zaprinast and Cardiac-Output--Low

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 beta-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 beta-adrenergic stimulation, and alterations in enzyme localization and reduced synthesis may blunt this pathway in cardiac failure, contributing to dampening of the beta-adrenergic response.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Adenylyl Cyclases; Adrenergic beta-Agonists; Animals; Blood Pressure; Cardiac Output, Low; Colforsin; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Dobutamine; Dogs; Female; Heart; Hemodynamics; Immunohistochemistry; Male; Myocardial Contraction; Myocardium; Phosphodiesterase Inhibitors; Piperazines; Purines; Purinones; Pyrazoles; Receptors, Adrenergic, beta; Signal Transduction; Sildenafil Citrate; Sulfones