Impairment of dilator responses of cerebral arterioles during diabetes mellitus: role of inducible NO synthase.

Background And Purpose: During diabetes, expression of inducible nitric oxide synthase (iNOS) plays an important role in the development of endothelial dysfunction in extracranial blood vessels. Progression of vascular dysfunction after the onset of diabetes differs among vascular beds. In this study, the effects of hyperglycemia/diabetes on vasomotor function were examined in cerebral arterioles at 2 different times in control and iNOS-deficient mice and compared with the effects on carotid arteries.

Vascular interleukin-10 protects against LPS-induced vasomotor dysfunction.

We tested the hypotheses that 1) systemic IL-10, after adenoviral gene transfer, protects arteries from impaired relaxation produced by LPS; 2) local expression of IL-10 within the arterial wall protects against vasomotor dysfunction after LPS; and 3) IL-10 protects against vascular dysfunction mediated by inducible NO synthase (iNOS) after LPS. In IL-10-deficient (IL-10-/-) and wild-type (WT, IL-10+/+) mice, LPS in vivo impaired relaxation of arteries to acetylcholine and gene transfer of IL-10 improved responses to acetylcholine. Superoxide levels were elevated in arteries after LPS, and increased levels of superoxide were prevented by gene transfer of IL-10.

Gene transfer of extracellular superoxide dismutase improves endothelial function in rats with heart failure.

Oxidative stress is associated with endothelial dysfunction in heart failure. The goals of this study were to determine whether 1) gene transfer of extracellular superoxide dismutase (ecSOD) reduces levels of superoxide and improves endothelial function in the aorta and mesenteric artery in rats with heart failure, and 2) the heparin-binding domain (HBD) of ecSOD, by which ecSOD binds to cells, is required for protective effects of ecSOD. Seven weeks after coronary ligation, in rats with heart failure and sham-operated rats, we injected adenoviral vectors intravenously that express ecSOD, ecSOD with deletion of the HBD (ecSODDeltaHBD), or a control vector.

Mechanisms of inducible nitric oxide synthase-mediated vascular dysfunction.

Objective: Inducible nitric oxide synthase (iNOS) is expressed in arteries during inflammation and may contribute to vascular dysfunction. Effects of gene transfer of iNOS to carotid arteries were examined in vitro in the absence of systemic inflammation to allow examination of mechanisms by which iNOS impairs contraction and relaxation.

Methods And Results: After gene transfer of iNOS with an adenovirus (AdiNOS), constrictor responses to phenylephrine (PE) and U46619 were impaired.

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

Lipopolysaccharide (LPS) impairs vascular function, in part by generation of reactive oxygen species. One goal of this study was to determine whether gene transfer of extracellular SOD (ECSOD) improves vascular responsiveness in LPS-treated rats. A second goal was to determine whether effects of ECSOD are dependent on the heparin-binding domain of the enzyme, which facilitates binding of ECSOD to the outside of cells.

Gene-targeted mice reveal a critical role for inducible nitric oxide synthase in vascular dysfunction during diabetes.

Background And Purpose: Inducible nitric oxide synthase (iNOS) is a mediator of vascular dysfunction during inflammation. The purpose of this study was to test the hypothesis that vascular dysfunction during diabetes is dependent on expression of iNOS.

Methods: Diabetes was produced in mice with streptozotocin (150 mg/kg IP).

Evidence for oxidative stress in NSAID-induced colitis in IL10-/- mice.

The goal of this study was to evaluate for evidence of oxidative stress in colonic inflammation in a novel model of inflammatory bowel disease, nonsteroidal anti-inflammatory drug- (NSAID-) treated interleukin-10-deficient (IL10(-/-)) mice. IL10(-/-) and wild-type (wt) mice were treated with a nonselective NSAID (piroxicam, 200 ppm in the diet) for 2 weeks to induce colitis, and parameters for oxidative stress in the colonic tissues were evaluated. Mean chemiluminescence enhanced with lucigenin in the colons from IL10(-/-) mice treated with piroxicam was more than 5-fold higher than that of the control wt group.

Gene transfer of inducible nitric oxide synthase impairs relaxation in human and rabbit cerebral arteries.

Background And Purpose: These studies evaluated whether gene transfer of inducible nitric oxide synthase (iNOS) is a sufficient stimulus to produce vascular dysfunction in cerebral arteries.

Methods: Intracranial (pial) arteries were dissected from human brain tissue obtained during elective surgery. Isolated human arteries were incubated in vitro with adenovirus containing iNOS (AdiNOS) or a nonexpressive transgene (control, AdBglII) (500 micro L, 3x10(9) plaque-forming units per milliliter), and vascular function was examined 24 hours later.

Interleukin-10 protects nitric oxide-dependent relaxation during diabetes: role of superoxide.

Interleukin (IL)-10, an anti-inflammatory cytokine, preserves endothelial function during acute inflammation. We tested the hypotheses that IL-10 plays a protective role in blood vessels during diabetes by suppressing impairment of endothelium-dependent relaxation and that protection by IL-10 is mediated by effects on superoxide (O(2-)). Streptozotocin (150 mg/kg i.

Virally mediated gene transfer to the vasculature.

Gene transfer technology provides valuable tools for the study of vascular biology. By using gene transfer, effects of specific gene products can be evaluated in a highly selective manner. In recent years, techniques used for gene transfer have been adapted for applications to blood vessels, including microvessels, both in vitro and in vivo.

NO-dependent vasorelaxation is impaired after gene transfer of inducible NO-synthase.

Proinflammatory stimuli produce expression of inducible NO-synthase (iNOS) within blood vessels and are associated with impaired endothelium-dependent relaxation. Gene transfer of iNOS was used to test the hypothesis that expression of iNOS in blood vessels produces impairment of NO-dependent relaxation as well as contraction. An adenoviral vector containing cDNA for murine iNOS, AdCMViNOS, and a control virus, AdCMVBglII, were used for gene transfer to rabbit carotid arteries in vitro and in vivo.

The future of gene therapy for stroke.

New diagnostic and treatment strategies are being developed for stroke. Gene therapy has several potential advantages over classical pharmacologic therapy. Direct administration of DNA into the brain offers the advantage of producing high concentrations of therapeutic agents in a relatively localized environment.

Tumor necrosis factor-alpha impairs contraction but not relaxation in carotid arteries from iNOS-deficient mice.

We used mice deficient in expression of inducible NO synthase (iNOS -/-) to directly examine the role of iNOS in impaired vasoconstrictor responses following tumor necrosis factor-alpha (TNF-alpha). In iNOS +/+ mice, contraction of carotid arteries in response to prostaglandin F(2alpha) (PGF(2alpha)) was impaired following TNF-alpha (100 microg/kg ip)(n = 10, P < 0.01).

IL-10 deficiency increases superoxide and endothelial dysfunction during inflammation.

Little is known about the role of interleukin-10 (IL-10), an anti-inflammatory cytokine, in blood vessels. We used IL-10-deficient mice (IL-10 -/-) to examine the hypothesis that IL-10 protects endothelial function after lipopolysaccharide (LPS) treatment. The responses of carotid arteries were studied in vitro 6 h after injection of a relatively low dose of LPS (10 microgram ip).

Vascular effects of lipopolysaccharide are enhanced in interleukin-10-deficient mice.

Background And Purpose: The role in blood vessels of interleukin-10 (IL-10), a potent anti-inflammatory cytokine, is not known. Using mice with targeted deletion of the gene for IL-10 (IL-10(-/-)), we examined the hypothesis that IL-10 is a major modulator of the vascular effects of lipopolysaccharide (LPS). Methods-We examined in vitro responses of carotid arteries obtained from wild-type (129/SvEv or C57BL/6; IL-10(+/+)) and IL-10-deficient mice 6 hours after injection of a relatively low dose of LPS (10 microgram).

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

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.

Menhaden oil feeding increases potential for renal free radical production in BHE/cdb rats.

The effects of feeding 9% beef tallow (BT) or menhaden oil (MO) in a 10% fat-60% sucrose-20% protein diet on renal cortex fatty acid profile, renal lipid peroxide formation potential, and the blood pressure response to a norepinephrine challenge was studied. Male weanling BHE/cdb prediabetic rats were studied after 8 weeks of diet treatment. Half the rats were subjected to a norepinephrine challenge, and their mean arterial blood pressure was determined.

High fish oil diet increases oxidative stress potential in mammary gland of spontaneously hypertensive rats.

1. The purpose of this study was to determine whether high omega-3 (19% menhaden oil, 1% corn oil) or high omega-6 (20% corn oil) fatty acid diets would decrease expression of hypertension in the female spontaneously hypertensive rat (SHR), promote tumourigenesis in the rat 7,12-dimethylbenz[a]anthracene (DMBA) model of mammary cancer or increase the susceptibility of the mammary gland to lipid peroxidation. A group of rats on a 5% corn oil diet served as the low fat control group.

The effects of patterned calorie-restricted diets on mammary tumor incidence and plasma endothelin levels in DMBA-treated rats.

Chronic caloric restriction has been shown to inhibit mammary tumor promotion in the 7,12-dimethyl-benz[a]anthracene (DMBA) rat mammary tumor model. The objectives of this study were to determine (i) the effects of chronic caloric cycling (yo-yo dieting) on mammary tumor promotion by high fat diets and (ii) the effect of three dietary regimens +/- superimposed mammary tumor burden on plasma endothelin-1,2 (ET) levels. Female Sprague-Dawley rats were treated with DMBA (5 mg/rat) and divided into three dietary groups: ad libitum (AL) (containing 15% corn oil); 40% calorie restricted (CR) (containing 20% corn oil so consumption of fat was equivalent between AL and CR); a calorie cycled (CC) group fed alternatively AL and CR diets each 48 h period.