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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.

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Time constants of channel inhibition.Notes: Exemplary current traces elicited by a rectangular voltage step to +50 mV under control conditions and after application of 30 μM (A) or 1,000 μM (B) midazolam in Xenopus oocytes. Time course of block development was determined by division. In both cases, development of block was fast, yielding time constants (τ) of 9.0 ms for 30 μM (C) and 4.1 ms for 1,000 μM (D) midazolam.
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f3-dddt-8-2263: Time constants of channel inhibition.Notes: Exemplary current traces elicited by a rectangular voltage step to +50 mV under control conditions and after application of 30 μM (A) or 1,000 μM (B) midazolam in Xenopus oocytes. Time course of block development was determined by division. In both cases, development of block was fast, yielding time constants (τ) of 9.0 ms for 30 μM (C) and 4.1 ms for 1,000 μM (D) midazolam.

Mentions: Block development was next analyzed using a single depolarizing voltage step to +50 mV. Kv1.5 current was measured under control conditions and after incubation with either 30 μM or 1,000 μM (Figure 3A and B). Incubation with 30 μM and 1,000 μM midazolam resulted in a current reduction of 12.25%±12% and 94.91%±3%, respectively (n=7) (Figure 3A and B). Time course of block development could be obtained by dividing the current trace after midazolam incubation by the corresponding current trace under control conditions (Figure 3C and D). In both cases, block development was fast, yielding a mean time constant of 9.0±2.1 ms for 30 μM midazolam (Figure 3C) and 4.1±0.8 ms for 1,000 μM midazolam (Figure 3D) (representative experiment of n=6).


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)

Time constants of channel inhibition.Notes: Exemplary current traces elicited by a rectangular voltage step to +50 mV under control conditions and after application of 30 μM (A) or 1,000 μM (B) midazolam in Xenopus oocytes. Time course of block development was determined by division. In both cases, development of block was fast, yielding time constants (τ) of 9.0 ms for 30 μM (C) and 4.1 ms for 1,000 μM (D) midazolam.
© Copyright Policy
Related In: Results  -  Collection

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

f3-dddt-8-2263: Time constants of channel inhibition.Notes: Exemplary current traces elicited by a rectangular voltage step to +50 mV under control conditions and after application of 30 μM (A) or 1,000 μM (B) midazolam in Xenopus oocytes. Time course of block development was determined by division. In both cases, development of block was fast, yielding time constants (τ) of 9.0 ms for 30 μM (C) and 4.1 ms for 1,000 μM (D) midazolam.
Mentions: Block development was next analyzed using a single depolarizing voltage step to +50 mV. Kv1.5 current was measured under control conditions and after incubation with either 30 μM or 1,000 μM (Figure 3A and B). Incubation with 30 μM and 1,000 μM midazolam resulted in a current reduction of 12.25%±12% and 94.91%±3%, respectively (n=7) (Figure 3A and B). Time course of block development could be obtained by dividing the current trace after midazolam incubation by the corresponding current trace under control conditions (Figure 3C and D). In both cases, block development was fast, yielding a mean time constant of 9.0±2.1 ms for 30 μM midazolam (Figure 3C) and 4.1±0.8 ms for 1,000 μM midazolam (Figure 3D) (representative experiment of n=6).

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