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Remote ischemic preconditioning of cardiomyocytes inhibits the mitochondrial permeability transition pore independently of reduced calcium-loading or sarcKATP channel activation.

Turrell HE, Thaitirarot C, Crumbie H, Rodrigo G - Physiol Rep (2014)

Bottom Line: However, only conventional-IPC reduced the Ca(2+)-loading during metabolic inhibition and this was independent of any change in sarcKATP channel activity but was associated with a reduction in Na(+)-loading, reflecting a decrease in Na/H exchanger activity.These data show that remote-IPC inhibits MPT pore opening to a similar degree as conventional IPC, however, the contribution of MPT pore inhibition to protection against reperfusion injury is independent of Ca(2+)-loading in remote IPC.We suggest that inhibition of the MPT pore and not Ca(2+)-loading is the common link in cardioprotection between conventional and remote IPC.

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiovascular Sciences, University of Leicester, Glenfield General Hospital, Leicester, UK.

No MeSH data available.


Related in: MedlinePlus

Resting membrane potential in conventional and remotely preconditioned myocytes subject to MI and reenergization. (A) (i) Concatenated record of whole‐cell membrane currents from a control myocyte showing the activation of sarcKATP current during perfusion with MI‐Tyrode. (Insert) Membrane current in response to depolarization from the holding potential of −50 mV to the test potential of 0 mV, in normal Tyrode (triangle) and at the peak sarcKATP current amplitude (circle). (ii) Bar chart showing the peak sarcKATP current density (top) and time to peak current during metabolic inhibition in control (black), conventional IPC (dark gray), and remote IPC myocytes (light gray). (B) (i) Record of resting membrane potential measured using DiBac4(3) fluorescence in control, conventional IPC, and remote IPC myocytes. Values are the mean ± SEM from a single experimental run where the RMP was determined simultaneously from 5 to 8 myocytes in a single field of view. (ii) Mean data ± SEM of the resting membrane potential recorded in normal Tyrode and in MI‐Tyrode at 4 and 8 min, from control naïve (black), conventional IPC (dark gray), and remote IPC myocytes (light gray). ANOVA followed by Tukey's post hoc test for significance. Control naïve‐myocytes = 6 hearts; 62 cells, conventional IPC‐myocytes = 4; 26, remote IPC‐myocytes = 6; 63.
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fig04: Resting membrane potential in conventional and remotely preconditioned myocytes subject to MI and reenergization. (A) (i) Concatenated record of whole‐cell membrane currents from a control myocyte showing the activation of sarcKATP current during perfusion with MI‐Tyrode. (Insert) Membrane current in response to depolarization from the holding potential of −50 mV to the test potential of 0 mV, in normal Tyrode (triangle) and at the peak sarcKATP current amplitude (circle). (ii) Bar chart showing the peak sarcKATP current density (top) and time to peak current during metabolic inhibition in control (black), conventional IPC (dark gray), and remote IPC myocytes (light gray). (B) (i) Record of resting membrane potential measured using DiBac4(3) fluorescence in control, conventional IPC, and remote IPC myocytes. Values are the mean ± SEM from a single experimental run where the RMP was determined simultaneously from 5 to 8 myocytes in a single field of view. (ii) Mean data ± SEM of the resting membrane potential recorded in normal Tyrode and in MI‐Tyrode at 4 and 8 min, from control naïve (black), conventional IPC (dark gray), and remote IPC myocytes (light gray). ANOVA followed by Tukey's post hoc test for significance. Control naïve‐myocytes = 6 hearts; 62 cells, conventional IPC‐myocytes = 4; 26, remote IPC‐myocytes = 6; 63.

Mentions: The data in Figure 4A show no effect of conventional IPC or rIPC on the peak sarcKATP current during metabolic inhibition. Fluorescence measurements show no difference in the basal RMP recorded from control myocytes −65.5 ± 3.1 mV, IPC‐myocytes −65.9 ± 2.7 mV, and rIPC myocyte −64.8 ± 2.1 mV. The induction of metabolic inhibition results in a steady depolarization of the RMP in IPC‐myocytes to −35.3 ± 4.1 mV and naïve rIPC myocyte −38.1 ± 3.4 mV after 8 min superfusion with MI‐Tyrode, which was not significantly different to control myocytes at −35.6 ± 2.7 mV (Fig. 4B). We have previously shown the conditioning of myocytes with pharmacological conditioning drug diazoxide, caused a delay in action potential failure during metabolic inhibition, indicating that diazoxide‐treatment delayed the onset to sarcKATP activation (Rodrigo et al. 2004). However, both IPC and rIPC had no significant effect on the time‐course of the activation of sarcKATP current or to depolarization in MI‐Tyrode.


Remote ischemic preconditioning of cardiomyocytes inhibits the mitochondrial permeability transition pore independently of reduced calcium-loading or sarcKATP channel activation.

Turrell HE, Thaitirarot C, Crumbie H, Rodrigo G - Physiol Rep (2014)

Resting membrane potential in conventional and remotely preconditioned myocytes subject to MI and reenergization. (A) (i) Concatenated record of whole‐cell membrane currents from a control myocyte showing the activation of sarcKATP current during perfusion with MI‐Tyrode. (Insert) Membrane current in response to depolarization from the holding potential of −50 mV to the test potential of 0 mV, in normal Tyrode (triangle) and at the peak sarcKATP current amplitude (circle). (ii) Bar chart showing the peak sarcKATP current density (top) and time to peak current during metabolic inhibition in control (black), conventional IPC (dark gray), and remote IPC myocytes (light gray). (B) (i) Record of resting membrane potential measured using DiBac4(3) fluorescence in control, conventional IPC, and remote IPC myocytes. Values are the mean ± SEM from a single experimental run where the RMP was determined simultaneously from 5 to 8 myocytes in a single field of view. (ii) Mean data ± SEM of the resting membrane potential recorded in normal Tyrode and in MI‐Tyrode at 4 and 8 min, from control naïve (black), conventional IPC (dark gray), and remote IPC myocytes (light gray). ANOVA followed by Tukey's post hoc test for significance. Control naïve‐myocytes = 6 hearts; 62 cells, conventional IPC‐myocytes = 4; 26, remote IPC‐myocytes = 6; 63.
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Related In: Results  -  Collection

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fig04: Resting membrane potential in conventional and remotely preconditioned myocytes subject to MI and reenergization. (A) (i) Concatenated record of whole‐cell membrane currents from a control myocyte showing the activation of sarcKATP current during perfusion with MI‐Tyrode. (Insert) Membrane current in response to depolarization from the holding potential of −50 mV to the test potential of 0 mV, in normal Tyrode (triangle) and at the peak sarcKATP current amplitude (circle). (ii) Bar chart showing the peak sarcKATP current density (top) and time to peak current during metabolic inhibition in control (black), conventional IPC (dark gray), and remote IPC myocytes (light gray). (B) (i) Record of resting membrane potential measured using DiBac4(3) fluorescence in control, conventional IPC, and remote IPC myocytes. Values are the mean ± SEM from a single experimental run where the RMP was determined simultaneously from 5 to 8 myocytes in a single field of view. (ii) Mean data ± SEM of the resting membrane potential recorded in normal Tyrode and in MI‐Tyrode at 4 and 8 min, from control naïve (black), conventional IPC (dark gray), and remote IPC myocytes (light gray). ANOVA followed by Tukey's post hoc test for significance. Control naïve‐myocytes = 6 hearts; 62 cells, conventional IPC‐myocytes = 4; 26, remote IPC‐myocytes = 6; 63.
Mentions: The data in Figure 4A show no effect of conventional IPC or rIPC on the peak sarcKATP current during metabolic inhibition. Fluorescence measurements show no difference in the basal RMP recorded from control myocytes −65.5 ± 3.1 mV, IPC‐myocytes −65.9 ± 2.7 mV, and rIPC myocyte −64.8 ± 2.1 mV. The induction of metabolic inhibition results in a steady depolarization of the RMP in IPC‐myocytes to −35.3 ± 4.1 mV and naïve rIPC myocyte −38.1 ± 3.4 mV after 8 min superfusion with MI‐Tyrode, which was not significantly different to control myocytes at −35.6 ± 2.7 mV (Fig. 4B). We have previously shown the conditioning of myocytes with pharmacological conditioning drug diazoxide, caused a delay in action potential failure during metabolic inhibition, indicating that diazoxide‐treatment delayed the onset to sarcKATP activation (Rodrigo et al. 2004). However, both IPC and rIPC had no significant effect on the time‐course of the activation of sarcKATP current or to depolarization in MI‐Tyrode.

Bottom Line: However, only conventional-IPC reduced the Ca(2+)-loading during metabolic inhibition and this was independent of any change in sarcKATP channel activity but was associated with a reduction in Na(+)-loading, reflecting a decrease in Na/H exchanger activity.These data show that remote-IPC inhibits MPT pore opening to a similar degree as conventional IPC, however, the contribution of MPT pore inhibition to protection against reperfusion injury is independent of Ca(2+)-loading in remote IPC.We suggest that inhibition of the MPT pore and not Ca(2+)-loading is the common link in cardioprotection between conventional and remote IPC.

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiovascular Sciences, University of Leicester, Glenfield General Hospital, Leicester, UK.

No MeSH data available.


Related in: MedlinePlus