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Differential synergy with nitric oxide across a panel of soluble guanylate cyclase stimulators
Author(s) -
Long Kimberly,
Tang Kim,
Sarno Renee,
Solinga Rob,
Masferrer Jaime
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.627.4
Subject(s) - nitric oxide , chemistry , enzyme , guanylate cyclase , in vitro , gucy1a3 , endogeny , receptor , biochemistry , pharmacology , nitric oxide synthase , gucy1b3 , biology , guanylate cyclase 2c , organic chemistry
Soluble guanylate cyclase (sGC) is the endogenous receptor for nitric oxide (NO). Upon binding of NO, sGC catalyzes the synthesis of cGMP which is involved in numerous downstream processes, including vasorelaxation, fibrosis, and inflammation. Dysregulation of this pathway has been implicated in multiple pathologies. sGC stimulators are a class of molecules which are capable of increasing the activity of the enzyme. While these stimulators are capable of activating the enzyme in the absence of NO, their effect is greatly amplified in the presence of NO. However, it is unclear if all stimulators synergize with NO equally. To examine differences in NO synergy across stimulators, we assessed a panel of compounds for their ability to stimulate cGMP synthesis with or without NO in a human whole cell assay. All compounds selected for this analysis were potent in vitro under high NO conditions (with EC 50 values ranging from 10 to 200nM) and were effective at lowering blood pressure in rodents at doses between 1 and 10 mg/kg. We found that all compounds tested had similar EC 50 values (~5µM) when examined in the absence of NO. However, in the presence of high NO the compounds exhibited a wide range of potency shifts relative to the NO‐free state (16‐320 fold). E max values for the compounds were also differentially affected by NO, with some compounds reaching the same E max regardless of the presence of NO, and others exhibiting a 4‐6 fold increase in E max upon addition of NO. These data suggest that synergy between NO and sGC stimulators is complex and varies considerably between compounds. We hypothesize that differences between compounds in NO synergy may be harnessed to maximize their therapeutic value in a variety of disease states and patient populations.