Reduced contractile response to alpha1-adrenergic stimulation in atria from mice with chronic cardiac calmodulin kinase II inhibition.

TY - JOUR

T1 - Reduced contractile response to alpha1-adrenergic stimulation in atria from mice with chronic cardiac calmodulin kinase II inhibition.

AU - Grimm, Michael

AU - El-Armouche, Ali

AU - Zhang, Rong

AU - Anderson, Mark E

AU - Eschenhagen, Thomas

PY - 2007

Y1 - 2007

N2 - The sustained positive inotropic effect of alpha-adrenoceptor agonists in the heart is associated with a small increase in intracellular Ca(2+) transients together with a larger sensitization of myofilaments to Ca(2+). The multifunctional Ca(2+) and calmodulin-dependent protein kinase II (CaMKII) could contribute to this effect, either by affecting the Ca(2+) release (ryanodine receptor) or by an uptake mechanism (via phospholamban [PLB] and SR Ca(2+) ATPase). Here we examined the role of CaMKII in the positive inotropic effect of the alpha-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 ( approximately 20%). Post-rest (30 s, 1 Hz, 37 degrees C) potentiation of force was absent (AC3-C, 190% of pre-rest amplitude). Basal force was approximately 20% lower at 1.8 mM Ca(2+), but normal at high Ca(2+) 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 approximately 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 alpha-adrenergic stimulation at low frequencies.

AB - The sustained positive inotropic effect of alpha-adrenoceptor agonists in the heart is associated with a small increase in intracellular Ca(2+) transients together with a larger sensitization of myofilaments to Ca(2+). The multifunctional Ca(2+) and calmodulin-dependent protein kinase II (CaMKII) could contribute to this effect, either by affecting the Ca(2+) release (ryanodine receptor) or by an uptake mechanism (via phospholamban [PLB] and SR Ca(2+) ATPase). Here we examined the role of CaMKII in the positive inotropic effect of the alpha-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 ( approximately 20%). Post-rest (30 s, 1 Hz, 37 degrees C) potentiation of force was absent (AC3-C, 190% of pre-rest amplitude). Basal force was approximately 20% lower at 1.8 mM Ca(2+), but normal at high Ca(2+) 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 approximately 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 alpha-adrenergic stimulation at low frequencies.

M3 - SCORING: Zeitschriftenaufsatz

VL - 42

SP - 643

EP - 652

JO - J MOL CELL CARDIOL

JF - J MOL CELL CARDIOL

SN - 0022-2828

IS - 3

M1 - 3

ER -