The Differential Effects of Midazolam and Diazepam on Intracellular Ca2+ Transients and Contraction in Adult Rat Ventricular Myocytes

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Abstract
We investigated the direct effects of midazolam and diazepam on cardiac excitation-contraction coupling in adult rat ventricular myocytes. Freshly isolated rat ventricular myocytes were loaded with fura-2/AM and field-stimulated at 28°C. Intracellular Ca2+ transients (340:380 ratio) and myocyte shortening (video edge detection) were simultaneously monitored in individual cells. Midazolam (3–100 μM) caused a dose-dependent decrease in both peak intracellular Ca2+ and cell shortening. Diazepam (30 and 100 μM) increased myocyte shortening and peak Ca2+ concomitant with a decrease in time to peak Ca2+. A larger concentration of diazepam (>300 μM) nearly abolished intracellular Ca2+ and cell shortening. Midazolam (100 μM) and diazepam (300 μM) decreased the amount of Ca2+ released from intracellular stores in response to caffeine. Diazepam (30 μM), but not midazolam (10 μM), caused a downward shift in the dose-response curve to extracellular Ca2+ for shortening, with no concomitant effect on peak intracellular Ca2+ transient. These results indicate that midazolam and diazepam have different inotropic effects on cardiac excitation-contraction coupling at the cellular level, which is mediated by altering the availability of intracellular-free Ca2+. However, the benzodiazepines have no direct influence on excitation-contraction coupling in rat ventricular myocytes, except at very large doses. Inhibition of Ca2+ release from caffeine-sensitive intracellular Ca2+ stores may play some part in myocardial depression at the larger concentrations of benzodiazepines. Diazepam, but not midazolam, decreased myofilament responsiveness to Ca2+.