Abstract 1556: Esmolol As A Cardioplegic Agent; An Effect Beyond β-blockade

Abstract

Esmolol, an ultra-short-acting β-blocker, is used in the treatment of hypertension and arrhythmias. We and others have shown that millimolar doses of esmolol is cardioprotective, and acts as a cardioplegic agent in both human and animal hearts. In vivo, the β-blocking effect explains the cardioprotective action but the mechanism for esmolol-induced arrest in isolated hearts is unknown. This study characterises the mode of action by which esmolol causes diastolic arrest at millimolar doses. Isolated rat ventricular myocytes were superfused with buffered Tyrode solution and electrically stimulated. We measured myocyte contraction by sarcomere shortening (SS) and calcium transient (Ca tr ) by fluorescence microscopy using fura-2 (340/380 nm ratio). Additional studies of L-type calcium currents ( I Ca,L ) using whole-cell voltage-clamping were conducted. Esmolol (0.3 mmol/L) decreased myocyte SS by 72% from 0.16±0.01 μm to 0.04±0.01 μm (mean±SE, n=7; P << med > 0.0001). The corresponding Ca tr fell from 0.13±0.02 to 0.07±0.02 (P<<med>0.001), a decrease of 47%. Inhibiting the SR with thapsigargan (1 μmol/L) did not alter the effect of esmolol: the SS (in an elevated bathing [Ca] of 7 mmol/L) decreased from 0.16±0.007 to 0.05±0.002 μm, a drop of 69% (n=7), and Ca tr fell from 0.12±0.006 to 0.06±0.003 (50% decrease). This suggested that high dose esmolol inhibits the L-type Ca channels; this was confirmed by voltage-clamp studies (Fig ). In separate studies on skinned myocytes, esmolol had no effect on myofilament sensitivity to calcium. We conclude that high doses of the β-blocker esmolol (that are already used in cardiac surgery) cause diastolic arrest by inhibiting L-type Ca channels.