Limits...
A Combined Approach Using Patch-Clamp Study and Computer Simulation Study for Understanding Long QT Syndrome and TdP in Women.

Furukawa T, Kurokawa J, Clancy CE - Curr Cardiol Rev (2008)

Bottom Line: Biological experiments including single-cell current recordings with the patch-clamp technique and biochemical experiments show that progesterone modulates cardiac K(+) current and Ca(2+) current via the non-genomic pathway of the progesterone receptor, and thus the cardiac repolarization duration, in a concentration-dependent manner.Incorporation of these biological findings into a computer model of single-cell and coupled-cell cardiomyocytes simulates fluctuations in QT(c) interval during the menstrual cycle with reasonable accuracy.A combined biological and computational approach may provide a powerful means to risk stratify TdP risk in women.

View Article: PubMed Central - PubMed

Affiliation: Department of Bio-Informational Pharmacology, Madical Research Institute, Tokyo Medical and Dental University.

ABSTRACT
Female sex is an independent risk factor for development of torsade de pointes (TdP)-type arrhythmias in both congenital and acquired long QT syndrome (LQTS). In females, QT(c) interval and TdP risk vary during the menstrual cycle and around delivery. Biological experiments including single-cell current recordings with the patch-clamp technique and biochemical experiments show that progesterone modulates cardiac K(+) current and Ca(2+) current via the non-genomic pathway of the progesterone receptor, and thus the cardiac repolarization duration, in a concentration-dependent manner. Incorporation of these biological findings into a computer model of single-cell and coupled-cell cardiomyocytes simulates fluctuations in QT(c) interval during the menstrual cycle with reasonable accuracy. Based on this model, progesterone is predicted to have protective effects against sympathetic nervous system-induced arrhythmias in congenital LQTS and drug-induced TdP in acquired LQTS. A combined biological and computational approach may provide a powerful means to risk stratify TdP risk in women.

No MeSH data available.


Related in: MedlinePlus

NO activates sGC, and produced cGMP regulates PKG, PDE2, PDE3, and/or protein phosphatase (PPase). NO also induces protein s-nitrosylation. ICa,L suppression by progesterone is via the sGC/cGMP pathway, while IKs activation is via the protein s-nitrosylation. Inset shows the antagonistic action between cAMP and cGMP for ICa,L regulation. It has been reported that in rabbit and frog ventricular myocytes, it occurs at the PDE2 level, while in guinea-pig and rat ventricular myocytes, it occurs at the PKG level [34]. The inhibition of PDE3 by cGMP and the activation of PPase by cGMP/PKG signaling pathway may also be involved.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC2801855&req=5

Figure 2: NO activates sGC, and produced cGMP regulates PKG, PDE2, PDE3, and/or protein phosphatase (PPase). NO also induces protein s-nitrosylation. ICa,L suppression by progesterone is via the sGC/cGMP pathway, while IKs activation is via the protein s-nitrosylation. Inset shows the antagonistic action between cAMP and cGMP for ICa,L regulation. It has been reported that in rabbit and frog ventricular myocytes, it occurs at the PDE2 level, while in guinea-pig and rat ventricular myocytes, it occurs at the PKG level [34]. The inhibition of PDE3 by cGMP and the activation of PPase by cGMP/PKG signaling pathway may also be involved.

Mentions: The ionic mechanism underlying APD shortening by progesterone is to modulate IKs and ICa,L, but not IKr. In the basal condition, progesterone enhanced IKs in a concentration-dependent manner with an EC50 value of 2.7 nM, while progesterone did not significantly affect ICa,L (Fig. 2A) [30]. SNS-stimulation caused enhancement of both ICa,L and IKs. Further application of progesterone reduced ICa,L to the level before cAMP and OA application, while it did not significantly change IKs [30]. The IC50 value for ICa,L suppression was 29.9 nM (Fig. 2B).


A Combined Approach Using Patch-Clamp Study and Computer Simulation Study for Understanding Long QT Syndrome and TdP in Women.

Furukawa T, Kurokawa J, Clancy CE - Curr Cardiol Rev (2008)

NO activates sGC, and produced cGMP regulates PKG, PDE2, PDE3, and/or protein phosphatase (PPase). NO also induces protein s-nitrosylation. ICa,L suppression by progesterone is via the sGC/cGMP pathway, while IKs activation is via the protein s-nitrosylation. Inset shows the antagonistic action between cAMP and cGMP for ICa,L regulation. It has been reported that in rabbit and frog ventricular myocytes, it occurs at the PDE2 level, while in guinea-pig and rat ventricular myocytes, it occurs at the PKG level [34]. The inhibition of PDE3 by cGMP and the activation of PPase by cGMP/PKG signaling pathway may also be involved.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2801855&req=5

Figure 2: NO activates sGC, and produced cGMP regulates PKG, PDE2, PDE3, and/or protein phosphatase (PPase). NO also induces protein s-nitrosylation. ICa,L suppression by progesterone is via the sGC/cGMP pathway, while IKs activation is via the protein s-nitrosylation. Inset shows the antagonistic action between cAMP and cGMP for ICa,L regulation. It has been reported that in rabbit and frog ventricular myocytes, it occurs at the PDE2 level, while in guinea-pig and rat ventricular myocytes, it occurs at the PKG level [34]. The inhibition of PDE3 by cGMP and the activation of PPase by cGMP/PKG signaling pathway may also be involved.
Mentions: The ionic mechanism underlying APD shortening by progesterone is to modulate IKs and ICa,L, but not IKr. In the basal condition, progesterone enhanced IKs in a concentration-dependent manner with an EC50 value of 2.7 nM, while progesterone did not significantly affect ICa,L (Fig. 2A) [30]. SNS-stimulation caused enhancement of both ICa,L and IKs. Further application of progesterone reduced ICa,L to the level before cAMP and OA application, while it did not significantly change IKs [30]. The IC50 value for ICa,L suppression was 29.9 nM (Fig. 2B).

Bottom Line: Biological experiments including single-cell current recordings with the patch-clamp technique and biochemical experiments show that progesterone modulates cardiac K(+) current and Ca(2+) current via the non-genomic pathway of the progesterone receptor, and thus the cardiac repolarization duration, in a concentration-dependent manner.Incorporation of these biological findings into a computer model of single-cell and coupled-cell cardiomyocytes simulates fluctuations in QT(c) interval during the menstrual cycle with reasonable accuracy.A combined biological and computational approach may provide a powerful means to risk stratify TdP risk in women.

View Article: PubMed Central - PubMed

Affiliation: Department of Bio-Informational Pharmacology, Madical Research Institute, Tokyo Medical and Dental University.

ABSTRACT
Female sex is an independent risk factor for development of torsade de pointes (TdP)-type arrhythmias in both congenital and acquired long QT syndrome (LQTS). In females, QT(c) interval and TdP risk vary during the menstrual cycle and around delivery. Biological experiments including single-cell current recordings with the patch-clamp technique and biochemical experiments show that progesterone modulates cardiac K(+) current and Ca(2+) current via the non-genomic pathway of the progesterone receptor, and thus the cardiac repolarization duration, in a concentration-dependent manner. Incorporation of these biological findings into a computer model of single-cell and coupled-cell cardiomyocytes simulates fluctuations in QT(c) interval during the menstrual cycle with reasonable accuracy. Based on this model, progesterone is predicted to have protective effects against sympathetic nervous system-induced arrhythmias in congenital LQTS and drug-induced TdP in acquired LQTS. A combined biological and computational approach may provide a powerful means to risk stratify TdP risk in women.

No MeSH data available.


Related in: MedlinePlus