Targeted disruption of glycogen synthase kinase-3β in the heart attenuates cardiac parasympathetic dysfunction in type 1 diabetic Akita mice

to cardiac myocyte hypertrophy, although exogenously administered BNP shows poor clinical efficacy in heart failure and hypertension. Here we tested whether PDE2A was directly involved in modulating cardiac neurotransmitter release from pre-hypertensive spontaneously hypertensive rats (SHRs) that show an enhanced Ca2+ phenotype. Methods and Results: [3H] labelled noradrenaline (NA) release was measured from isolated spontaneously beating atrial in response to 5Hz field stimulation for 1 minute at the 16th (S1, control) and 40th (S2, with 250nM BNP) minutes. PDE2A activity in the SHR (n = 8) was higher (~60%) than in WKY stellate ganglia tissue (n= 8). BNP significantly reduced [3H]-NA release (S1:+0.92 ± 0.09%, S2: +0.59 ± 0.09% n= 9,) in the WKY, whereas it failed in the SHR (S1: +1.34 ± 0.34% vs S2:+1.16 ± 0.23%, n = 9). Overexpression of PDE2A in the right atria abrogated the response to BNP in the WKY and mimicked the neurotransmission seen in the SHR neuron. This response was rescued by inhibition of PDE2A by BAY60-7550 or the dominant negative of PDE2A. Conclusion: These data support the hypothesis that higher PDE2A expression in the SHR abolishes the capacity of BNP to reduce neurotransmitters release. They also suggest that inhibiting neuronal PDE2 may be important in restoring the efficacy of BNP to decrease sympathetic neurotransmission in cases of dysautonomia.