Generic placeholder image

Current Pharmaceutical Design


ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

General Research Article

Dose-dependent Effects of Esmolol-epinephrine Combination Therapy in Myocardial Ischemia and Reperfusion Injury

Author(s): Yoshimasa Oyama, Justin Blaskowsky and Tobias Eckle*

Volume 25, Issue 19, 2019

Page: [2199 - 2206] Pages: 8

DOI: 10.2174/1381612825666190618124829

Price: $65


Background: Animal studies on cardiac arrest found that a combination of epinephrine with esmolol attenuates post-resuscitation myocardial dysfunction. Based on these findings, we hypothesized that esmololepinephrine combination therapy would be superior to a reported cardioprotective esmolol therapy alone in a mouse model of myocardial ischemia and reperfusion (IR) injury.

Methods: C57BL/6J mice were subjected to 60 min of myocardial ischemia and 120 min of reperfusion. Mice received either saline, esmolol (0.4 mg/kg/h), epinephrine (0.05 mg/kg/h), or esmolol combined with epinephrine (esmolol: 0.4 mg/kg/h or 0.8 mg/kg/h and epinephrine: 0.05 mg/kg/h) during reperfusion. After reperfusion, infarct sizes in the area-at-risk and serum cardiac troponin-I levels were determined. Hemodynamic effects of drugs infused were determined by measurements of heart rate (HR) and mean arterial blood pressure (MAP) via a carotid artery catheter.

Results: Esmolol during reperfusion resulted in robust cardioprotection (esmolol vs. saline: 24.3±8% vs. 40.6±3% infarct size), which was abolished by epinephrine co-administration (38.1±15% infarct size). Increasing the esmolol dose, however, was able to restore esmolol-cardioprotection in the epinephrine-esmolol (18.6±8% infarct size) co-treatment group with improved hemodynamics compared to the esmolol group (epinephrine-esmolol vs. esmolol: MAP 80 vs. 75 mmHg, HR 452 vs. 402 beats/min).

Conclusion: These results confirm earlier studies on esmolol-cardioprotection from myocardial IR-injury and demonstrate that a dose optimized epinephrine-esmolol co-treatment maintains esmolol-cardioprotection with improved hemodynamics compared to esmolol treatment alone. These findings might have implications for current clinical practice in hemodynamically unstable patients suffering from myocardial ischemia.

Keywords: Epinephrine, esmolol, myocardial ischemia and reperfusion injury, troponin, TTC, blood pressure, heart rate.

« Previous
Allwood MJ, Cobbold AF, Ginsburg J. Peripheral vascular effects of noradrenaline, isopropylnoradrenaline and dopamine. Br Med Bull 1963; 19: 132-6.
[] [PMID: 14012200]
Soar J, Donnino MW, Maconochie I, et al. 2018 International consensus on cardiopulmonary resuscitation and emergency cardiovascular care science with treatment recommendations summary. Resuscitation 2018; 133: 194-206.
[] [PMID: 30409433]
Hagihara A, Hasegawa M, Abe T, Nagata T, Wakata Y, Miyazaki S. Prehospital epinephrine use and survival among patients with out-of-hospital cardiac arrest. JAMA 2012; 307(11): 1161-8.
[] [PMID: 22436956]
Lin S, Callaway CW, Shah PS, et al. Adrenaline for out-of-hospital cardiac arrest resuscitation: A systematic review and meta-analysis of randomized controlled trials. Resuscitation 2014; 85(6): 732-40.
[] [PMID: 24642404]
Perkins GD, Ji C, Deakin CD, et al. A Randomized Trial of Epinephrine in Out-of-Hospital Cardiac Arrest. N Engl J Med 2018; 379(8): 711-21.
[] [PMID: 30021076]
Tang W, Weil MH, Sun S, Noc M, Yang L, Gazmuri RJ. Epinephrine increases the severity of postresuscitation myocardial dysfunction. Circulation 1995; 92(10): 3089-93.
[] [PMID: 7586280]
Levy B, Clere-Jehl R, Legras A, et al. Epinephrine versus norepinephrine for cardiogenic shock after acute myocardial infarction. J Am Coll Cardiol 2018; 72(2): 173-82.
[] [PMID: 29976291]
Geissler HJ. Reduction of myocardial reperfusion injury by high-dose beta-blockade with esmolol. Thorac Cardiovasc Surg 2002; 50(6): 367-72.
[] [PMID: 12457318]
Er F, Dahlem KM, Nia AM, et al. Randomized control of sympathetic drive with continuous intravenous esmolol in patients with acute st-segment elevation myocardial infarction: The beta-blocker therapy in acute myocardial infarction (BEAT-AMI) Trial. JACC Cardiovasc Interv 2016; 9(3): 231-40.
[] [PMID: 26847114]
Zhang Q, Li C. Combination of epinephrine with esmolol attenuates post-resuscitation myocardial dysfunction in a porcine model of cardiac arrest. PLoS One 2013; 8(12)e82677
[] [PMID: 24367539]
Bonney S, Kominsky D, Brodsky K, Eltzschig H, Walker L, Eckle T. Cardiac Per2 functions as novel link between fatty acid metabolism and myocardial inflammation during ischemia and reperfusion injury of the heart. PLoS One 2013; 8(8)e71493
[] [PMID: 23977055]
Eckle T, Hartmann K, Bonney S, et al. Adora2b-elicited Per2 stabilization promotes a HIF-dependent metabolic switch crucial for myocardial adaptation to ischemia. Nat Med 2012; 18(5): 774-82.
[] [PMID: 22504483]
Bartman CM, Oyama Y, Brodsky K, et al. Intense light-elicited upregulation of miR-21 facilitates glycolysis and cardioprotection through Per2-dependent mechanisms. PLoS One 2017; 12(4)e0176243
[] [PMID: 28448534]
Ibrahim-Zada I, Rhee P, Gomez CT, Weller J, Friese RS. Inhibition of sepsis-induced inflammatory response by β1-adrenergic antagonists. J Trauma Acute Care Surg 2014; 76(2): 320-7.
[] [PMID: 24458040]
Eckle T, Grenz A, Köhler D, et al. Systematic evaluation of a novel model for cardiac ischemic preconditioning in mice. Am J Physiol Heart Circ Physiol 2006; 291(5): H2533-40.
[] [PMID: 16766632]
Eckle T, Koeppen M, Eltzschig H. Use of a hanging weight system for coronary artery occlusion in mice. J Vis Exp 2011; (50): 2526.
[] [PMID: 21540816]
Eckle T, Köhler D, Lehmann R, El Kasmi K, Eltzschig HK. Hypoxia-inducible factor-1 is central to cardioprotection: a new paradigm for ischemic preconditioning. Circulation 2008; 118(2): 166-75.
[] [PMID: 18591435]
Warth A, Eckle T, Köhler D, et al. Upregulation of the water channel aquaporin-4 as a potential cause of postischemic cell swelling in a murine model of myocardial infarction. Cardiology 2007; 107(4): 402-10.
[] [PMID: 17284903]
Koeppen M, Harter PN, Bonney S, et al. Adora2b signaling on bone marrow derived cells dampens myocardial ischemia-reperfusion injury. Anesthesiology 2012; 116(6): 1245-57.
[] [PMID: 22531331]
Köhler D, Eckle T, Faigle M, et al. CD39/ectonucleoside triphosphate diphosphohydrolase 1 provides myocardial protection during cardiac ischemia/reperfusion injury. Circulation 2007; 116(16): 1784-94.
[] [PMID: 17909107]
Seo SW, Koeppen M, Bonney S, et al. Differential tissue-specific function of Adora2b in cardioprotection. J Immunol 2015; 195(4): 1732-43.
[] [PMID: 26136425]
Vasile VC, Babuin L, Giannitsis E, Katus HA, Jaffe AS. Relationship of MRI-determined infarct size and cTnI measurements in patients with ST-elevation myocardial infarction. Clin Chem 2008; 54(3): 617-9.
[] [PMID: 18310155]
Koeppen M, Eckle T, Eltzschig HK. Selective deletion of the A1 adenosine receptor abolishes heart-rate slowing effects of intravascular adenosine in vivo. PLoS One 2009; 4(8)e6784
[] [PMID: 19707555]
Revelly JP, Gardaz JP, Nussberger J, Schutz Y, Chioléro R. Effect of epinephrine on oxygen consumption and delivery during progressive hemorrhage. Crit Care Med 1995; 23(7): 1272-8.
[] [PMID: 7600837]
Schaper J, Kostin S. Cell death and adenosine triphosphate: The paradox. Circulation 2005; 112(1): 6-8.
[] [PMID: 15998693]
van Diepen S. Norepinephrine as a first-line inopressor in cardiogenic shock: Oversimplification or best practice? J Am Coll Cardiol 2018; 72(2): 183-6.
[] [PMID: 29976292]
Reimer KA, Rasmussen MM, Jennings RB. Reduction by propranolol of myocardial necrosis following temporary coronary artery occlusion in dogs. Circ Res 1973; 33(3): 353-63.
[] [PMID: 4746723]
Rasmussen MM, Reimer KA, Kloner RA, Jennings RB. Infarct size reduction by propranolol before and after coronary ligation in dogs. Circulation 1977; 56(5): 794-8.
[] [PMID: 912840]
Lange R, Kloner RA, Braunwald E. First ultra-short-acting beta-adrenergic blocking agent: its effect on size and segmental wall dynamics of reperfused myocardial infarcts in dogs. Am J Cardiol 1983; 51(10): 1759-67.
[] [PMID: 6134464]
Ibanez B, Macaya C, Sánchez-Brunete V, et al. Effect of early metoprolol on infarct size in ST-segment-elevation myocardial infarction patients undergoing primary percutaneous coronary intervention: The Effect of Metoprolol in Cardioprotection During an Acute Myocardial Infarction (METOCARD-CNIC) trial. Circulation 2013; 128(14): 1495-503.
[] [PMID: 24002794]
Levy B, Perez P, Perny J, Thivilier C, Gerard A. Comparison of norepinephrine-dobutamine to epinephrine for hemodynamics, lactate metabolism, and organ function variables in cardiogenic shock. A prospective, randomized pilot study. Crit Care Med 2011; 39(3): 450-5.
[] [PMID: 21037469]
De Backer D, Biston P, Devriendt J, et al. Comparison of dopamine and norepinephrine in the treatment of shock. N Engl J Med 2010; 362(9): 779-89.
[] [PMID: 20200382]
Vincent JL. Understanding cardiac output. Crit Care 2008; 12(4): 174.
[] [PMID: 18771592]
Milani-Nejad N, Janssen PM. Small and large animal models in cardiac contraction research: Advantages and disadvantages. Pharmacol Ther 2014; 141(3): 235-49.
[] [PMID: 24140081]
Georgakopoulos D, Kass D. Minimal force-frequency modulation of inotropy and relaxation of in situ murine heart. J Physiol 2001; 534(Pt. 2): 535-45.
[] [PMID: 11454970]

Rights & Permissions Print Export Cite as
© 2022 Bentham Science Publishers | Privacy Policy