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

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.