The differential effects of midazolam and diazepam on intracellular Ca2+ transients and contraction in adult rat ventricular myocytes.
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 degrees C. Intracellular Ca(2+) transients (340:380 ratio) and myocyte shortening (video edge detection) were simultaneously monitored in individual cells. Midazolam (3-100 micro M) caused a dose-dependent decrease in both peak intracellular Ca(2+) and cell shortening. Diazepam (30 and 100 micro M) increased myocyte shortening and peak Ca(2+) concomitant with a decrease in time to peak Ca(2+). A larger concentration of diazepam (>300 micro M) nearly abolished intracellular Ca(2+) and cell shortening. Midazolam (100 micro M) and diazepam (300 micro M) decreased the amount of Ca(2+) released from intracellular stores in response to caffeine. Diazepam (30 micro M), but not midazolam (10 micro M), caused a downward shift in the dose-response curve to extracellular Ca(2+) for shortening, with no concomitant effect on peak intracellular Ca(2+) 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 Ca(2+). However, the benzodiazepines have no direct influence on excitation-contraction coupling in rat ventricular myocytes, except at very large doses. Inhibition of Ca(2+) release from caffeine-sensitive intracellular Ca(2+) stores may play some part in myocardial depression at the larger concentrations of benzodiazepines. Diazepam, but not midazolam, decreased myofilament responsiveness to Ca(2+).


CONCLUSIONS
Midazolam and diazepam differentially alter the cardiac excitation-contraction coupling at the cellular level, which is mediated by altering the availability of intracellular free Ca(2+) in adult rat ventricular myocytes. In addition, diazepam, but not midazolam, decreases myofilament Ca(2+) sensitivity. However, the benzodiazepines have no direct influence on excitation-contraction coupling, except at very large doses.
Kanaya
Noriaki
N
Center for Anesthesiology Research, The Cleveland Clinic Foundation, Ohio, USA. kanaya@sapmed.ac.jp
Murray
Paul A
PA
Damron
Derek S
DS
D000759:Adjuvants, Anesthesia / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D003975:Diazepam / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006352:Heart Ventricles; D008874:Midazolam / Q000494:pharmacology*; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism; D051381:Rats; D012519:Sarcoplasmic Reticulum / Q000378:metabolism
D000759:Adjuvants, Anesthesia; D003975:Diazepam; D008874:Midazolam; D002118:Calcium