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Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, Maryland 21287, USA; and
* Department of Pathology, New York Medical College, Valhalla, New York, USA
2Correspondence: Halsted 500, Division of Cardiology, Johns Hopkins Medical Institutions, 600 N. Wolfe St., Baltimore, MD 21287, USA. E-mail: dkass{at}bme.jhu.edu
Recent studies implicate increased cGMP synthesis as a postreceptor contributor to reduced cardiac sympathetic responsiveness. Here we provide the first evidence that modulation of this interaction by cGMP-specific phosphodiesterase PDE5A is also diminished in failing hearts, providing a novel mechanism for blunted ß-adrenergic signaling in this disorder. In normal conscious dogs chronically instrumented for left ventricular pressure-dimension analysis, PDE5A inhibition by EMD82639 had modest basal effects but markedly blunted dobutamine-enhanced systolic and diastolic function. In failing hearts (tachypacing model), however, EMD82639 had negligible effects on either basal or dobutamine-stimulated function. Whole myocardium from failing hearts had 50% lower PDE5A protein expression and 30% less total and EMD92639-inhibitable cGMP-PDE activity. Although corresponding myocyte protein and enzyme activity was similar among groups, the proportion of EMD82639-inhibitable activity was significantly lower in failure cells. Immunohistochemistry confirmed PDE5A expression in both the vasculature and myocytes of normal and failing hearts, but there was loss of z-band localization in failing myocytes that suggested altered intracellular localization. Thus, PDE5A regulation of cGMP in the heart can potently modulate ß-adrenergic stimulation, and alterations in enzyme localization and reduced synthesis may blunt this pathway in cardiac failure, contributing to dampening of the ß-adrenergic response.—Senzaki, H., Smith, C. J., Juang, G. J., Isoda, T., Mayer, S. P., Ohler, A., Paolocci, N., Tomaselli, G. F., Hare, J. M., Kass, K. A. Cardiac phosphodiesterase 5 (cGMP-specific) modulates ß-adrenergic signaling in vivo and is down-regulated in heart failure.
Key Words: tissue activity • protein expression • coronary blood flow • PDE5
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