Inhibition of phosphodiesterase type 5 by the activator of nitric oxide-sensitive guanylyl cyclase BAY 41-2272

By the formation of cGMP, nitric oxide (NO)-sensitive guanylyl cyclase (GC) acts as the effector for the signaling molecule NO and mediates the relaxation of vascular smooth muscle and the inhibition of platelet aggregation. The compounds YC-1 and BAY 41-2272 are regarded as NO-independent activator...

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Bibliographic Details
Published in:Circulation (New York, N.Y.) N.Y.), 2004-04, Vol.109 (14), p.1711-1713
Main Authors: MULLERSHAUSEN, Florian, RUSSWURM, Michael, FRIEBE, Andreas, KOESLING, Doris
Format: Article
Language:English
Subjects:
3',5'-Cyclic-GMP Phosphodiesterases - antagonists & inhibitors
3',5'-Cyclic-GMP Phosphodiesterases - genetics
Biological and medical sciences
Blood and lymphatic vessels
Cardiology. Vascular system
Cell Line
Cyclic GMP - physiology
Cyclic Nucleotide Phosphodiesterases, Type 5
Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous
Enzyme Activation - drug effects
Guanylate Cyclase
Humans
Indazoles - pharmacology
Kidney
Medical sciences
Nitric Oxide - physiology
Nitric Oxide Donors - metabolism
Phosphodiesterase Inhibitors - pharmacology
Pyrazoles - pharmacology
Pyridines - pharmacology
Quaternary Ammonium Compounds - metabolism
Receptors, Cytoplasmic and Nuclear - physiology
Recombinant Fusion Proteins - antagonists & inhibitors
S-Nitrosoglutathione - pharmacology
Soluble Guanylyl Cyclase
Transfection
Vasodilation - physiology
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Summary:By the formation of cGMP, nitric oxide (NO)-sensitive guanylyl cyclase (GC) acts as the effector for the signaling molecule NO and mediates the relaxation of vascular smooth muscle and the inhibition of platelet aggregation. The compounds YC-1 and BAY 41-2272 are regarded as NO-independent activators and sensitizers of NO-sensitive GC. In vivo effects, for example, lowering blood pressure and prolonging tail-bleeding times, turn the compounds into promising candidates for the therapy of cardiovascular diseases. However, YC-1 has also been shown to inhibit the major cGMP-degrading enzyme phosphodiesterase type 5 (PDE5). The synergistic properties of YC-1 on cGMP formation and degradation lead to an excessive NO-induced cGMP accumulation in cells, explaining the observed physiological effects. We assessed a potential inhibition of PDE5 by the new GC activator BAY 41-2272. The effects of BAY 41-2272 on NO-sensitive GC and PDE5 activities were tested in vitro. BAY 41-2272 not only sensitized NO-sensitive GC toward activation by NO but also, with comparable potency, inhibited cGMP degradation by PDE5. In intact platelets, BAY 41-2272 greatly potentiated the NO-induced cGMP response that was caused by a synergistic effect of BAY 41-2272 on cGMP formation and degradation. The physiological effects of BAY 41-2272, which are commonly ascribed to the NO-independent activation of NO-sensitive GC, are rather due to the synergism of sensitization of NO-sensitive GC and inhibition of PDE5.
ISSN:0009-7322
1524-4539
DOI:10.1161/01.cir.0000126286.47618.bd