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


RESULTS
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.


CONCLUSIONS
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.
Mullershausen
Florian
F
Insititut für Pharmakologie und Toxikologie, Ruhr-Universität Bochum, Bochum, Germany.
Russwurm
Michael
M
Friebe
Andreas
A
Koesling
Doris
D
D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors* / Q000235:genetics; D002460:Cell Line; D006152:Cyclic GMP / Q000502:physiology; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D004789:Enzyme Activation / Q000187:drug effects*; D006162:Guanylate Cyclase; D006801:Humans; D007191:Indazoles / Q000494:pharmacology*; D007668:Kidney; D009569:Nitric Oxide / Q000502:physiology*; D020030:Nitric Oxide Donors / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D000644:Quaternary Ammonium Compounds / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000037:antagonists & inhibitors; D026422:S-Nitrosoglutathione / Q000494:pharmacology; D000071756:Soluble Guanylyl Cyclase; D014162:Transfection; D014664:Vasodilation / Q000502:physiology
C423582:3-(4-Amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo(3,4-b)pyridine; D007191:Indazoles; D020030:Nitric Oxide Donors; D010726:Phosphodiesterase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D000644:Quaternary Ammonium Compounds; D018160:Receptors, Cytoplasmic and Nuclear; D011993:Recombinant Fusion Proteins; C406802:diethylammonium-1-(N,N-diethylamino)diazen-1-ium-1,2-diolate; C090937:3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole; D009569:Nitric Oxide; D026422:S-Nitrosoglutathione; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517381:PDE5A protein, human; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP