Role of calmodulin kinase II in inotropic effect of α1‐adrenergic stimulation in the heart

Abstract

The multifunctional Ca2+ and calmodulin‐dependent kinase II (CaMKII) may play a role in cardiac function by affecting Ca2+ release or uptake mechanisms through phosphorylation of its downstream targets phospholamban (PLB) and the ryanodine receptor. Here we examined the role of CaMKII in the positive inotropic effect of the α1‐adrenoceptor agonist phenylephrine (PE). In left atria isolated from a genetic mouse model of cardiac CaMKII inhibition (AC3‐I) PLB‐T17 phosphorylation was 20% of wild type (WT) or AC3‐C (scrambled peptide). Respectively, basal force (1 Hz) was 20% lower at 1.8 mM Ca2+, but normal at high Ca2+ (>4.5 mM). The maximal positive inotropic effect of PE, which was more pronounced at low frequencies in WT and AC3‐C, lost its frequency dependence in the AC3‐I atria. Thus, the effect of PE was reduced by 50% at 1 Hz, but was normal at 8 Hz. Post‐rest (30 s, 1 Hz) potentiation of force was also absent. Subsequent studies were carried out examining response to PE in CaMKIIδ knockout mice. Basal and PE (100 μM)‐stimulated left ventricular pressures were not altered in Langendorff perfused hearts from these mice, despite significantly reduced PLB‐T17 phosphorylation after 10 min PE (20% of WT). Our data suggest a role of CaMKII in the positive inotropic effect of atrial α1‐adrenergic stimulation. Further studies are needed to determine the role of CaMKII in cardiac function under pathophysiological conditions.