In fact, myocardial iNOS activity has been reported in response to endotoxin and cytokines and inversely correlated with myocardial performance. Low-to-moderate doses of iNOS inhibitors restore myocardial contractility in hearts exposed to proinflammatory cytokines, whereas at higher doses, the effects are reversed. This finding may indicate that small amounts of NO produced by iNOS may be necessary to maintain contractility and can be cardio-protective in experimental sepsis.

## Nitric oxide in Septic Shock

A list of effects of NO in sepsis is as follows.

- (1) Inhibition of nitric oxide synthesis causes myocardial ischemia in endotoxemic rats
- (2) Nitric oxide causes dysfunction of coronary autoregulation in endotoxemic rats
- (3) Prolonged inhibition of nitric oxide synthesis in severe septic shock
- (4) Effect of L-NAME, an inhibitor of nitric oxide synthesis, on cardiopulmonary function in human septic shock
- (5) Pulmonary hypertension and reduced cardiac output during inhibition of nitric oxide synthesis
- in human septic shock
- (6) Effect of L-NAME, an inhibitor of nitric oxide synthesis, on plasma levels of IL-6, IL-8, TNF-u and nitrite/nitrate in human septic shock
- (7) Endothelin-1 and blood pressure after inhibition of nitric oxide synthesis in human septic shock
- (8) Distribution and metabolism of NO-nitro-L-arginine methyl ester in patients with septic shock

The possible involvement of the L-arginine-NO pathway in both the vascular and cellular processes seen in sepsis has been supported by numerous in vitro and in vivo studies. iNOS appears to be expressed in a wide array of cell types during sepsis, including immune cells (such as macrophages, neutrophils, T lymphocytes), as well as cells outside the classical immune system (for example, hepatocytes, Kuppfer cells, vascular smooth muscle cells, endothelial cells, and fibroblasts). Expression of iNOS is regulated, both positively and negatively, by a number of mediators present during infection and inflammation. The main stimuli for iNOS induction indude lipopolysaccharide (LPS), interferon-y, interleukin (IL)-10, and tumor necrosis factor (TNF)-a; inhibitory cytokines, such as transforming growth factor-5, IL-4 and IL-10, as well as glucocorticoids, can prevent this induction. The expression of iNOS in response to these agents differs among cell types, but a maximal inducing effect is generally obtained by the combination of microbial products and cytokines acting synergistically. iNOS activity is also regulated by substrate and cofactor availability. Tetrahydrobiopterin (BH4), an essential cofactor for the enzyme, is coinduced with iNOS in cytokine-stimulated vascular smooth muscle cells. NO is a simple molecule, but its widespread production in sepsis, coupled with its effects on a variety of intracellular and extracellular target molecules, results in a complex array of biologic roles. Interaction of NO with the metalloproteins in a number of key enzymes can modulate their activity. Many of the signaling actions of 'NO are mediated by soluble guanylate cyclase. By binding the iron on the heme component of soluble guanylate cyclase, NO is able to activate the enzyme leading to cyclic guanosine monophosphate (cGMP) formation. Increased cGMP levels account for several of the important cellular