Skip to main content
SpringerLink
Log in

Inhibitory effect of YM-244769, a novel Na+/Ca2+ exchanger inhibitor on Na+/Ca2+ exchange current in guinea pig cardiac ventricular myocytes

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

Abstract

Recently, YM-244769 (N-(3-aminobenzyl)-6-{4-[(3-fluorobenzyl)oxy]phenoxy} nicotinamide) has been reported as a new potent and selective Na+/Ca2+ exchange (NCX) inhibitor by using various cells transfected with NCX using the 45Ca2+ fluorescent technique. However, the electrophysiological study of YM-244769 on NCX had not been performed in the mammalian heart. We examined the effects of YM-244769 on NCX current (INCX) in single cardiac ventricular myocytes of guinea pigs by using the whole-cell voltage clamp technique. YM-244769 suppressed the bidirectional INCX in a concentration-dependent manner. The IC50 values of YM-244769 for the bidirectional outward and inward INCX were both about 0.1 μM. YM-244769 suppressed the unidirectional outward INCX (Ca2+ entry mode) with an IC50 value of 0.05 μM. The effect on the unidirectional inward INCX (Ca2+ exit mode) was less potent, with 10 μM of YM-244769 resulting in the inhibition of only about 50 %. At 5 mM intracellular Na+ concentration, YM-244769 suppressed INCX more potently than it did at 0 mM [Na+]i. Intracellular application of trypsin via the pipette solution did not change the blocking effect of YM-244769. In conclusion, YM-244769 inhibits the Ca2+ entry mode of NCX more potently than the Ca2+ exit mode, and inhibition by YM-244769 is [Na+]i-dependent and trypsin-insensitive. These characteristics are similar to those of other benzyloxyphenyl derivative NCX inhibitors such as KB-R7943, SEA0400, and SN-6. The potency of YM-244769 as an NCX1 inhibitor is higher than those of KB-R7943 and SN-6 and is similar to that of SEA0400.

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. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  • Amran MS, Homma N, Hashimoto K (2003) Pharmacology of KB-R7943: A Na+-Ca2+ exchange inhibitor. Cardiovasc Drug Rev 21:255–276

    Article  CAS  PubMed  Google Scholar 

  • Birinyi P, Acsai K, Bányász T, Tóth A, Horváth B, Virág L, Szentandrássy N, Magyar J, Varró A, Fülöp F, Nánási PP (2005) Effects of SEA0400 and KB-R7943 on Na+/Ca2+ exchange current and L-type Ca2+ current in canine ventricular cardiomyocytes. Naunyn-Schmiedeberg’s Arch Pharmacol 372:63–70

    Article  CAS  Google Scholar 

  • Blaustein MP, Lederer WJ (1999) Sodium/calcium exchange: its physiological implications. Physiol Rev 79:763–854

    CAS  PubMed  Google Scholar 

  • Gotoh Y, Kita S, Fujii M, Tagashira H, Horie I, Arai Y, Uchida S, Iwamoto T (2015) Genetic knockout and pharmacologic inhibition of NCX2 cause natriuresis and hypercalciuria. Biochem Biophys Res Commun 456:670–675

    Article  CAS  PubMed  Google Scholar 

  • Hilgemann DW, Matsuoka S, Nagel GA, Collins A (1992) Steady-state and dynamic properties of cardiac sodium-calcium exchange. Sodium-dependent inactivation. J Gen Physiol 100:905–932

    Article  CAS  PubMed  Google Scholar 

  • Iwamoto T (2004) Forefront of Na+/Ca2+ exchanger studies: molecular pharmacology of Na+/Ca2+ exchange inhibitors. J Pharmacol Sci 96:27–32

    Article  CAS  PubMed  Google Scholar 

  • Iwamoto T, Kita S (2006) YM-244769, a novel Na+/Ca2+ exchange inhibitor that preferentially inhibits NCX3, efficiently protects against hypoxia/reoxygenation-induced SH-SY5Y neuronal cell damage. Mol Pharmacol 70:2075–2083

    Article  CAS  PubMed  Google Scholar 

  • Iwamoto T, Inoue Y, Ito K, Sakaue T, Kita S, Katsuragi T (2004a) The exchanger inhibitory peptide region-dependent inhibition of Na+/Ca2+ exchange by SN-6 [2-[4-(nitrobenzyloxy)benzyl]thiazolidine-4-carboxylic acid ethyl ester], a novel benzyloxyphenyl derivative. Mol Pharmacol 66:45–55

    Article  CAS  PubMed  Google Scholar 

  • Iwamoto T, Kita S, Uehara A, Imanaga I, Matsuda T, Baba A, Katsuragi T (2004b) Molecular determinants of Na+/Ca2+ exchange (NCX1) inhibition by SEA0400. J Biol Chem 279:7544–7553

    Article  CAS  PubMed  Google Scholar 

  • Iwamoto T, Kita S, Uehara A, Inoue Y, Taniguchi Y, Imanaga I, Shigekawa M (2001) Structural domains influencing sensitivity to isothiourea derivative inhibitor KB-R7943 in cardiac Na+/Ca2+ exchanger. Mol Pharmacol 59:524–531

    CAS  PubMed  Google Scholar 

  • Iwamoto T, Uehara A, Imanaga I, Shigekawa M (2000) The Na+/Ca2+ exchanger NCX1 has oppositely oriented reentrant loop domains that contain conserved aspartic acids whose mutation alters its apparent Ca2+ affinity. J Biol Chem 275:38571–38580

    Article  CAS  PubMed  Google Scholar 

  • Iwamoto T, Watanabe Y, Kita S, Blaustein MP (2007) Na+/Ca2+ exchange inhibitors: a new class of calcium regulators. Cardiovasc Haematol Disord Drug Targets 7:188–198

    Article  CAS  Google Scholar 

  • Jackson JG, Robinson MB (2015) Reciprocal regulation of mitochondrial dynamics and calcium signaling in astrocyte processes. J Neurosci 35:15199–15213

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kimura J, Watano T, Kawahara M, Sakai E, Yatabe J (1999) Direction-independent block of bi-directional Na+/Ca2+ exchange current by KB-R7943 in guinea pig cardiac myocytes. Br J Pharmacol 128:969–974

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee C, Visen NS, Dhalla NS, Le HD, Isaac M, Choptiany P, Gross G, Omelchenko A, Matsuda T, Baba A, Takahashi K, Hnatowich M, Hryshko LV (2004) Inhibitory profile of SEA0400 [2-[4-[(2,5-Difuorophenyl)methoxy]phenoxy]-5-ethoxyaniline] assessed on the cardiac Na+-Ca2+ exchanger, NCX1.1. J Pharmacol Exp Ther 311:748–757

    Article  CAS  PubMed  Google Scholar 

  • Lee C, Dhalla NS, Hryshko LV (2005) Therapeutic potential of novel Na+-Ca2+ exchange inhibitors in attenuating ischemia-reperfusion injury. Can J Cardiol 21:509–516

    CAS  PubMed  Google Scholar 

  • Niu CF, Watanabe Y, Ono K, Iwamoto T, Yamashita K, Satoh H, Urushida T, Hayashi H, Kimura J (2007) Characterization of SN-6, a novel benzyloxyphenyl Na+/Ca2+ exchange inhibitor in guinea pig ventricular myocytes. Eur J Pharmacol 573:161–169

    Article  CAS  PubMed  Google Scholar 

  • Ozdemir S, Bito V, Holemans P, Vinet L, Mercadier JJ, Varro A, Sipido KR (2008) Pharmacological inhibition of Na/Ca exchange results in increased cellular Ca2+ load attributable to the predominance of forward mode block. Circ Res 102:1398–1405

    Article  CAS  PubMed  Google Scholar 

  • Qiu Z, Nicoll DA, Philipson KD (2001) Helix packing of functionally important regions of the cardiac Na+-Ca2+ exchanger. J Biol Chem 276:194–199

    Article  CAS  PubMed  Google Scholar 

  • Ren X, Philipson KD (2013) The topology of the cardiac Na+/Ca2+ exchanger, NCX1. J Mol Cell Cardiol 57:68–71

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schulze DH, Polumuri SK, Gille T, Ruknudin A (2002) Functional regulation of alternatively spliced Na+/Ca2+ exchanger (NCX1) isoforms. Ann N Y Acad Sci 976:187–196

    Article  CAS  PubMed  Google Scholar 

  • Szerencsei RT, Kinjo TG, Schnetkamp PPM (2013) The topology of the C-terminal sections of the NCX1 Na+/Ca2+ exchanger and the NCKX2 Na+/Ca2+-K+ exchanger. Channels 7:109–114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tanaka H, Nishimura K, Aikawa T, Hirayama W, Tanaka Y, Shigenobu K (2002) Effect of SEA0400, a novel inhibitor of sodium-calcium exchanger on myocardial ionic currents. Br J Pharmacol 135:1096–1100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Watanabe Y, Kimura J (2000) Inhibitory effect of amiodarone on Na+/Ca2+ exchange current guinea-pig cardiac myocytes. Br J Pharmacol 131:80–84

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Watanabe Y, Koide Y, Kimura J (2006) Topics on the Na+/Ca2+ exchanger: pharmacological characterization of Na+/Ca2+ exchanger inhibitors. J Pharmacol Sci 102:7–16

    Article  CAS  PubMed  Google Scholar 

  • Watanabe Y, Iwamoto T, Matsuoka I, Ohkubo S, Ono T, Watano T, Shigekawa M, Kimura J (2001) Inhibitory effect of 2,3-butanedione monoxime (BDM) on Na+/Ca2+ exchange current in guinea-pig cardiac ventricular myocytes. Br J Pharmacol 132:1317–1325

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Watano T, Kimura J, Morita T, Nakanishi H (1996) A novel antagonist, No. 7943, of the Na+/Ca2+ exchange current in guinea pig cardiac ventricular cells. Br J Pharmacol 119:555–563

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by grants-in-aid from the Ministry of Education, Science, Sports, and Culture of Japan (17590223, 21590288) to J.K. and a grant-in-aid from the Smoking Research Foundation (KI18003) to J.K.

Author information

Authors and Affiliations

  1. Division of Pharmacological Science, Department of Health Science, Hamamatsu University School of Medicine, Hamamatsu, Japan

    Kanna Yamashita & Yasuhide Watanabe

  2. Department of Pharmacology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan

    Satomi Kita & Takahiro Iwamoto

  3. Department of Pharmacology, School of Medicine, Fukushima Medical University, Fukushima, Japan

    Junko Kimura

Authors
  1. Kanna Yamashita
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yasuhide Watanabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Satomi Kita
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Takahiro Iwamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Junko Kimura
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yasuhide Watanabe.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yamashita, K., Watanabe, Y., Kita, S. et al. Inhibitory effect of YM-244769, a novel Na+/Ca2+ exchanger inhibitor on Na+/Ca2+ exchange current in guinea pig cardiac ventricular myocytes. Naunyn-Schmiedeberg's Arch Pharmacol 389, 1205–1214 (2016). https://doi.org/10.1007/s00210-016-1282-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00210-016-1282-y

Keyword

Search

Navigation