Mullershausen Florian, Russwurm Michael, Friebe Andreas, Koesling Doris
Insititut für Pharmakologie und Toxikologie, Ruhr-Universität Bochum, Bochum, Germany.
Circulation. 2004 Apr 13;109(14):1711-3. doi: 10.1161/01.CIR.0000126286.47618.BD. Epub 2004 Apr 5.
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.
通过环磷酸鸟苷（cGMP）的形成，一氧化氮（NO）敏感的鸟苷酸环化酶（GC）作为信号分子NO的效应器，介导血管平滑肌舒张和血小板聚集抑制。化合物YC-1和BAY 41-2272被视为NO敏感GC的非NO依赖性激活剂和敏化剂。例如，其体内效应包括降低血压和延长尾部出血时间，使这些化合物成为心血管疾病治疗的有前景的候选药物。然而，YC-1也已被证明可抑制主要的cGMP降解酶5型磷酸二酯酶（PDE5）。YC-1对cGMP形成和降解的协同特性导致细胞中NO诱导的cGMP过度积累，解释了观察到的生理效应。我们评估了新型GC激活剂BAY 41-2272对PDE5的潜在抑制作用。
在体外测试了BAY 41-2272对NO敏感GC和PDE5活性的影响。BAY 41-2272不仅使NO敏感GC对NO激活更敏感，而且以相当的效力抑制PDE5介导的cGMP降解。在完整血小板中，BAY 41-2272通过对cGMP形成和降解的协同作用极大地增强了NO诱导的cGMP反应。
BAY 41-2272的生理效应通常归因于对NO敏感GC的非NO依赖性激活，而实际上是由于NO敏感GC的敏化和PDE5抑制的协同作用。
