Caspofungin Modulates Ryanodine Receptor-Mediated Calcium Release in Human Cardiac Myocytes

Abstract

Recent studies showed that critically ill patients might be at risk for hemodynamic impairment during caspofungin (CAS) therapy. The aim of our present study was to examine the mechanisms behind CAS-induced cardiac alterations. We revealed a dose-dependent increase in intracellular Ca²⁺ concentration ([Ca²⁺]_i) after CAS treatment. Ca²⁺ ions were found to be released from intracellular caffeine-sensitive stores, most probably via the activation of ryanodine receptors.

Keywords: adverse drug reaction; antifungal agents; cardiac output; cardiac toxicity.

FIG 1

Boxplot diagram showing maximum (Max.) of % oscillation frequency in 1/s⁻¹ under the influence of different dosages of CAS in rat cardiomyocytes. Boxplot whiskers represent confidence intervals of median. ***, P < 0.001; n.s., not significant.

FIG 2

Boxplot diagram demonstrating the influence of physiological and Ca²⁺-free buffer media, CAF, RYN, and CAS on changes in intracellular Ca²⁺ levels in individual rat cardiomyocytes determined by fluorescence microscopy of Fura-2-AM signal. Administration of substances is characterized with + (CAS +, 140 μg/ml CAS; Ca²⁺ +, 2.5 mM Ca²⁺; RYN +, 40 μM RYN) and −. ***, P < 0.001.

FIG 3

Dose-response curve of intracellular calcium levels measured with fluorescence microscopy in relation to different dosages of CAS. Ca²⁺ + and Ca²⁺ − symbolize Ca²⁺-containing and Ca²⁺-free buffer media, respectively. ED₅₀, 50% effective dose.