Skip to main content
SpringerLink
Log in

Mechanisms of landiolol-mediated positive inotropy in critical care settings

  • Review
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

To present the potential mechanisms by which landiolol enhances a positive inotropic response in critically ill patients.

Methods

Analysis of preclinical, animal, and clinical data to provide novel knowledge and translate research findings into potential clinical application.

Results

The super-selective β1-antagonist landiolol may increase inotropy and may be associated with positive outcomes in critically ill patients with acute decompensated heart failure or sepsis.

Conclusion

This review sheds light on the potential mechanisms by which landiolol enhances a positive inotropic response, potentially alleviating the long-held concern over possible negative hemodynamic effects in critically ill patients.

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

Availability of data and materials

Not applicable.

References

  1. Shiga T (2022) Benefits and safety of landiolol for rapid rate control in patients with atrial tachyarrhythmias and acute decompensated heart failure. Eur Heart J Suppl 24:D11–D21. https://doi.org/10.1093/eurheartjsupp/suac023

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Iguchi S, Iwamura H, Nishizaki M, Hayashi A, Senokuchi K, Kobayashi K, Sakaki K, Hachiya K, Ichioka Y, Kawamura M (1992) Development of a highly cardioselective ultra short-acting beta-blocker, ONO-1101. Chem Pharm Bull (Tokyo) 40:1462–1469. https://doi.org/10.1248/cpb.40.1462. PMID: 1356643

  3. Nasrollahi-Shirazi S, Sucic S, Yang Q, Freissmuth M, Nanoff C (2016) Comparison of the β-adrenergic receptor antagonists landiolol and esmolol: receptor selectivity, partial agonism, and pharmacochaperoning actions. J Pharmacol Exp Ther 359:73–81. https://doi.org/10.1124/jpet.116.232884

    Article  CAS  PubMed  Google Scholar 

  4. Eagle Pharmaceuticals announces submission of New Drug Application to US Food and Drug Administration for landiolol, a beta-1 adrenergic blocker. News release (2003) Eagle Pharmaceuticals, Inc. https://www.globenewswire.com/news-release/2022/06/01/2454027/0/en/Eagle-Pharmaceuticals-Announces-Submission-of-New-Drug-Application-to-U-S-Food-and-Drug-Administration-for-Landiolol-a-Beta-1-Adrenergic-Blocker.html. Accessed 17 May 2023

  5. Hindricks G, Potpara T, Dagres N, Arbelo E, Bax JJ, Blomström-Lundqvist C, Boriani G, Castella M, Dan GA, Dilaveris PE, Fauchier L, Filippatos G, Kalman JM, La Meir M, Lane DA, Lebeau JP, Lettino M, Lip GYH, Pinto FJ, Thomas GN, Valgimigli M, Van Gelder IC, Van Putte BP, Watkins CL, ESC Scientific Document Group (2021) 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J 42:373–498. https://doi.org/10.1093/eurheartj/ehaa612

  6. Domanovits H, Wolzt M, Stix G (2018) Landiolol: pharmacology and its use for rate control in atrial fibrillation in an emergency setting. Eur Heart J Suppl 20:A1–A3. https://doi.org/10.1093/eurheartj/sux037

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Garnock-Jones KP (2012) Esmolol: a review of its use in the short-term treatment of tachyarrhythmias and the short-term control of tachycardia and hypertension. Drug 72:109–132. https://doi.org/10.2165/11208210-000000000-00000

    Article  CAS  Google Scholar 

  8. Sasao J, Tarver SD, Kindscher JD, Taneyama C, Benson KT, Goto H (2001) In rabbits, landiolol, a new ultra-short-acting beta-blocker, exerts a more potent negative chronotropic effect and less effect on blood pressure than esmolol. Can J Anaesth 48:985–989. https://doi.org/10.1007/BF03016588

    Article  CAS  PubMed  Google Scholar 

  9. Ikeshita K, Nishikawa K, Toriyama S, Yamashita T, Tani Y, Yamada T, Asada A (2008) Landiolol has a less potent negative inotropic effect than esmolol in isolated rabbit hearts. J Anesth 22:361–366. https://doi.org/10.1007/s00540-008-0640-4

    Article  PubMed  Google Scholar 

  10. Wada Y, Aiba T, Tsujita Y, Itoh H, Wada M, Nakajima I, Ishibashi K, Okamura H, Miyamoto K, Noda T, Sugano Y, Kanzaki H, Anzai T, Kusano K, Yasuda S, Horie M, Ogawa H (2016) Practical applicability of landiolol, an ultra-short-acting β1-selective blocker, for rapid atrial and ventricular tachyarrhythmias with left ventricular dysfunction. J Arrhythm 32:82–88. https://doi.org/10.1016/j.joa.2015.09.002

    Article  PubMed  Google Scholar 

  11. Shibata O, Nishioka K, Yamaguchi M, Makita T, Sumikawa K (2008) High concentrations of landiolol, a beta(1)-adrenoceptor antagonist, stimulate smooth muscle contraction of the rat trachea through the Rho-kinase pathway. J Anesth 22:21–26. https://doi.org/10.1007/s00540-007-0567-1

    Article  PubMed  Google Scholar 

  12. Plosker GL (2013) Landiolol: a review of its use in intraoperative and postoperative tachyarrhythmias. Drugs 73:959–977. https://doi.org/10.1007/s40265-013-0077-4

    Article  CAS  PubMed  Google Scholar 

  13. Hasuo H, Tomiyasu S, Hojo M, Fujigaki T, Fukusaki M, Sumikawa K (1998) Effect of ONO-1101, a novel short-acting β-blocker on hemodynamic responses to isoflurane inhalation and tracheal intubation. J Anesth 12:115–118. https://doi.org/10.1007/BF02480087

    Article  PubMed  Google Scholar 

  14. Hasegawa D, Sato R, Nishida O (2021) β1-blocker in sepsis. J Intensive Care 9:39. https://doi.org/10.1186/s40560-021-00552-w

    Article  PubMed  PubMed Central  Google Scholar 

  15. Hasegawa D, Sato R, Prasitlumkum N, Nishida K, Takahashi K, Yatabe T, Nishida O (2021) Effect of ultrashort-acting β-blockers on mortality in patients with sepsis with persistent tachycardia despite initial resuscitation: a systematic review and meta-analysis of randomized controlled trials. Chest 159:2289–2300. https://doi.org/10.1016/j.chest.2021.01.009

    Article  CAS  PubMed  Google Scholar 

  16. Brodde OE, Schüler S, Kretsch R, Brinkmann M, Borst HG, Hetzer R, Reidemeister JC, Warnecke H, Zerkowski HR (1986) Regional distribution of beta-adrenoceptors in the human heart: coexistence of functional beta 1- and beta 2-adrenoceptors in both atria and ventricles in severe congestive cardiomyopathy. J Cardiovasc Pharmacol 8:1235–1242. https://doi.org/10.1097/00005344-198611000-00021

    Article  CAS  PubMed  Google Scholar 

  17. Michel MC, Insel PA (2006) Adrenergic receptors in clinical medicine. In: Perez D (ed) The receptors: the adrenergic receptors in clinical medicine. Humana Press Inc., Totowa, NJ, pp 129–147

    Chapter  Google Scholar 

  18. Wachter SB, Gilbert EM (2012) Β-Adrenergic receptors, from their discovery and characterization through their manipulation to beneficial clinical application. Cardiology 122:104–112. https://doi.org/10.1159/000339271

    Article  CAS  PubMed  Google Scholar 

  19. Kobayashi S, Susa T, Tanaka T, Murakami W, Fukuta S, Okuda S, Doi M, Wada Y, Nao T, Yamada J, Okamura T, Yano M, Matsuzaki M (2012) Low-dose β-blocker in combination with milrinone safely improves cardiac function and eliminates pulsus alternans in patients with acute decompensated heart failure. Circ J 76:1646–1653. https://doi.org/10.1253/circj.cj-12-0033

  20. Sakaguchi M, Sasaki Y, Hirai H, Hosono M, Nakahira A, Seo H, Suehiro S (2012) Efficacy of landiolol hydrochloride for prevention of atrial fibrillation after heart valve surgery. Int Heart J 53:359–363. https://doi.org/10.1536/ihj.53.359

    Article  CAS  PubMed  Google Scholar 

  21. Hamaguchi S, Nagao M, Takahashi Y, Ikeda T, Yamaguchi S (2014) Low dose landiolol combined with catecholamine can decrease heart rate without suppression of cardiac contraction after cardiopulmonary bypass. Dokkyo J Med Sci 41:27–33

    Google Scholar 

  22. Kobayashi S, Murakami W, Myoren T, Tateishi H, Okuda S, Doi M, Nao T, Wada Y, Matsuzaki M, Yano M (2014) A low-dose β1-blocker effectively and safely slows the heart rate in patients with acute decompensated heart failure and rapid atrial fibrillation. Cardiology 127:105–113. https://doi.org/10.1159/000355312

  23. Sakai M, Jujo S, Kobayashi J, Ohnishi Y, Kamei M (2019) Use of low-dose β1-blocker for sinus tachycardia in patients with catecholamine support following cardiovascular surgery: a retrospective study. J Cardiothorac Surg 14:145. https://doi.org/10.1186/s13019-019-0966-z

    Article  PubMed  PubMed Central  Google Scholar 

  24. Ditali V, Garatti L, Morici N, Villanova L, Colombo C, Oliva F, Sacco A (2022) Effect of landiolol in patients with tachyarrhythmias and acute decompensated heart failure (ADHF): a case series. ESC Heart Fail 9:766–770. https://doi.org/10.1002/ehf2.13763

    Article  PubMed  Google Scholar 

  25. Dabrowski W, Siwicka-Gieroba D, Piasek E, Schlegel TT, Jaroszynski A (2020) Successful combination of landiolol and levosimendan in patients with decompensated heart failure. Int Heart J 61:384–389. https://doi.org/10.1536/ihj.19-420

    Article  PubMed  Google Scholar 

  26. Fujiwara H, Sakurai M, Namai A, Kawamura T (2009) Effect of low-dose landiolol, an ultrashort-acting beta-blocker, on postoperative atrial fibrillation after CABG surgery. Gen Thorac Cardiovasc Surg 57:132–137. https://doi.org/10.1007/s11748-008-0341-9

    Article  PubMed  Google Scholar 

  27. Feuerstein TJ, Krumpl G (2022) The superselective β1-blocker landiolol enhances inotropy of endogenous and exogenous catecholamines in acute heart failure. Cardiol Cardiovasc Med 6:502–511. https://doi.org/10.26502/fccm.92920291

  28. Gherbi K, May LT, Baker JG, Briddon SJ, Hill SJ (2015) Negative cooperativity across β1-adrenoceptor homodimers provides insights into the nature of the secondary low-affinity CGP 12177 β1-adrenoceptor binding conformation. FASEB J 29:2859–2871. https://doi.org/10.1096/fj.14-265199

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Cecconi M, De Backer D, Antonelli M, Beale R, Bakker J, Hofer C, Jaeschke R, Mebazaa A, Pinsky MR, Teboul JL, Vincent JL, Rhodes A (2014) Consensus on circulatory shock and hemodynamic monitoring. Task force of the European Society of Intensive Care Medicine. Intensive Care Med 40:1795–1815. https://doi.org/10.1007/s00134-014-3525-z

    Article  PubMed  PubMed Central  Google Scholar 

  30. Guarracino F, Baldassarri R, Pinsky MR (2013) Ventriculo-arterial decoupling in acutely altered hemodynamic states. Crit Care 17:213. https://doi.org/10.1186/cc12522

    Article  PubMed  PubMed Central  Google Scholar 

  31. Ohte N, Cheng CP, Little WC (2003) Tachycardia exacerbates abnormal left ventricular-arterial coupling in heart failure. Heart Vessels 18:136–141. https://doi.org/10.1007/s00380-003-0697-9

    Article  PubMed  Google Scholar 

  32. Gambert S, Héliès-Toussaint C, Grynberg A (2007) Extracellular glycerol regulates the cardiac energy balance in a working rat heart model. Am J Physiol Heart Circ Physiol 292:H1600–1606. https://doi.org/10.1152/ajpheart.00563.2006

  33. Duckles SP, Jensen RA (1972) Effects of glycerol treatment on contractility and transmembrane potentials in cardiac tissue. J Mol Cell Cardiol 4:49–58. https://doi.org/10.1016/0022-2828(72)90096-x

    Article  CAS  PubMed  Google Scholar 

  34. Cheav SL, Chahine R, Mroué MS (1992) Inotropic and chronotropic effect of glycerol formal on the isolated rabbit heart. Arzneimittelforschung 42:997–1000

    CAS  PubMed  Google Scholar 

  35. Barbee JH, Cokelet GR (1971) The Fahraeus effect. Microvasc Res 3:6–16. https://doi.org/10.1016/0026-2862(71)90002-1

    Article  CAS  PubMed  Google Scholar 

  36. Yang J, Yoo SS, Lee TR (2017) Effect of fractional blood flow on plasma skimming in the microvasculature. Phys Rev E 95:040401. https://doi.org/10.1103/PhysRevE.95.040401

    Article  PubMed  Google Scholar 

  37. Reinhart WH, Piety NZ, Shevkoplyas SS (2017) Influence of feeding hematocrit and perfusion pressure on hematocrit reduction (Fåhraeus effect) in an artificial microvascular network. Microcirculation 24. https://doi.org/10.1111/micc.12396

  38. Lupu F, Kinasewitz G, Dormer K (2020) The role of endothelial shear stress on haemodynamics, inflammation, coagulation and glycocalyx during sepsis. J Cell Mol Med 24:12258–12271. https://doi.org/10.1111/jcmm.15895

    Article  PubMed  PubMed Central  Google Scholar 

  39. Dekker RJ, van Thienen JV, Rohlena J, de Jager SC, Elderkamp YW, Seppen J, de Vries CJ, Biessen EA, van Berkel TJ, Pannekoek H, Horrevoets AJ (2005) Endothelial KLF2 links local arterial shear stress levels to the expression of vascular tone-regulating genes. Am J Pathol 167:609–618. https://doi.org/10.1016/S0002-9440(10)63002-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Barauna VG, Campos LC, Miyakawa AA, Krieger JE (2011) ACE as a mechanosensor to shear stress influences the control of its own regulation via phosphorylation of cytoplasmic Ser(1270). PLoS ONE 6:e22803. https://doi.org/10.1371/journal.pone.0022803

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. De Backer D, Creteur J, Dubois MJ, Sakr Y, Vincent JL (2004) Microvascular alterations in patients with acute severe heart failure and cardiogenic shock. Am Heart J 147:91–99. https://doi.org/10.1016/j.ahj.2003.07.006

    Article  PubMed  Google Scholar 

  42. Jung C, Ferrari M, Rödiger C, Fritzenwanger M, Goebel B, Lauten A, Pfeifer R, Figulla HR (2009) Evaluation of the sublingual microcirculation in cardiogenic shock. Clin Hemorheol Microcirc 42:141–148. https://doi.org/10.3233/CH-2009-1194

    Article  PubMed  Google Scholar 

  43. Ferraris A, Jacquet-Lagrèze M, Cazenave L, Fornier W, Jalalzai W, Rousseau-Saine N, Allaouchiche B, Junot S, Pozzi M, Fellahi JL; Anesthésie-Réanimation Coeur-Thorax-Vaisseaux (ARCOTHOVA) Group (2021) Microcirculatory effects of landiolol: a double-blind, randomised, controlled study after cardiac surgery. Br J Anaesth 126:e212–e214. https://doi.org/10.1016/j.bja.2021.03.013

    Article  CAS  Google Scholar 

  44. Hagiwara S, Iwasaka H, Maeda H, Noguchi T (2009) Landiolol, an ultrashort-acting beta1-adrenoceptor antagonist, has protective effects in an LPS-induced systemic inflammation model. Shock 31:515–520. https://doi.org/10.1097/SHK.0b013e3181863689

    Article  CAS  PubMed  Google Scholar 

  45. Matsumoto S, Tokumaru O, Ogata K, Kuribayashi Y, Oyama Y, Shingu C, Yokoi I, Kitano T (2022) Dose-dependent scavenging activity of the ultra-short-acting β1-blocker landiolol against specific free radicals. J Clin Biochem Nutr 71:185–190. https://doi.org/10.3164/jcbn.21-157

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Ince C, Sinaasappel M (1999) Microcirculatory oxygenation and shunting in sepsis and shock. Crit Care Med 27:1369–1377. https://doi.org/10.1097/00003246-199907000-00031

    Article  CAS  PubMed  Google Scholar 

  47. Chalkias A, Xenos M (2022) Relationship of effective circulating volume with sublingual red blood cell velocity and microvessel pressure difference: a clinical investigation and computational fluid dynamics modeling. J Clin Med 11:4885. https://doi.org/10.3390/jcm11164885

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute for Translational Medicine and Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104-5158, USA

    Athanasios Chalkias

  2. Outcomes Research Consortium, Cleveland, OH, 44195, USA

    Athanasios Chalkias

  3. Department of Pharmacy Practice, College of Pharmacy, Midwestern University, Downers Grove, IL, 60515, USA

    E. Paul O’Donnell

Authors
  1. Athanasios Chalkias
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. E. Paul O’Donnell
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Athanasios Chalkias and E. Paul O’Donnell contributed equally to the manuscript.

Corresponding author

Correspondence to Athanasios Chalkias.

Ethics declarations

Ethics approval

Not applicable.

Informed consent

Not applicable.

Competing interests

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chalkias, A., O’Donnell, E.P. Mechanisms of landiolol-mediated positive inotropy in critical care settings. Eur J Clin Pharmacol 79, 1607–1612 (2023). https://doi.org/10.1007/s00228-023-03584-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-023-03584-3

Keywords

Search

Navigation