Cardiac phosphodiesterase 5 (cGMP-specific) modulates beta-adrenergic signaling in vivo and is down-regulated in heart failure

Recent studies implicate increased cGMP synthesis as a postreceptor contrib utor to reduced cardiac sympathetic responsiveness. Here we provide the fir st evidence that modulation of this interaction by cGMP-specific phosphodie sterase PDE5A is also diminished in failing hearts, providing a novel mecha nism for blunted beta -adrenergic signaling in this disorder. In normal con scious dogs chronically instrumented for left ventricular pressure-dimensio n analysis, PDE5A inhibition by EMD82639 had modest basal effects but marke dly blunted dobutamine-enhanced systolic and diastolic function. In failing hearts (tachypacing model), however, EMD82639 had negligible effects on ei ther basal or dobutamine-stimulated function. Whole myocardium from failing hearts had 50% lower PDE5A protein expression and 30% less total and EMD92 639-inhibitable cGMP-PDE activity. Although corresponding myocyte protein a nd enzyme activity was similar among groups, the proportion of EMD82639-inh ibitable activity was significantly lower in failure cells. Immunohistochem istry confirmed PDE5A expression in both the vasculature and myocytes of no rmal and failing hearts, but there was loss of z-band localization in faili ng myocytes that suggested altered intracellular localization. Thus, PDE5A regulation of cGMP in the heart can potently modulate beta -adrenergic stim ulation, and alterations in enzyme localization and reduced synthesis may b lunt this pathway in cardiac failure, contributing to dampening of the beta -adrenergic response.