ABSTRACT
Expression of the inducible form of nitric oxide synthase (iNOS) has been reported in a variety of cardiovascular diseases. The resulting high output nitric oxide (NO) formation, besides the level of iNOS expression, depends also on the expression of the metabolic pathways providing the enzyme with substrate and cofactor. NO may trigger short and long term effects which are either beneficial or deleterious, depending on the molecular targets with which it interacts. These interactions are governed by local factors (like the redox state). In the cardiovascular system, the major targets involve not only guanylyl cyclase, but also other haem proteins, protein thiols, iron-non-haem complexes, and superoxide anion (forming peroxynitrite). The latter has several intracellular targets and may be cytotoxic, despite the existence of endogenous defence mechanisms. These interactions may either trigger NO effects or represent releasable NO stores, able to buffer NO and prolong its effects in blood vessels and in the heart. Besides selectively inhibiting iNOS, a number of other therapeutic strategies are conceivable to alleviate deleterious effects of excessive NO formation, including peroxynitrite (ONOO-) scavenging and inhibition of metabolic pathways triggered by ONOO-. When available, these approaches might have the advantage to preserve beneficial effects of iNOS induction. Counteracting vascular hyper-responsiveness to endogenous vasoconstrictor agonists in septic shock, or inducing cardiac protection against ischaemia-reperfusion injury are examples of such beneficial effects of iNOS induction.
