Natural compounds from cured tobacco are reversible inhibitors of soluble guanylyl cyclase

As a key enzyme in the NO/cGMP signaling pathway, soluble guanylyl cyclase (sGC) has become an important target in the therapy of cardiovascular diseases. In addition to activating compounds, inhibitors of sGC are important tools in research and may even be useful as therapeutic agents under certain conditions.In a previous study, we investigated the effects of aqueous extracts from tobacco cigarette smoke on vessel function in vitro. Thereby, we found inhibitory properties of these extracts on purified bovine lung sGC. In addition, this inhibition was fully reversible by mere dilution.In the current study we found that extracts directly obtained from cured tobacco share these properties. To a certain extend it was possible to enrich the inhibitory ingredient(s). This was achieved by extracting tobacco from cigarettes with ethanol and further fractionation by liquid-liquid extraction and preparative thin layer chromatography. The obtained fractions were then tested in activity assays using isolated bovine lung sGC. Our data show that an enrichment could clearly be achieved, but the most active fraction still comprises several individual constituents. Thus, we could demonstrate that cured tobacco contains a compound (mixture), that reversibly inhibits sGC. Work is currently underway to further purify and identify this (these) inhibitor(s).