcium transients during excitation-contraction coupling in mammalian heart: Aequorin signals of canine Purkinje fibers. Science 207:1085–1087

    Google Scholar 

  • Wier WG, Isenberg G (1982) Intracellular [Ca2+] transients in voltage clamped cardiac Purkinje fibers. Pflügers Arch 392:284–290

    Google Scholar 

  • Wolf A, Levi R (1986) Histamine and cardiac arrhythmias. Circ Res 58:1–16

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institut für Zellphysiologie, Ruhr-Universität Bochum, Postfach 102148, D-4630, Bochum, Federal Republic of Germany

    M. Boller & L. Pott

Authors
  1. M. Boller
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. L. Pott
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

This work was supported by the Deutsche Forschungsgemeinschaft (FG Konzell)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Boller, M., Pott, L. β-Adrenergic modulation of transient inward current in guinea-pig cardiac myocytes. Pflügers Arch 415, 276–288 (1989). https://doi.org/10.1007/BF00370877

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00370877

Key words

Search

Navigation