Reduced contractile response to alpha1-adrenergic stimulation in atria from mice with chronic cardiac calmodulin kinase II inhibition.
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.
Grimm
Michael
M
Institute of Experimental and Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
El-Armouche
Ali
A
Zhang
Rong
R
Anderson
Mark E
ME
Eschenhagen
Thomas
T
D000577:Amides / Q000494:pharmacology; D000818:Animals; D001896:Boron Compounds / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006321:Heart / Q000187:drug effects*; D051379:Mice; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism*; D010656:Phenylephrine / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism*; D013997:Time Factors
D000577:Amides; D001896:Boron Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011942:Receptors, Adrenergic, alpha; C108830:Y 27632; D010656:Phenylephrine; C109986:2-aminoethoxydiphenyl borate; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002118:Calcium