Limits...
Inhibition of cardiac Kv1.5 potassium current by the anesthetic midazolam: mode of action.

Vonderlin N, Fischer F, Zitron E, Seyler C, Scherer D, Thomas D, Katus HA, Scholz EP - Drug Des Devel Ther (2014)

Bottom Line: Despite its widespread clinical use, detailed information about cardiac side effects of midazolam is largely lacking.We further showed that midazolam did not affect the half-maximal activation voltage of Kv1.5 channels.These data add to the current understanding of the pharmacological profile of midazolam.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine III, University Hospital Heidelberg, Heidelberg, Germany.

ABSTRACT
Midazolam is a short-acting benzodiazepine that is widely used in anesthesia. Despite its widespread clinical use, detailed information about cardiac side effects of midazolam is largely lacking. Using the double-electrode voltage clamp technique, we studied pharmacological effects of midazolam on heterologously expressed Kv1.5 channels underlying atrial repolarizing current I(Kur). Midazolam dose-dependently inhibited Kv1.5 current, yielding an IC50 of 17 μM in an HEK cell line and an IC50 of 104 μM in Xenopus oocytes. We further showed that midazolam did not affect the half-maximal activation voltage of Kv1.5 channels. However, a small negative shift of the inactivation curve could be observed. Midazolam acted as a typical open-channel inhibitor with rapid onset of block and without frequency dependence of block. Taken together, midazolam is an open channel inhibitor of cardiac Kv1.5 channels. These data add to the current understanding of the pharmacological profile of midazolam.

Show MeSH

Related in: MedlinePlus

Pharmacological properties of Kv1.5 current inhibition.Notes: Typical families of Kv1.5 current traces elicited by a double-step voltage protocol (inset in [A]) before (A) and after (B) incubation with 100 μM midazolam in Xenopus oocytes. (C) Current–voltage relationship of Kv1.5 current under control conditions (filled boxes) and after incubation with midazolam (open circles) measured at peak current (n=6). (D) Kv1.5 activation curves established by dividing peak current amplitude by the electrochemical driving force. Midazolam did not significantly influence the half-maximal activation voltage (V1/2) (n=6). (E) Kv1.5 channel inactivation curves established by plotting tail current amplitude versus the potential of the first voltage step. Midazolam resulted in a small but significant shift of the inactivation curve (n=6).
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4232042&req=5

f2-dddt-8-2263: Pharmacological properties of Kv1.5 current inhibition.Notes: Typical families of Kv1.5 current traces elicited by a double-step voltage protocol (inset in [A]) before (A) and after (B) incubation with 100 μM midazolam in Xenopus oocytes. (C) Current–voltage relationship of Kv1.5 current under control conditions (filled boxes) and after incubation with midazolam (open circles) measured at peak current (n=6). (D) Kv1.5 activation curves established by dividing peak current amplitude by the electrochemical driving force. Midazolam did not significantly influence the half-maximal activation voltage (V1/2) (n=6). (E) Kv1.5 channel inactivation curves established by plotting tail current amplitude versus the potential of the first voltage step. Midazolam resulted in a small but significant shift of the inactivation curve (n=6).

Mentions: Effects of midazolam on biophysical properties of Kv1.5 channels were further analyzed using a double-step voltage protocol. From a holding potential of −80 mV, cells were depolarized by a variable voltage step (1,250 ms) ranging from −90 to +50 mV (10 mV increments). This variable step was followed by a constant return pulse to +50 mV (50 ms) eliciting outward tail currents. Figure 2A and B display typical families of Kv1.5 current traces before and after application of midazolam (100 μM) (see inset for voltage protocol). The corresponding current–voltage relationship measured at peak current amplitude (measured at the first dashed line in Figure 2A and B) is displayed in Figure 2C. Kv1.5 channel activation curves were established, as reported previously, by dividing current amplitude by the corresponding electrochemical driving force (Figure 2D).21 The I-V relationship of each cell before and after midazolam application was fitted with a Boltzmann function in order to obtain half-maximal activation voltages (V1/2). Under control conditions, Kv1.5 channels revealed a mean V1/2 of 1.93±0.85 mV (n=6) (Figure 2D). Inhibition by midazolam did not significantly influence the V1/2 (V1/2 =3.21±1.47 mV, n=6, P>0.05) (Figure 2D).


Inhibition of cardiac Kv1.5 potassium current by the anesthetic midazolam: mode of action.

Vonderlin N, Fischer F, Zitron E, Seyler C, Scherer D, Thomas D, Katus HA, Scholz EP - Drug Des Devel Ther (2014)

Pharmacological properties of Kv1.5 current inhibition.Notes: Typical families of Kv1.5 current traces elicited by a double-step voltage protocol (inset in [A]) before (A) and after (B) incubation with 100 μM midazolam in Xenopus oocytes. (C) Current–voltage relationship of Kv1.5 current under control conditions (filled boxes) and after incubation with midazolam (open circles) measured at peak current (n=6). (D) Kv1.5 activation curves established by dividing peak current amplitude by the electrochemical driving force. Midazolam did not significantly influence the half-maximal activation voltage (V1/2) (n=6). (E) Kv1.5 channel inactivation curves established by plotting tail current amplitude versus the potential of the first voltage step. Midazolam resulted in a small but significant shift of the inactivation curve (n=6).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4232042&req=5

f2-dddt-8-2263: Pharmacological properties of Kv1.5 current inhibition.Notes: Typical families of Kv1.5 current traces elicited by a double-step voltage protocol (inset in [A]) before (A) and after (B) incubation with 100 μM midazolam in Xenopus oocytes. (C) Current–voltage relationship of Kv1.5 current under control conditions (filled boxes) and after incubation with midazolam (open circles) measured at peak current (n=6). (D) Kv1.5 activation curves established by dividing peak current amplitude by the electrochemical driving force. Midazolam did not significantly influence the half-maximal activation voltage (V1/2) (n=6). (E) Kv1.5 channel inactivation curves established by plotting tail current amplitude versus the potential of the first voltage step. Midazolam resulted in a small but significant shift of the inactivation curve (n=6).
Mentions: Effects of midazolam on biophysical properties of Kv1.5 channels were further analyzed using a double-step voltage protocol. From a holding potential of −80 mV, cells were depolarized by a variable voltage step (1,250 ms) ranging from −90 to +50 mV (10 mV increments). This variable step was followed by a constant return pulse to +50 mV (50 ms) eliciting outward tail currents. Figure 2A and B display typical families of Kv1.5 current traces before and after application of midazolam (100 μM) (see inset for voltage protocol). The corresponding current–voltage relationship measured at peak current amplitude (measured at the first dashed line in Figure 2A and B) is displayed in Figure 2C. Kv1.5 channel activation curves were established, as reported previously, by dividing current amplitude by the corresponding electrochemical driving force (Figure 2D).21 The I-V relationship of each cell before and after midazolam application was fitted with a Boltzmann function in order to obtain half-maximal activation voltages (V1/2). Under control conditions, Kv1.5 channels revealed a mean V1/2 of 1.93±0.85 mV (n=6) (Figure 2D). Inhibition by midazolam did not significantly influence the V1/2 (V1/2 =3.21±1.47 mV, n=6, P>0.05) (Figure 2D).

Bottom Line: Despite its widespread clinical use, detailed information about cardiac side effects of midazolam is largely lacking.We further showed that midazolam did not affect the half-maximal activation voltage of Kv1.5 channels.These data add to the current understanding of the pharmacological profile of midazolam.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine III, University Hospital Heidelberg, Heidelberg, Germany.

ABSTRACT
Midazolam is a short-acting benzodiazepine that is widely used in anesthesia. Despite its widespread clinical use, detailed information about cardiac side effects of midazolam is largely lacking. Using the double-electrode voltage clamp technique, we studied pharmacological effects of midazolam on heterologously expressed Kv1.5 channels underlying atrial repolarizing current I(Kur). Midazolam dose-dependently inhibited Kv1.5 current, yielding an IC50 of 17 μM in an HEK cell line and an IC50 of 104 μM in Xenopus oocytes. We further showed that midazolam did not affect the half-maximal activation voltage of Kv1.5 channels. However, a small negative shift of the inactivation curve could be observed. Midazolam acted as a typical open-channel inhibitor with rapid onset of block and without frequency dependence of block. Taken together, midazolam is an open channel inhibitor of cardiac Kv1.5 channels. These data add to the current understanding of the pharmacological profile of midazolam.

Show MeSH
Related in: MedlinePlus