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

Abstract

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.

Phosphodiesterase-5 Inhibitor Sildenafil Preconditions Adult Cardiac Myocytes against Necrosis and Apoptosis

“…There has been a dominant view that PDE5 is not present in the myocardium (11) recent study where abundant expression of PDE5 was observed in isolated canine ventricular cardiomyocytes with immunohistochemistry (23). In agreement with this observation, our study demonstrated for the first time the presence of PDE5 in murine ventricular cardiomyocytes (Fig.…”

“…J, bar diagram showing quantitative data from three independent experiments. PDE5 band (90 -100 kDa) were observed, which is consistent with the previously reported PDE5A in dog cardiomyocytes (23). Furthermore, using immunohistochemistry and laser confocal microscopy, the green fluorescence for PDE5A in normal isolated myocyte was clearly evident, thereby confirming the localization of PDE5A in adult mouse cardiomyocytes (Fig.…”

“…Immunohistochemistry of PDE5-Localization of PDE5A protein in cardiomyocytes was performed according to the method of Senzaki et al (23). The cardiomyocytes were fixed in 4% paraformaldehyde and then treated with 0.1% sodium citrate and 0.1% Triton X-100.…”

The effects of chronic phosphodiesterase-5 inhibitor use on different organ systems

“…Erectile dysfunction (ED) is a common medical condition linked both to endothelial dysfunction [1][2][3][4][5][6][7][8][9][10][11][12][13] as well as multiple other comorbid conditions. [14][15][16][17] Historically, the treatment for ED has been limited to a selected group of specialists, namely urologists and sexual therapists.…”

Tissue expression, distribution, and regulation of PDE5

“…All studies using either RT-PCR or Northern blot have demonstrated PDE5 mRNA expression in the heart, 1-5 and a separate study using immunohistochemical staining and functional assays also demonstrated PDE5 expression in canine cardiomyocytes. 6 However, PDE5 enzymatic activity was reported to be absent in a human ventricular homogenate. 7 Two PDE5 isoforms, PDE5A1 and PDE5A2, have been identified in humans and dogs.…”