Obesity is a risk factor for cardiovascular disease and is associated with increased plasma levels of the adipose-derived hormone leptin. Vascular smooth muscle cells (VSMC) express leptin receptors (LepR); however, their physiological role is unclear. We hypothesized that leptin, at levels to mimic morbid obesity, impairs vascular relaxation. To test this, we used control and VSM-LepR knockout mice (VSM-LepR KO) created with a tamoxifen-inducible specific Cre recombinase to delete the LepR gene in VSMC. Control (10-12 wk old) and VSM-LepR KO (10-12 wk old) mice were fed a diet containing tamoxifen (50 mg/kg) for 6 wk, after which vascular reactivity was studied in isolated carotid arteries using an organ chamber bath. Vessels were incubated with leptin (100 ng/ml) or vehicle (0.1 mM Tris·HCl) for 30 min. Leptin treatment resulted in significant impairment of vessel relaxation to the endothelial-specific agonist acetylcholine (ACh). When these experiments were repeated in the presence of the superoxide scavenger tempol, relaxation responses to ACh were restored. VSM-LepR deletion resulted in a significant attenuation of leptin-mediated impaired ACh-induced relaxation. These data show that leptin directly impairs vascular relaxation via a VSM-LepR-mediated mechanism, suggesting a potential pathogenic role for leptin to increase cardiovascular risk during obesity.
In order to minimize
unintentional detonation, munitions researchers
have focused on the development of chemical compounds that are insensitive
to external stimuli while maintaining their effectiveness. Although
these compounds, known as high-performance insensitive munition compounds,
are promising in terms of potency and stability, their environmental
impacts have either not been fully understood or are yet to be investigated.
In the present research, we have performed a quantum chemical investigation
on electronic structures and properties of an insensitive munition
compound 4,6-bis(nitroimino)-1,3,5-triazinan-2-one (DNAM). The density
functional theory using the B3LYP and M06-2X functionals and MP2 methodology
were used for geometry optimization of various tautomeric forms of
DNAM. The effect of bulk water solution was evaluated using the conductor-like
polarizable continuum model and the density-based solvation model.
Ionization potentials, electron affinities, redox properties, and
pK
a values were also computed and compared
with the available experimental data. These physical and chemical
properties of DNAM have been discussed with regard to the varying
tautomeric forms in which DNAM can exist.
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