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. METHODS AND 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.
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. METHODS AND 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.
Authors: Oleg V Evgenov; Pál Pacher; Peter M Schmidt; György Haskó; Harald H H W Schmidt; Johannes-Peter Stasch Journal: Nat Rev Drug Discov Date: 2006-09 Impact factor: 84.694