Effects of the sGC stimulator BAY 41-2272 are not mediated by phosphodiesterase 5 inhibition.

Not Mediated by Phosphodiesterase 5 Inhibition To the Editor: A major conclusion of the recent publication of Mullershausen et al1 is that “the physiological effects of BAY 41-2272 . . . are due to the synergism of sensitization of NO-sensitive GC [guanylate cyclase] and inhibition of PDE5.” This conclusion is based on the authors’ finding that BAY 41-2272 stimulates sGC and inhibits human PDE5A1 at the same half-maximal concentration of 3 mol/L. These observations are inconsistent with our own observations as well as results generated by others. We have hypothesized that the only significant activity of BAY 41-2272 is the NO-independent activation of NO-sensitive GC. In our laboratory, as little as 0.001 mol/L BAY 41-2272 stimulates the highly purified recombinant sGC, and maximal stimulation is achieved by 1 mol/L.2 Moreover, BAY 41-2272 activates sGC in a stably sGC-overexpressing CHO cell line and in a cGMP reporter cell line with EC50 of 0.09 mol/L and 0.17 mol/L,3 respectively. Even in tissues, IC50s for BAY 41-2272 have been reported by Cellek’s group several times that are 6to 20-fold lower than the 3mol/L range observed by Mullershausen1; these include anococcygenus muscle from control and diabetic rats, rabbit vaginal wall and clitoris corpus cavernosum, human and rabbit penile corpus cavernosum, and rabbit aortas.2,4 On the other hand, we find that BAY 41-2272 fails to significantly inhibit highly purified recombinant human PDE5 expressed in a baculovirus system at concentrations up to 10 mol/L2 (confirmed at MDS Pharma Services), whereas the PDE5 inhibitors sildenafil and our vardenafil show IC50 values of 0.007 and 0.0007 mol/L, respectively. Moreover, BAY 412272 also does not inhibit other cGMP-specific/metabolizing PDEs, such as PDE-1, -2 and -9. Taking all these points into account, we believe that Mullershausen1 overestimated the potency of BAY 41-2272 on PDE5 and underestimated its potency on sGC. In an effort to validate their hypothesis in a cellular system, Mullershausen1 next demonstrated that BAY 41-2272 at 100 mol/L elevates platelet cGMP in the presence of an NO donor and that a mixture of sildenafil and EHNA (which inhibits both PDE2 and PDE5) also elevates cGMP under these conditions. Because these results would be anticipated without ascribing PDE5-inhibitory activity to BAY 41-2272, they do not test its hypothetical synergistic mechanism. Furthermore, it is unclear to us why BAY 41-2272 was used at 100 mol/L when we have demonstrated its antiaggregatory effect with an IC50 of 0.04 mol/L,2 and Hobbs and Moncada have shown its antiplatelet effect with concentrations between 0.01 mol/L and 0.3 mol/L.5