FIGURE 19–2 Regulation of vasorelaxation by endothelial-derived nitric oxide (NO). Endogenous vasodilators, eg, acetylcholine and bradykinin, cause calcium (Ca2+) efflux from the endoplasmic reticulum in the luminal endothelial cells into the cytoplasm. Calcium binds to calmodulin (CaM), which activates endothelial NO synthase (eNOS), resulting in NO synthesis from L-arginine. NO diffuses into smooth muscle cells, where it activates soluble guanylyl cyclase and cyclic guanosine monophosphate (cGMP) synthesis from guanosine triphosphate (GTP). cGMP binds and activates protein kinase G (PKG), resulting in an overall reduction in calcium influx, and inhibition of calcium-dependent muscle contraction. PKG can also block other pathways that lead to muscle contraction. cGMP signaling is terminated by phosphodiesterases, which convert cGMP to GMP.
atheromatous plaques. This effect is due to the inhibitory effect of NO on the expression of adhesion molecules on the endothelial cell surface. The antiatherogenic effect of NO may also involve an antioxidant effect, blocking the oxidation of low-density lipoproteins and thus preventing or reducing the formation of foam cells in the vascular wall. Plaque formation is also reduced by NO-dependent reduction of endothelial cell permeability to lipoproteins. The importance of eNOS in cardiovascular disease is supported by experiments showing increased atherosclerosis in animals treated with eNOS inhibitors. Atherosclerosis risk factors, such as smoking, hyperlipidemia, diabetes, and hypertension, are associated with decreased endothelial NO production, and thus with a loss of the diverse antiatherogenic effects of NO.
Sepsis is a systemic inflammatory response caused by infection. Endotoxin components from the bacterial wall along with endogenously generated tumor necrosis factor-α and other cytokines induce synthesis of iNOS in macrophages, neutrophils, and T cells, as well as hepatocytes, smooth muscle cells, endothelial cells, and fibroblasts. This widespread generation of NO results in exaggerated hypotension, shock, and, in some cases, death. This hypotension is reduced or reversed by NOS inhibitors in humans as well as in animal models (Table 19–3). A similar reversal of hypotension is produced by compounds that prevent the action of NO, such as the sGC inhibitor methylene blue. Furthermore, knockout mice lacking a functional iNOS gene are more resistant to endotoxin than wild-type mice. However, despite the ability of NOS inhibitors to ameliorate hypotension in sepsis, there is no overall improvement in survival in patients with gram-negative sepsis treated with NOS inhibitors. The absence of benefit may reflect the inability of
TABLE 19–3 Some inhibitors of nitric oxide synthesis or action.
BBS-2, a pyrimide imidazole; NOS, nitric oxide synthase.
the NOS inhibitors used in these trials to differentiate between NOS isoforms, or may reflect concurrent inhibition of beneficial aspects of iNOS signaling.