Reduced contractile response to α1-adrenergic stimulation in atria from mice with chronic cardiac calmodulin kinase II inhibition

Michael Grimm, Ali El-Armouche, Rong Zhang, Mark E. Anderson, Thomas Eschenhagen

Research output: Contribution to journalArticle

Abstract

The sustained positive inotropic effect of α-adrenoceptor agonists in the heart is associated with a small increase in intracellular Ca2+ transients together with a larger sensitization of myofilaments to Ca2+. The multifunctional Ca2+ and calmodulin-dependent protein kinase II (CaMKII) could contribute to this effect, either by affecting the Ca2+ release (ryanodine receptor) or by an uptake mechanism (via phospholamban [PLB] and SR Ca2+ ATPase). Here we examined the role of CaMKII in the positive inotropic effect of the α-adrenoceptor agonist phenylephrine in left atria isolated from a genetic mouse model of cardiac CaMKII inhibition (AC3-I). Compared to atria from wild-type (WT) or AC3-C (scrambled peptide), AC3-I atria showed the following abnormalities. PLB phosphorylation at Thr17, a known CaMKII target, was significantly lower (∼ 20%). Post-rest (30 s, 1 Hz, 37 °C) potentiation of force was absent (AC3-C, 190% of pre-rest amplitude). Basal force was ∼ 20% lower at 1.8 mM Ca2+, but normal at high Ca2+ concentration (> 4.5 mM). The maximal positive inotropic effect of phenylephrine, which was more pronounced at low frequencies in WT and AC3-C atria, lost its frequency dependence (1 Hz to 8 Hz). Thus, the effect of phenylephrine was reduced by ∼ 50% at 1 Hz, but was normal at 8 Hz. All three groups showed a negative force-frequency relation, and did not differ in the frequency-dependent acceleration of relaxation. Our data indicate a role of CaMKII in post-rest potentiation and the positive inotropic effect of α-adrenergic stimulation at low frequencies.

Original languageEnglish (US)
Pages (from-to)643-652
Number of pages10
JournalJournal of Molecular and Cellular Cardiology
Volume42
Issue number3
DOIs
StatePublished - Mar 1 2007
Externally publishedYes

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Keywords

  • Alpha1 adrenergic
  • Cam Kinase
  • Heart contractility
  • Post-rest potentiation

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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