Published online before print December 2, 2004, doi: 10.1161/01.RES.0000152262.22968.72
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Submitted on September 1, 2004
Revised on November 16, 2004
Accepted on November 19, 2004
cGMP Catabolism by PDE5A Regulates Cardiac Adrenergic Stimulation by NOS3-Dependent Mechanism
Eiki Takimoto ;
From the Division of Cardiology (E.T., H.C.C., D.B., J.M., T.I., D.A.K.), Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, Md; Dulbecco Telethon Institute at the Venetian Institute of Molecular Medicine (M.M., M.Z.), Padova, Italy; Department of Pharmacology and Toxicology (E.M.), Ruhr-Universität Bochum, Medizinische Fakultät, Bochum, Germany; Department of Pharmacology (D.C.M., K.A., C.J.S.), New York Medical College, Valhalla; and Department of Pharmacology (W.R.D.), University of Vermont, Burlington.
* To whom correspondence should be addressed. E-mail: dkass{at}jhmi.edu.
-Adrenergic agonists stimulate cardiac contractility and simultaneously blunt this response by coactivating NO synthase (NOS3) to enhance cGMP synthesis and activate protein kinase G (PKG-1). cGMP is also catabolically regulated by phosphodiesterase PDE5A. PDE5A inhibition by sildenafil (Viagra) increases cGMP and is used widely to treat erectile dysfunction; however, its role in the heart and its interaction with -adrenergic and NOS3/cGMP stimulation is largely unknown. In nontransgenic (control) murine in vivo hearts and isolated myocytes, PDE5A inhibition (sildenafil) minimally altered rest function. However, when the hearts or isolated myocytes were stimulated with isoproterenol, PDE5A inhibition was associated with a suppression of contractility that was coupled to elevated cGMP and increased PKG-1 activity. In contrast, NOS3-null hearts or controls with NOS inhibited by NG-nitro-L-arginine methyl ester, or soluble guanylate cyclase (sGC) inhibited by ODQ, showed no effect of PDE5A inhibition on -stimulated contractility or PKG-1 activation. This lack of response was not attributable to altered PDE5A gene or protein expression or in vitro PDE5A activity, but rather to an absence of sGC-generated cGMP specifically targeted to PDE5A catabolism and to a loss of PDE5A localization to z-bands. Re-expression of active NOS3 in NOS3-null hearts by adenoviral gene transfer restored PDE5A z-band localization and the antiadrenergic efficacy of PDE5A inhibition. These data support a novel regulatory role of PDE5A in hearts under adrenergic stimulation and highlight specific coupling of PDE5A catabolic regulation with NOS3-derived cGMP attributable to protein subcellular localization and targeted synthetic/catabolic coupling.
Key words: PDE5 • phosphodiesterase • sildenafil • nitric oxide synthase • contractility • z-band
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