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Phosphodiesterase 9a Inhibition in Mouse Models of Diastolic Dysfunction.
- Source :
-
Circulation. Heart failure [Circ Heart Fail] 2020 May; Vol. 13 (5), pp. e006609. Date of Electronic Publication: 2020 May 18. - Publication Year :
- 2020
-
Abstract
- Background: Low myocardial cGMP-PKG (cyclic guanosine monophosphate-protein kinase G) activity has been associated with increased cardiomyocyte diastolic stiffness in heart failure with preserved ejection fraction. Cyclic guanosine monophosphate is mainly hydrolyzed by PDE (phosphodiesterases) 5a and 9a. Importantly, PDE9a expression has been reported to be upregulated in human heart failure with preserved ejection fraction myocardium and chronic administration of a PDE9a inhibitor reverses preestablished cardiac hypertrophy and systolic dysfunction in mice subjected to transverse aortic constriction (TAC). We hypothesized that inhibiting PDE9a activity ameliorates diastolic dysfunction.<br />Methods: To examine the effect of chronic PDE9a inhibition, 2 diastolic dysfunction mouse models were studied: (1) TAC-deoxycorticosterone acetate and (2) Lepr <superscript> db/db </superscript> . PDE9a inhibitor (5 and 8 mg/kg per day) was administered to the mice via subcutaneously implanted osmotic minipumps for 28 days. The effect of acute PDE9a inhibition was investigated in intact cardiomyocytes isolated from TAC-deoxycorticosterone acetate mice. Atrial natriuretic peptide together with PDE9a inhibitor were administered to the isolated intact cardiomyocytes through the cell perfusate.<br />Results: For acute inhibition, no cellular stiffness reduction was found, whereas chronic PDE9a inhibition resulted in reduced left ventricular chamber stiffness in TAC-deoxycorticosterone acetate, but not in Lepr <superscript> db/db </superscript> mice. Passive cardiomyocyte stiffness was reduced by chronic PDE9a inhibition, with no differences in myocardial fibrosis or cardiac morphometry. PDE9a inhibition increased the ventricular-arterial coupling ratio, reflecting impaired systolic function.<br />Conclusions: Chronic PDE9a inhibition lowers left ventricular chamber stiffness in TAC-deoxycorticosterone acetate mice. However, the usefulness of PDE9a inhibition to treat high-diastolic stiffness may be limited as the required PDE9a inhibitor dose also impairs systolic function, observed as a decline in ventricular-arterial coordination, in this model.
- Subjects :
- 3',5'-Cyclic-AMP Phosphodiesterases metabolism
Animals
Diastole
Disease Models, Animal
Male
Mice, Inbred C57BL
Myocytes, Cardiac enzymology
Phosphodiesterase Inhibitors toxicity
Ventricular Dysfunction, Left enzymology
Ventricular Dysfunction, Left physiopathology
3',5'-Cyclic-AMP Phosphodiesterases antagonists & inhibitors
Myocytes, Cardiac drug effects
Phosphodiesterase Inhibitors pharmacology
Ventricular Dysfunction, Left drug therapy
Ventricular Function, Left drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1941-3297
- Volume :
- 13
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Circulation. Heart failure
- Publication Type :
- Academic Journal
- Accession number :
- 32418479
- Full Text :
- https://doi.org/10.1161/CIRCHEARTFAILURE.119.006609