First 11 pages of thesis. - OPUS - Universität Würzburg

substrate and co-factor concentration nNOS generates superoxide 119 . In
addition to superoxide nNOS is capable of generating of hydrogen peroxide
(H2O2) in the absence of substrate, using molecular oxygen as the terminal
electron acceptor 120 . In this reaction, BH4 plays a critical role in regulating the
generation of superoxide and hydrogen peroxide 121 . In terms of enzymatic
activity during uncoupling, nNOS differs from other NOS isoforms in its
readiness to catalyze the uncoupled reaction i.e., nNOS oxidizes NADPH at a
higher rate than the other NOS isoforms 122 . Supporting this concept, in the
absence of substrate, nNOS produces higher amounts of superoxide than
iNOS 123 .
1.4.2.3 Inducible nitric oxide synthase (iNOS)
Unlike eNOS and nNOS which are constitutively expressed, iNOS is
expressed only when induced by external stimuli. Nitric oxide generated by
iNOS mediates the cytotoxic actions of activated macrophages and neutrophils
and plays an important role in the non specific immune response of the
pathogenic defense mechanism. iNOS is expressed in many nucleated cells of
the cardiovascular system namely vascular smooth muscle cells, endothelial
cells, cardiac myocytes, inflammatory cells found in sub endothelial space such
as leukocytes, fibroblasts and mast cells during various diseased conditions. In
contrast to eNOS and nNOS which are regulated by intracellular calcium levels,
iNOS contains irreversibly bound calmodulin and hence is independent of
intracellular calcium levels. Thus, induction of iNOS results in generation of
tremendous levels of nitric oxide 124 .
- 25 -