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 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.
Senzaki
H
H
Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, Maryland 21287, USA.
Smith
C J
CJ
Juang
G J
GJ
Isoda
T
T
Mayer
S P
SP
Ohler
A
A
Paolocci
N
N
Tomaselli
G F
GF
Hare
J M
JM
Kass
D A
DA
D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology*; D000262:Adenylyl Cyclases / Q000378:metabolism; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure; D002303:Cardiac Output, Low / Q000201:enzymology*; D005576:Colforsin / Q000494:pharmacology; D006152:Cyclic GMP / Q000378:metabolism; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D004280:Dobutamine / Q000494:pharmacology; D004285:Dogs; D005260:Female; D006321:Heart / Q000187:drug effects; D006439:Hemodynamics; D007150:Immunohistochemistry; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000201:enzymology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011687:Purines; D011688:Purinones / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D015398:Signal Transduction; D000068677:Sildenafil Citrate; D013450:Sulfones
C433767:(4-(4-(2-ethylphenylamino)methylene)-3-methyl-5-oxo-4,5-dihydropyrazol-1-yl)benzoic acid; D000318:Adrenergic beta-Agonists; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D011688:Purinones; D011720:Pyrazoles; D011943:Receptors, Adrenergic, beta; D013450:Sulfones; D005576:Colforsin; D004280:Dobutamine; D000068677:Sildenafil Citrate; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D000262:Adenylyl Cyclases; C011145:zaprinast; D006152:Cyclic GMP