Effects of L-type Ca2+ channel modulation on direct myocardial effects of diazepam and midazolam in adult rat ventricular myocytes

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Abstract
Our objective was to determine whether an L-type Ca2+ channel modulation could alter myocardial depression induced by midazolam or diazepam in adult rat ventricular myocytes. Freshly isolated rat ventricular myocytes were loaded with fura-2/AM and field-stimulated (0.3 Hz) at 28°C. Amplitude and timing of intracellular Ca2+ concentration ([Ca2+]i) and myocyte shortening were simultaneously monitored in individual cells. Midazolam (3–100 µM) caused a decrease in both peak [Ca2+]i and shortening. Diazepam (30, 100 µM) increased myocyte shortening and peak [Ca2+]i; however, higher concentration of diazepam (300 µM) decreased shortening and peak [Ca2+]i. Bay K 8644 (0.01–10 µM), an L-type Ca2+ channel agonist, caused dose-dependent increases in peak [Ca2+]i and shortening. In contrast, verapamil (0.1–50 µM), an L-type Ca2+ channel antagonist, caused dose-dependent decreases in peak [Ca2+]i and shortening. Dose–response curves to benzodiazepines on peak [Ca2+]i and shortening were not affected by pretreatment with Bay K 8644 (0.1 µM) or verapamil (1 µM). Diazepam (30, 100 µM), but not midazolam (3–30 µM), increased shortening and [Ca2+]i in the presence or absence of L-type Ca2+ channel modulators. Diazepam (30 µM) and midazolam (10 µM) had no effect on peak [Ca2+]i of a caffeine-induced [Ca2+]i transient, which was used as a measure of SR Ca2+ content. Midazolam and diazepam have differential effects on cardiac E-C coupling. Diazepam, but not midazolam, enhances cardiac E-C coupling independent of L-type Ca2+ channel modulation.