Of the 3 major members of the nitric oxide synthase family, inducible nitric oxide synthase (iNOS) is the most highly conserved, and is capable of high levels of expression and proficient conversion of large quantities of nitric oxide from L-arginine following cytokine stimulation. There is little or no iNOS in the normal cardiac myocyte, but there is both exuberant expression and protein translation following cytokine stimulation. This expression appears to be sustained in conditions such as heart failure.
Acute release of NO by iNOS in the heart can decrease cardiac contractility and induce adaptive protection by increasing cGMP, decreasing cAMP and modulating both β adrenergic and muscarinic systems. However, large quantities of NO in an oxidative environment can lead to production of peroxynitrite and other nitrosylated free radicals. These have direct cytostatic and cytotoxic effects, and account for the functional duality of NO.
Increased iNOS expression and protein can be found in diverse cardiac conditions beside sepsis. In acute myocardial infarction, iNOS is found in the infarct region, especially in infiltrating macrophages. In myocarditis, the acute induction of iNOS appears to be critical in host protection against the pathogen, but chronic induction leads to cardiomyopathy. Similarly in dilated and ischemic cardiomyopathies, iNOS induction is found in most patients, and may contribute to the decrease in contractility and progression of disease. Finally, in cardiac transplant rejection, there is both acute and chronic iNOS induction, contributing to graft dysfunction and necrosis.
Thus iNOS induction is a universal defense mechanism against tissue injury. Acute adaptation through NO release is important to sustain survival, but chronic induction is pathogenic. The manipulation of NO and iNOS to be a friend rather than foe will continue be our therapeutic challenge in cardiovascular disease.