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Increased PKA activity and its influence on isoprenaline-stimulated L-type Ca2+ channels in the heart from

Kenneth W L Kam1, Gennadi M Kravtsov, Jing Liu

  • 1Department of Physiology, Faculty of Medicine, the University of Hong Kong, Pokfulam, Hong Kong SAR, China.

British Journal of Pharmacology
|February 3, 2005
PubMed

Insights

Oestrogen protects the heart by reducing beta1-adrenoceptor (beta1-AR) signaling. Oestrogen deficiency increases protein kinase A (PKA) activity and L-type Ca2+ channel function, impacting cardiac contractility.

Area of Science:

  • Cardiovascular Physiology
  • Endocrinology
  • Molecular Pharmacology

Background:

  • Oestrogen confers cardioprotection, partly via downregulation of cardiac beta1-adrenoceptors (beta1-AR).
  • The precise post-beta1-AR signaling cascade influenced by oestrogen remains incompletely understood.
  • Protein kinase A (PKA) and L-type Ca2+ channels are key regulators of cardiac contractility.

Purpose of the Study:

  • To investigate the effect of oestrogen on the post-beta1-AR signaling cascade.
  • To determine the role of PKA activity and its influence on L-type Ca2+ channels in oestrogen-mediated cardioprotection.
  • To elucidate the impact of oestrogen deficiency on intracellular Ca2+ transients and cardiac contractility.

Main Methods:

  • Utilized adult female Sprague-Dawley rats divided into sham-operated, ovariectomized (Ovx), and oestrogen-replaced (Ovx + E2) groups.
  • Measured electrically induced intracellular Ca2+ transients (E[Ca2+]i), 45Ca2+ uptake via L-type Ca2+ channels, heart rate, and force of contraction.
  • Assessed basal and isoprenaline-stimulated PKA activity, cAMP accumulation, and responsiveness to PKA inhibition using KT5720.

Main Results:

  • Ovariectomized rats exhibited significantly greater E[Ca2+]i, Ca2+ channel activity, heart rate, and contractility compared to controls and oestrogen-replaced rats.
  • Basal and isoprenaline-induced PKA activities were elevated in ovariectomized rat hearts.
  • PKA inhibition significantly reduced Ca2+ channel activity, with a more pronounced effect in ovariectomized rats, indicating PKA's role in regulating channel function.

Conclusions:

  • Oestrogen deficiency leads to increased PKA activity and enhanced L-type Ca2+ channel function, contributing to altered cardiac contractility.
  • Suppression of PKA activity, alongside beta1-AR downregulation, is crucial for oestrogen's cardioprotective effects.
  • These findings reveal a novel mechanism of oestrogen action on cardiac intracellular signaling pathways.

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