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


METHODS
Freshly isolated rat ventricular myocytes were loaded with fura-2/AM and field-stimulated (0.3 Hz) at 28 degrees C. Amplitude and timing of intracellular Ca2+ concentration ([Ca2+]i) and myocyte shortening were simultaneously monitored in individual cells.


RESULTS
Midazolam (3-100 microM) caused a decrease in both peak [Ca2+]i and shortening. Diazepam (30, 100 microM) increased myocyte shortening and peak [Ca2+]i; however, higher concentration of diazepam (300 microM) decreased shortening and peak [Ca2+]i. Bay K 8644 (0.01-10 microM), an L-type Ca2+ channel agonist, caused dose-dependent increases in peak [Ca2+]i and shortening. In contrast, verapamil (0.1-50 microM), an L-type Ca(2+) 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 microM) or verapamil (1 microM). Diazepam (30, 100 microM), but not midazolam (3-30 microM), increased shortening and [Ca2+]i in the presence or absence of L-type Ca2+ channel modulators. Diazepam (30 microM) and midazolam (10 microM) had no effect on peak [Ca2+]i of a caffeine-induced [Ca2+]i transient, which was used as a measure of SR Ca2+ content.


CONCLUSIONS
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.
Kanaya
Noriaki
N
Department of Anesthesiology, Sapporo Medical University School of Medicine, S-1, W-16, Chuo-ku, Sapporo 060-8643, Japan.
Murray
Paul A
PA
Damron
Derek S
DS
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000187:drug effects*; D003975:Diazepam / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006352:Heart Ventricles; D008874:Midazolam / Q000494:pharmacology*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D014700:Verapamil / Q000494:pharmacology
D020746:Calcium Channels, L-Type; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D014700:Verapamil; D003975:Diazepam; D008874:Midazolam; D002118:Calcium