Editorial [Hot Topic: Nitric Oxide (Guest Editor: Greg Thatcher)]

Despite the fact that certain nitrogen oxide species (e.g. nitroglycerin) have been used to treat vascular ailments such as angina for over 100 years, the discovery of endogenous generation of nitric oxide (NO) and its role in the regulation of vascular function took many by surprise since it represented a unique and novel signaling paradigm in mammalian biology. Since this discovery, there has been a virtual explosion of research activity on the physiology, pathophysiology, biochemistry, chemistry and pharmacology of NO and related nitrogen oxides. The therapeutic potential associated with pharmacological manipulation of NO (and related/derived nitrogen oxides) has advanced beyond the mere treatment of angina. It is becoming increasingly clear that an unbalance in nitrogen oxide homeostasis is involved in a variety of illnesses and disorders. Nitrogen oxide related therapies, involving either increases or decreases in nitrogen oxides, can be envisioned (or are currently in use) for the treatment of a variety of vascular disorders including pulmonary hypertension, atherosclerosis, male erectile dysfunction, smooth muscle cell restenosis and shock as well as for the prevention and/or treatment of ischemia reperfusion injury, neurodegenerative disease, heart failure, and cancer, among many others. This list will most assuredly grow as the intense research on the physiology and pathophysiology of NO, and related nitrogen oxides, continues. Like many biological signaling/effector species, NO has numerous and diverse activities ranging from its role as an important vascular agent to its function as a neurotransmitter and immune response agent. Although the important biological actions of nitrogen oxides makes their manipulation an important therapeutic strategy for a number of illnesses, the diversity of activity also presents some difficulties with respect to pharmacological/physiological specificity. Thus, the development and characterization of specific inhibitors or activators of the various isoforms of the nitric oxide synthases, as well as the generation of NO-donors with varied pharmacokinetic and/or distribution profiles are vitally important to the future of NO-based therapies. A single class or family of NO-donor or NOS regulator agents is insufficient in addressing all the possibilities associated with NO-related therapy. Moreover, it is now established that redox congeners of the nitrogen oxides may have distinct biological actions. One of the best examples of this is the difference between the activities of NO and HNO, which are related to each other by a single electron but have, for the most part, "orthogonal" biological properties. Indeed, the therapeutic potential for NO and HNO is quite distinct. Thus, the development of a variety of donors of specific nitrogen oxides (e.g. NO versus HNO) is also vital to the further growth of this field. This issue of "Current Topics in Medicinal Chemistry" is focused on work regarding the development and utility of nitrogen oxide-based therapies. This issue serves to, among other things, illustrate the diversity of strategies for the manipulation of biological nitrogen oxides as well as bring to light the importance of doing so. Clearly, the realization of the tremendous potential of nitrogen oxide-based therapy requires the development of diverse chemistry as illustrated herein. Finally, a further demand for expanding the "chemical repertoire" for manipulating nitrogen oxide biology will come as discoveries of new roles for nitrogen oxides in biology are made.