Vascular effects of LPS in mice deficient in expression of the gene for inducible nitric oxide synthase

Abstract

The inducible isoform of nitric oxide synthase (iNOS) is expressed after systemic administration of lipopolysaccharide (LPS). The importance of expression of iNOS in blood vessels is poorly defined. Because nitric oxide from iNOS may alter vasomotor function, we examined effects of LPS on vasomotor function in carotid arteries from iNOS-deficient mice. We studied contraction of the carotid artery from wild-type and iNOS-deficient mice in vitro 12 h after injection of LPS (20 mg/kg ip). Contractile responses to PGF2α (3–30 μM) and thromboxane A2 analog (U-46619; 3–100 nM) were evaluated using vascular rings from mice treated with vehicle or LPS. Maximum force of contraction generated by rings in response to PGF2α was 0.39 ± 0.02 and 0.25 ± 0.01 (SE) g ( n = 14) in vehicle and LPS-treated wild-type mice, respectively ( P < 0.001 vs. vehicle). Thus LPS reduced constrictor responses in wild-type mice. Thiocitrulline and aminoguanidine (inhibitors of iNOS) improved contractile responses from LPS-treated wild-type vessels. Indomethacin also improved constrictor responses in arteries from wild-type mice injected with LPS. In contrast, contraction of the carotid arteries in response to PGF2α and U-46619 was not impaired in LPS-treated iNOS-deficient mice, and contraction was not altered by inhibitors of iNOS. Expression of iNOS mRNA was confirmed using RT-PCR in carotid arteries from wild-type mice after injection of LPS but not vehicle. PCR products for iNOS were not observed in iNOS-deficient mice. These findings provide the first direct evidence that iNOS mediates impairment of vascular contraction after treatment with LPS.

Gene transfer of extracellular superoxide dismutase improves relaxation of aorta after treatment with endotoxin

“…The finding that ECSOD did not improve impaired constrictor responses to phenylephrine suggests that extracellular superoxide may not be functionally important in impairment. LPS induces inducible nitric oxide (NO) synthase (iNOS) in arteries, and iNOS mediates impaired constrictor responses produced by LPS (3,14,27). A likely mechanism by which iNOS impairs vasoconstrictor responses is by a direct effect of high levels of NO.…”

Interleukin-10 Protects Nitric Oxide–Dependent Relaxation During Diabetes

“…Based on preliminary data, we intentionally chose a duration of diabetes that had modest effects on vascular function in wild-type mice because we anticipated that dysfunction would be augmented in IL-10 Ϫ/Ϫ mice. Vasomotor function of carotid arteries was evaluated in vitro by measurement of isometric tension as described previously (4,23,24). Briefly, carotid arteries from mice were removed and immediately placed in oxygenated Krebs buffer.…”

“…Interleukin (IL)-10 attenuates expression and/or production of proinflammatory cytokines (3). IL-10 preserves vascular function, including endothelium-dependent relaxation, during acute inflammation produced by endotoxin (4,5). We hypothesized that IL-10 is also important for preservation of endothelium-dependent relaxation during diabetes.…”

Nitric oxide monocyte production levels in patients with the hepatosplenic form of Scistosoma mansoni infection who underwent splenectomy, ligature of the left gastric vein and auto implantation of spleen tissue in the major omentum

“…The pathogenic role of NO in overwhelming infection and septic shock can, in fact, 20 . Mice lacking iNOS have been reported to be resistant to endotoxin-induced mortality 21 and vascular hypocontractility 22 , supporting a key role for iNOS in endotoxin shock. In addition to endotoxin, cell wall components and enterotoxin from gram-positive organisms are also able to stimulate NO release 20 .…”