Abstract 17467: Gemfibrozil is an Allosteric Regulator of Soluble Guanylyl Cyclase Activity and Function
Introduction: In addition to nitric oxide (NO) the NO receptor soluble guanylyl cyclase (sGC) is also activated by a number of synthetic NO-independent regulators. These regulators include heme-replacing activators (BAY58-2667 and HMR1766) and heme-dependent stimulators (BAY41-2272 and YC-1), which only moderately activate sGC, but sensitize it to low NO and to CO gas. Structural diversity of sGC regulators, allowed us to hypothesize that other compounds, including pharmaceuticals, may also regulate sGC activity and function.
Results: In search of new allosteric regulators, we screened a library of “off-patent” drugs and identified gemfibrozil (dimethylphenoxy-dimethylpentanoic acid), an anti-hyperlipidemic drug, as a novel NO-independent sGC activator. Using purified sGC we characterized the mechanism of gemfibrozil's action. We found that gemfibrozil increases the Vmax of sGC >10 fold, but does not change its GTP-Km. Unlike heme-replacing activators, gemfibrozil effect is not influenced by sGC heme oxidation. In contrast to sGC stimulators, gemfibrozil does not change the EC50 for NO and enhances sGC activation by CO only additively, not synergistically. Finally, gemfibrozil's effect is additively enhanced by BAY41-2272, suggesting non-overlapping sites of action for these molecules. In agreement with enzymatic studies, gemfibrozil relaxed preconstricted rat aortic rings and was additively enhanced by BAY41−2272. Consistent with direct sGC activation, endothelium denudation did not affect gemfibrozil's vasorelaxing properties. Evaluating the effect of gemfibrozil on the activity of truncated catalytically active sGC, we determined that sGC regulatory domain is essential for gemfibrozil's mode of action. We also performed structure-activity studies based on several structurally related fibrate drugs and molecules with phenoxy or dimethylpentanoic acid groups. We identified gemfibrozil's moieties strictly necessary for sGC activation and moieties receptive to modifications.
Conclusion: These data indicate that gemfibrozil represents a new class of sGC activators with a unique mode of action. It also indicates that besides anti-lipidemic function gemfibrozil and its derivative may also have vasorelaxing functions.
- © 2010 by American Heart Association, Inc.