title: Esmolol cardioplegia: the cellular mechanism of diastolic arrest.
abstract: OBJECTIVE
  Esmolol, an ultra-short-acting beta-blocker, acts as a cardioplegic agent at millimolar concentrations. We investigated the mechanism by which esmolol induces diastolic ventricular arrest.
  
  
  RESULTS
  In unpaced Langendorff-perfused rat hearts, esmolol (0.03-3 mmol/L) had a profound negative inotropic effect resulting in diastolic arrest at 1 mmol/L and above. This inhibition of contraction was maintained during ventricular pacing. At 3 mmol/L, esmolol also abolished action potential conduction. To determine the cellular mechanism for the negative inotropism, we measured contraction (sarcomere shortening) and the calcium transient (fura-2 fluorescence ratio; Ca(tr)) in electrically-stimulated rat ventricular myocytes at 23 and 34 degrees C. The decrease in contraction (by 72% at 23 degrees C, from 0.16 +/- 0.01 to 0.04 +/- 0.01 microm, P < 0.001) was similar to that of isolated hearts and was caused by a large decrease in Ca(tr) (from 0.13 +/- 0.02 to 0.07 +/- 0.02, P < 0.001). There was no additional effect on myofilament Ca(2+) sensitivity. Esmolol's effects on contraction and Ca(tr) were not shared or altered by the beta-blocker, atenolol (1 mmol/L). Sarcoplasmic reticulum inhibition with thapsigargin did not alter the inhibitory effects of esmolol. Whole-cell voltage-clamp experiments revealed that esmolol inhibited the L-type calcium current (I(Ca,L)) and the fast sodium current (I(Na)), with IC(50) values of 0.45 +/- 0.05 and 0.17 +/- 0.025 mmol/L, respectively.
  
  
  CONCLUSIONS
  Esmolol at millimolar concentrations causes diastolic ventricular arrest by two mechanisms: at 1 mmol/L (and below), the pronounced negative inotropic effect is due largely to inhibition of L-type Ca(2+) channels; additionally, higher concentrations prevent action potential conduction, probably due to the inhibition of fast Na(+) channels.
authors.affiliation: Cardiac Surgical Research, The Rayne Institute (King's College London), St Thomas' Hospital, London, UK.
authors.forename: Hazem B
authors.initials: HB
authors.lastname: Fallouh
authors.forename: Sonya C
authors.initials: SC
authors.lastname: Bardswell
authors.forename: Linda M
authors.initials: LM
authors.lastname: McLatchie
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Shattock
authors.forename: David J
authors.initials: DJ
authors.lastname: Chambers
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Kentish
mesh_terms: D000200:Action Potentials; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D002304:Cardiac Pacing, Artificial; D004305:Dose-Response Relationship, Drug; D006324:Heart Arrest, Induced / Q000379:methods*; D006352:Heart Ventricles / Q000187:drug effects* / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D009210:Myofibrils / Q000187:drug effects / Q000378:metabolism; D010477:Perfusion; D011412:Propanolamines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D026941:Sodium Channel Blockers / Q000494:pharmacology; D015222:Sodium Channels / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D016276:Ventricular Function / Q000187:drug effects*
chemical_list: D000319:Adrenergic beta-Antagonists; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D011412:Propanolamines; D026941:Sodium Channel Blockers; D015222:Sodium Channels; C036604:esmolol