Effects of the sGC Stimulator BAY 41-2272 Are Not Mediated by Phosphodiesterase 5 Inhibition * Response

E. Bischoff
2004 Circulation  
A major conclusion of the recent publication of Mullershausen et al 1 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
more » ... 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 EC 50 of 0.09 mol/L and 0.17 mol/L, 3 respectively. Even in tissues, IC 50 s for BAY 41-2272 have been reported by Cellek's group several times that are 6-to 20-fold lower than the 3-mol/L range observed by Mullershausen 1 ; 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/L 2 (confirmed at MDS Pharma Services), whereas the PDE5 inhibitors sildenafil and our vardenafil show IC 50 values of 0.007 and 0.0007 mol/L, respectively. Moreover, BAY 41-2272 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 Mullershausen 1 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, Mullershausen 1 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 IC 50 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
doi:10.1161/01.cir.0000142209.28862.12 pmid:15381669 fatcat:fzgbw7rdsfajtpjgtsnefua2cq