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ANESTHETIC PHARMACOLOGY

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

Center for Anesthesiology Research, The Cleveland Clinic Foundation, Ohio

Address correspondence and reprint requests to Noriaki Kanaya, MD, Department of Anesthesiology, Sapporo Medical University, School of Medicine, S-1, W-16, Chuo-ku, Sapporo, 060–8643 Japan. Address e-mail to kanaya{at}sapmed.ac.jp

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⁺.

IMPLICATIONS: Midazolam and diazepam differentially alter the cardiac excitation-contraction coupling at the cellular level, which is mediated by altering the availability of intracellular free Ca²⁺ in adult rat ventricular myocytes. In addition, diazepam, but not midazolam, decreases myofilament Ca²⁺ sensitivity. However, the benzodiazepines have no direct influence on excitation-contraction coupling, except at very large doses.