: Cardioplegic effect beyond β-blockade

Student thesis: Doctoral ThesisDoctor of Philosophy


The use of hyperkalaemic cardioplegia in cardiac surgery induces depolarised arrest and it is currently the gold standard for myocardial protection. Although hyperkalaemia is by far the most commonly used clinically, it has been established that depolarised arrest has detrimental effects due to sodium and calcium loading. This triggered interest in establishing alternative means of cardioplegia. Esmolol, an ultra-short acting β-blocker, was found to induce cardioplegic arrest at high (millimolar) concentrations and offers improved protection to hyperkalaemic arrest. Unlike other alternative cardioplegic agents, esmolol has been used, safely, clinically in high doses, which make it clinically relevant. However the arrest by esmolol in Langendorff perfused hearts isolated from any catecholamine background cannot be explained by its β-blocking mode of action. The aim is to establish the arresting mode of action of esmolol. Pilot data suggested that esmolol has a myofilament desensitising as well as an inhibitory effect on the calcium transient (Catr) in the isolated ventricular myocyte. Esmolol reduced the Catr at high concentration (IC50=~250μm). This was independent from the β-blocking effect. The effect on the sarcoplasmic reticulum (SR) was excluded by blocking the SR effect using thapsigargin and the negative inotropic effect of esmolol was maintained. Using skinned rat myocytes, esmolol did not induce myofibril desensitisation. The effect of esmolol on the L-type calcium channels was studied using patch clamp techniques. Esmolol was found to inhibit the L-type calcium channels (IC50=~450μm). Esmolol also inhibited the fast Na channels (IC50=~150 μm). The arrest by esmolol was caused by direct inhibition of the myocardium and not by inhibiting the conductive system only using paced Langendorff perfused hearts. It was concluded that esmolol induces arrest by blocking sodium and Calcium channels. It was last established that, in the Langendorff perfused rat heart, adding a K+ channel opener,adenosine 0.25mM, to esmolol 0.6 mM offers better protection to St. Thomas’ Hospital cardioplegia (STH) with 1 hour recovery LVDP of 69±3.7 and 51±4.6 (% of control, p<0.01) in 4-hour ischaemia with room temperature multiple infusion cardioplegia.
Date of Award2013
Original languageEnglish
Awarding Institution
  • King's College London
SupervisorJonathan Kentish (Supervisor)

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