The physiological chemistry and biological activity of nitroxyl (HNO): The neglected, misunderstood, and enigmatic nitrogen oxide

It is clear that HNO possesses unique and a potentially important biological activity that is distinct from NO (and other nitrogen oxides). The "orthogonal" signaling relationship between HNO (acting via cAMP pathways) and NO (acting via cGMP pathways) provides an intriguing scenario in which these two species may be utilized physiologically to control various aspects of, for example, cardiovascular function by independent pathways (55). The idea that HNO and NO are naturally occurring signaling partners with distinct mechanisms of action is, in part, dependent on the demonstration of endogenous and regulated HNO generation. Because endogenous production of HNO has yet to be demonstrated, the idea that HNO and NO represent a normal, coordinated, and/ or integrated signaling system is purely speculative at this point. Regardless, the pharmacological potential of HNO is clear and warrants continued investigation of its biology and chemistry. As with NO, the biological utility of HNO lies in its chemistry and, from a purely chemical perspective, HNO is a fascinating molecule with fundamentally unique properties. The biology of HNO is equally fascinating, and it is intriguing to think that it may be an important signaling agent in mammalian systems. At the very least, it possesses important pharmacological properties that may have significant therapeutic applications. However, our current understanding of HNO biochemistry is, at best, scant and inadequate. There is little doubt that thiol proteins can be major targets for HNO, but there are assuredly other potential sites of action as well. Moreover, there remains the question of whether HNO is capable of exhibiting a specific reactivity with select thiol proteins, as opposed to being a nonspecific thiol modifying agent. This question along with delineation of other biochemical mechanisms of HNO biology will undoubtedly occupy many labs for years to come. Furthermore, other profound biological actions of HNO will undoubtedly be discovered as more researchers become interested in this previously unheralded species. We are only in the early stages of understanding both the biology and the biological chemistry of HNO, and there is little doubt that other major discoveries await.