Gemfibrozil is a potential allosteric regulator of soluble guanylyl cyclase activity and function

In addition to nitric oxide, soluble guanylyl cyclase (sGC) is also activated through several allosteric mechanisms by a number of structurally diverse molecules. Considering the vast structural diversity of existing small molecule drugs we hypothesized that some of them may affect sGC activity and function. We screened a library of “off‐patent” drugs and identified gemfibrozil, an anti‐hyperlipidemic fibrate, as NO‐independent sGC activator. Other tested fibrates did not activate sGC. Structure‐activity studies identified moieties of gemfibrozil strictly necessary for sGC activation and those which can be subjected to further chemical modifications. We found that unlike known sGC activators, gemfibrozil activation is not affected by changes in the redox state of sGC heme. In contrast to sGC stimulators, gemfibrozil does not affect the EC50 for NO. Truncation mutagenesis revealed that sGC regulatory regions are required for activation by gemfibrozil. Gemfibrozil had a vasorelaxing effect on rat aortic rings, including endothelium denuded, and was additively enhanced by BAY41‐2272. These data suggest that gemfibrozil is a new class of sGC activators with a unique mode of action. These data also indicate that in addition to anti‐lipidemic properties gemfibrozil and some of its analogues may also affect vascular plasticity. Supported by NIH (R01HL088128 and R01HL088128‐S1) and AHA (09GRNT2060182).