Esmolol cardioplegia: the cellular mechanism of diastolic arrest

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. 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 mu m, 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 Ca2+ 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,I-L) and the fast sodium current (I-Na), with IC50 values of 0.45 +/- 0.05 and 0.17 +/- 0.025 mmol/L, respectively. 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 Ca2+ channels; additionally, higher concentrations prevent action potential conduction, probably due to the inhibition of fast Na+ channels.