Nitric oxide donor drugs: an update on pathophysiology and therapeutic potential

The discovery of the multiple physiological and pathophysiological processes in which nitric oxide (NO) is involved has promoted a great number of pharmacological researches to develop new drugs that are capable of influencing NO production directly and/or indirectly for therapeutic purposes (i.e, NO-releasing drugs, NO-inhibiting drugs, and phosphodiesterase V inhibitors). In particular, the so-called NO donor drugs could actually have an important therapeutic effect in the treatment of many diseases such as arteriopathies (atherosclerosis and its sequelae, arterial hypertension and some forms of male sexual impotence), various acute and chronic inflammatory conditions (colitis, rheumatoid arthritis and tissue remodelling), and several degenerative diseases (Alzheimer's disease and cancer). The old organic nitrates show some well-known pitfalls including the induction of tolerance and acute side effects related to abrupt vasodilation such as cephalea and hypotension, which limit their therapeutic indications. A low therapeutic index (i.e., peroxynitrite toxicity) has always characterised the sydnonimines class. A series of interesting new classes of NO donors are under intense pharmacological investigation and scrutiny (S-nitrosothiols, diazeniumdiolates and NO hybrid drugs), each characterised by a particular pharmacokinetic and pharmacodynamic profile. The most important obstacle in the field of NO donor drugs is represented by the difficulty in targeting NO release, and thereby its effects, to a particular tissue.