Unsaturated fatty acids identified as reversible soluble guanylyl cyclase inhibitors

As key enzyme in the NO/cGMP pathway, soluble guanylyl cyclase (sGC) has become an important therapeutic target in the treatment of cardiovascular diseases. In addition to activating compounds, inhibitors of sGC are necessary tools in research and may even be desirable as therapeutic agents in certain situations, like migraine. In a previous study we observed reversible inhibition of isolated sGC by aqueous extracts from tobacco cigarette smoke. In the current study, we found that extracts prepared from cured tobacco share these properties. The active compounds were isolated and identified as unsaturated fatty acids. Further characterization of the inhibitory effect indicated a potential interaction with the heme binding site. In addition, initial experiments with vascular endothelial cells suggest that the observed effect may be relevant to blood vessels function in vivo.