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

Abstract

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 μmol/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 μmol/L BAY 41-2272 stimulates the highly purified recombinant sGC, and maximal stimulation is achieved by 1 μmol/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 μmol/L and 0.17 μmol/L,3 respectively. Even in tissues, IC50s for BAY 41-2272 have been reported by Cellek’s group several times that are 6- to 20-fold lower than the 3-μmol/L range observed by Mullershausen1; these include anococcygenus muscle from control and diabetic rats, …