First 11 pages of thesis. - OPUS - Universität Würzburg

state of decreased nitric oxide bioavailability. In contrast, our data shows that
iNOS increases total nitric oxide production of the vessel wall in the apoE ko
model. Since iNOS activity is not regulated by calcium influx, the iNOS
mediated nitric oxide production does not locally mediate endothelium derived
vasorelaxation. Instead, the iNOS mediated increased nitric oxide production
observed during bacterial sepsis can result in life threatening hypotension due
to systemic vasorelaxation 204 . Our study is consistent with the previously
published report by Minor et al., who showed increased nitrogen oxides in the
aorta of atherosclerotic rabbits 205 . This study employed an indirect method for
nitric oxide detection and didn’t specify the source of nitric oxide production.
Thus, the induction of iNOS expression in atherosclerosis results in increased
vascular nitric oxide production, compared to wild type mice.
Increased superoxide production can decrease nitric oxide bioavailability
and result in proatherogenic oxidative stress. Aside from other enzymatic
sources of superoxide, iNOS itself may contribute directly to superoxide
production. Therefore, we evaluated superoxide production in apoE ko and
apoE/iNOS dko mice. Employing two independent direct methods, we found a
significant decrease in vascular wall superoxide production in apoE/iNOS dko,
compared to apoE ko. In addition, total vascular reactive oxygen species (ROS)
production, assessed by measuring the conversion of CMH to nitroxide CM .
was significantly reduced in apoE/iNOS dko, compared to apoE ko animals
(data not shown). Since decreased oxidative stress in chronically iNOS deficient
mice could also result from secondary changes, i.e. iNOS mediated regulation
of gene expression; we tested whether acute pharmacological iNOS inhibition
reduces vascular superoxide production. And indeed, pretreatment of the
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