Molecular and Cellular Biochemistry

, Volume 321, Issue 1–2, pp 155–164 | Cite as

Prevalent role of Akt and ERK activation in cardioprotective effect of Ca2+ channel- and beta-adrenergic receptor blockers

  • Krisztina Kovacs
  • Katalin Hanto
  • Zita Bognar
  • Antal Tapodi
  • Eszter Bognar
  • Gyongyi N. Kiss
  • Aliz Szabo
  • Gabor Rappai
  • Tamas Kiss
  • Balazs Sumegi
  • Ferenc GallyasJr.
Article

Abstract

We studied cardioprotective as well as Akt and extracellular signal-activated kinase (ERK) activating effect of a Ca2+ antagonist and a beta-adrenergic receptor blocker during ischemia-reperfusion, and compared these properties of the substances with that of a poly(ADP-ribose) polymerase (PARP) inhibitor used as a positive control throughout the experiments. Langendorff-perfused isolated rat hearts were subjected to 25 min global ischemia followed by 45 min reperfusion, and recovery of energy metabolism as well as functional cardiac parameters were monitored. Although to varying extents, all substances improved recovery of creatine phosphate, ATP, intracellular pH, and reutilization of inorganic phosphate. These favorable changes were accompanied by improved recovery of heart function parameters and reduced infarct size. In addition and again to varying extents, all studied substances decreased oxidative damage (lipid peroxidation and protein oxidation), and activated Akt, glycogen synthase kinase (GSK)-3β, and ERK1/2. Correlation between cardioprotective and kinase activating effectivity of the compounds proved to be statistically significant. Physiological significance of these kinase activations was established by demonstrating that inhibition of Akt by LY294002 and ERK1/2 by PD98059 compromised the cardioprotective effect of all the substances studied. In conclusion, we demonstrated for the first time that activation of phosphatidylinositol-3-kinase (PI-3K)-Akt and ERK2 pathways significantly contributed to cardioprotective effects of a Ca2+ antagonist and a β-adrenergic receptor blocker. Furthermore, we found a strong correlation between cardioprotective and kinase-activating potencies of the substances studied (Verapamil, Metoprolol and two PARP inhibitors), which indicated the potentiality of these kinases as drug-targets in the therapy of ischemic heart disease.

Keywords

Ischemia-reperfusion Beta-adrenergic receptor blocker Ca-channel blocker Akt ERK 

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Copyright information

© Springer Science+Business Media, LLC. 2008

Authors and Affiliations

  • Krisztina Kovacs
    • 1
  • Katalin Hanto
    • 2
  • Zita Bognar
    • 1
  • Antal Tapodi
    • 1
  • Eszter Bognar
    • 1
  • Gyongyi N. Kiss
    • 1
  • Aliz Szabo
    • 1
  • Gabor Rappai
    • 3
  • Tamas Kiss
    • 2
  • Balazs Sumegi
    • 1
  • Ferenc GallyasJr.
    • 1
  1. 1.Department of Biochemistry and Medical ChemistryUniversity of Pecs Medical SchoolPecsHungary
  2. 2.Department of Anaesthesia and Intensive TherapyUniversity of Pecs Medical SchoolPecsHungary
  3. 3.Department of Statistics and Demography, Faculty of EconomicsUniversity of PecsPecsHungary

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