Background: Phosphodiesterases (PDE) critically regulate myocardial cAMP and cGMP levels. PDE2 is stimulated by cGMP to hydrolyze cAMP, mediating a negative crosstalk between both pathways. PDE2 upregulation in heart failure contributes to desensitization to β-adrenergic overstimulation. After isoprenaline (ISO) injections, PDE2 overexpressing mice (PDE2 OE) were protected against ventricular arrhythmia. Here, we investigate the mechanisms underlying the effects of PDE2 OE on susceptibility to arrhythmias. Methods: Cellular arrhythmia, ion currents, and Ca2+-sparks were assessed in ventricular cardiomyocytes from PDE2 OE and WT littermates. Results: Under basal conditions, action potential (AP) morphology were similar in PDE2 OE and WT. ISO stimulation significantly increased the incidence of afterdepolarizations and spontaneous APs in WT, which was markedly reduced in PDE2 OE. The ISO-induced increase in ICaL seen in WT was prevented in PDE2 OE. Moreover, the ISO-induced, Epac- and CaMKII-dependent increase in INaL and Ca2+-spark frequency was blunted in PDE2 OE, while the effect of direct Epac activation was similar in both groups. Finally, PDE2 inhibition facilitated arrhythmic events in ex vivo perfused WT hearts after reperfusion injury. Conclusion: Higher PDE2 abundance protects against ISO-induced cardiac arrhythmia by preventing the Epac- and CaMKII-mediated increases of cellular triggers. Thus, activating myocardial PDE2 may represent a novel intracellular anti-arrhythmic therapeutic strategy in HF.
Ordered-alloy domains of epitaxially grown ͑Ga,In͒P layers have been observed elsewhere using transmission electron microscopy and transmission electron diffraction. We used diffraction anomalous fine-structure ͑DAFS͒ experiments at superlattice reflections occurring in several ͗111͘ directions to explore the short-range order around Ga atoms in such ordered domains in epitaxial ͑Ga,In͒P layers grown on ͑001͒ GaAs substrates. The requirements for a reliable measurement of the reflection intensity depending on the photon energy are described. A quantitative DAFS analysis resulting in short-range order parameters is explained in detail. The local structure around Ga in the whole ͑Ga,In͒P layer (F4 3m) can be understood by a local structure model, while contrary to that the local structure around Ga atoms in the ordered regions (R3m) can be described by the values expected on the basis of the virtual-crystal model. ͓S0163-1829͑99͒09023-2͔
Diffraction anomalous ®ne structure (DAFS) experiments were applied to an epitaxially grown (Ga,In)P layer on a [001] GaAs substrate as a single-crystalline model substance. The requirements for the reliable measurement of re¯ection intensities as a function of photon energy, as well as the quantitative DAFS analysis resulting in the complex-valued ®ne-structure function of the scattering factor, are described. In the case of single crystals, effort had to be put into performing the DAFS measurements in order to hold the position of the Bragg re¯ection exactly during the energy scan. Using the zinc-blende-type structure as an example, it is shown for the ®rst time that, similar to singlecrystal structure analysis, the lack of inversion symmetry has a signi®cant impact on the DAFS signal, so that DAFS may contribute to structure analysis as well.
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