The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are unequivocally useful for lowering cholesterol levels in patients with dyslipidemias. In addition to cholesterol lowering properties, statins exert a number of pleiotropic, vascular-protective effects include improvement of endothelial function, increased nitric oxide (NO) bioavailability, antioxidant properties. Since endothelial dysfunction and reactive oxygen species (ROS) are important pathophysiological determinants of essential hypertension, these actions of statins raise the possibility that statin therapy may be useful for simultaneously clinical hypertension management. However, the signaling mechanisms of statins that improve hypertension remain unclear. Our previous study showed, in the NTS, insulin may decrease blood pressure and heart rates through PI3K-Akt-eNOS pathway, and NTS integrates convergent information from peripheral baroreceptors and central cardiovascular regulatory center. Statins also prevent the synthesis of other important isoprenoid intermediates of the cholesterol biosynthetic pathway, members of the Ras and Rac1 GTPase family are major substrates for posttranslational modification by isoprenylation and may be important targets for inhibition by statins. Statins could inhibit Rac1 isoprenylation and Rac1-mediated nicotinamide adenine dinucleotide phosphate oxidase activity attenuates reactive oxygen species production. The aim of this study was to investigate the possible signaling pathways involved in simvastatin-mediated blood pressure regulation in the nucleus tractus solitarii (NTS). Male 20-week-old spontaneously hypertensive rats (SHR) were divided into two groups: control group and intracerebroventricular injection with simvastatin group for three days. We found that systolic blood pressure measured with tail-cuff method of the simvastatin-treated rats decreased significantly, and the NO level in the NTS was significantly increased. In addition, we observed that simvastatin could lower the ROS level and increase Ras GTPase activity in the NTS. Immunoblotting and immunohistochemistry analysis further showed that simvastatin increased the phosphorylation ratio of ERK1/2, Akt, and endothelial nitric oxide synthase (eNOS) in the NTS. Taken together, these results suggest that eNOS signaling in the NTS may play an important role in simvastatin-induced blood pressure lowering effects. Keywords: statins, nucleus tractus solitarii, nitric oxide, oxidative stress, central cardiovascular regulatory, isoprenylation

Recent studies demonstrated that fructose intake can increase blood pressure in experimental animals. Oxidative stress has emerged as an important pathogenic factor in the development of hypertension. It has been reported that increased superoxide production in fructose-fed rat mediated through nicotinamide adenine dinucleotide phosphate NAD(P)H oxidase. Superoxide dismutase (SOD) is one of the most important enzymes against oxidative stress. However, the signaling mechanisms of fructose which induce hypertension through superoxide remain unclear. Nucleus tractus solitarii (NTS) is the integrative center for baroreflex. Our previous study had revealed that accumulation of superoxide in the NTS can induce hypertension. As an important antioxidant in red wine, resveratrol is likely to contribute to the potential of red wine to prevent cardiovascular disease. At pharmacological doses, resveratrol increases vascular nitric oxide (NO) levels and improves NO bioavailability in animal models. Resveratrol is a potent activator of AMPK in neuronal cell lines, primary neurons, and the brain. Recent reports have indicated that metformin targets AMPK which activates nNOS and eNOS. Therefore, we hypothesized that resveratrol causes blood pressure decrease through regulating nitric oxide and superoxide production in the NTS of fructose-fed rats. There were three specific aims: 1. To investigate whether fructose induce superoxide production and causes hypertension in the NTS. 2. To investigate which signaling pathway is involved in fructose-induced hypertension. 3. To investigate which signaling pathway is involved in resveratrol modulates blood pressure. Male Wistar Kyoto rats (WKY) were divided into two groups: control group and fed with 10% fructose water group for 1 week. After one-week treatment, the systolic blood pressure and superoxide production increased significantly and the nitrate level in the NTS was significantly decreased. Immunoblotting showed that administration of fructose significantly increased NADPH oxidase subunits p22-phox, p67-phox activity, RAGE activity and reduce SOD2 activity in the NTS. Based on our previous studies, male Wistar-Kyoto rats (WKY) were divided into five groups: Group I: Control group; Group II: fructose-fed rats (FFR) fed with 10% fructose for 4 weeks; Group III: Control + resveratrol (R) rats received a gavage of resveratrol; Group IV: FFR+ resveratrol (FR) fed with 10% fructose and resveratrol ; Group V: FFR + 2weeks resveratrol (F2R) fed with 10% fructose and received a gavage of resveratrol 2 weeks. We found that systolic blood pressure measured by tail-cuff method in F group rats and F2R group rats revealed a significantly increased than C group rats continuously through week 0 to week 2 but R group rats and FR group rats were no difference with C group. However, received a gavage of resveratrol (10 mg/kg/d) 2 weeks, F2R group revealed a significantly decrease in SBP than the F group continuously through week 2 to week 4. Fructose-induced hypertension increased NADPH oxidase activity and SOD2 activity related to inhibit the production of NO in the regulation of blood pressure. These results suggest that in the NTS, intake of fructose induces NADPH oxidase activity and reduces SOD2 activity to increase blood pressure. Resveratrol can not only reverse fructose-induced hypertension but also prevent fructose-induced hypertension.

We hypothesized that the interaction between tumor necrosis factor alpha(TNF)/nuclear factor-kappaB (NFkB) via activation of IKK may amplify one anotherresulting in the evolution of vascular disease and insulin resistance associated withdiabetes. The interaction between TNFa and monocyte chemoattractant protein-1 (MCP-1) may contribute to the evolution of vascular inflammation and endothelial dysfunctionin coronary arterioles in type 2 diabetes. To test this hypothesis, endothelium-dependent(ACh) and –independent (SNP) vasodilation of isolated, pressurized coronary arterioles(40-100 μm) from mLeprdb (heterozygote, normal), Leprdb (homozygote, diabetic) andLeprdb mice null for TNF (dbTNF-/dbTNF-) were examined. Although dilation of vesselsto SNP was not different between Leprdb and mLeprdb mice, dilation to ACh was reducedin Leprdb mice. The NFkB antagonist, MG-132, IKK inhibitor, sodium salicylate(NaSal), or Anti-MCP-1 partially restored endothelium-dependent coronary arteriolardilation in Leprdb mice. Protein expression of IKK and IKK were higher in Leprdb thanin mLeprdb mice. The expression of IKK, but not the expression of IKK was increasedin dbTNF-/dbTNF- mice. Leprdb mice showed increased insulin resistance, but NaSal improved insulin sensitivity. Protein expression of TNFa, NFkB, phosphorylation ofIKK and JNK were greater in Leprdb mice, but NaSal attenuated protein expression ofthem in Leprdb mice. The ratio of phosphorylated IRS-1 at Ser307 (pIRS-1)/IRS-1protein expression was elevated in Leprdb mice; both NaSal and JNK inhibitor SP600125reduced pIRS-1/IRS-1 in Leprdb mice. MG-132 or neutralization of TNF reducedsuperoxide production in Leprdb mice. Anti-MCP-1 attenuated superoxide productionand protein expression of nitrotyrosine (N-Tyr), which is an indicator of peroxynitriteproduction, in isolated coronary arterioles of Leprdb mice. Immunostaining resultsshowed that expression of MCP-1 and vascular cellular adhesion molecule-1 (VCAM) isco-localized with endothelial cells and macrophages. Anti-TNFa or anti-MCP-1markedly reduced macrophage infiltration and the number of MCP-1 positive cells.Neutralization of TNFa or anti-MCP-1 reduced the expression of adhesion molecules. Inconclusion, our results indicate that the interaction between NFkB and TNFa signalinginduces activation of IKKb. In addition, TNFa and TNFa-related signaling, includingthe expression of MCP-1 and adhesion molecules, further exacerbates oxidative stressleading to endothelial dysfunction in type 2 diabetes.

As global focus shifts towards the health and conservation of the planet, greater importance is placed upon the hazardous emissions of our fossil fuels, as well as their finite supply. These two areas remain intense topics of research in order to reduce green house gas emissions and increase the fuel efficiency of our vehicles. A particular solution to this problem is the diesel engine, with its inherently fuel-lean combustion, which gives rise to low CO2 production and higher efficiencies than its gasoline counterpart. Diesel engines, however, typically exhibit higher nitrogen oxides (NOx [NOx = NO NO2, where NO is nitric oxide and NO2 is nitrogen dioxide]) and soot. There exists the possibility to simultaneously reduce both emissions with the application of low temperature diesel combustion (LTC). While exhibiting great characteristics in simultaneous reductions in nitrogen oxides and soot, LTC faces challenges with higher carbon monoxide (CO) and hydrocarbon (HC) emissions, as well as penalties in fuel efficiency. The following study examines the characteristics of LTC which contribute to the differences in emissions and efficiency compared to typical conventional diesel combustion. More specifically, key engine parameters which are used to enable LTC, such as EGR and fuel pressure are swept through a full range to determine their effects on each combustion regime. Analysis will focus on comparing both combustion regimes to determine how exhaust gas recirculation (EGR) and fuel pressure relate to lowering NO and smoke concentrations, and how these relate to a penalty in fuel efficiency. This study finds that the application of LTC is able to realize a 99 percent reduction in NO while simultaneously reducing smoke by 17 percent compared to the conventional combustion counterpart. Through a sweep increasing EGR, LTC is able to defeat the typical soot – NO tradeoff; however, brake fuel conversion efficiency decreases 6.8 percent for LTC, while conventional combustion realizes a 4 percent increase in efficiency. The sweep of increasing fuel pressure confirms typical increases in NO and decreases in smoke for both LTC and conventional combustion; however, brake fuel conversion efficiency increases 2.3 percent for LTC and drops 4 percent for conventional combustion.

Interest in biodiesel has piqued with advent of stringent emissions regulations. Biodiesel is a viable substitute for petroleum diesel because biodiesel produces significantly lower particulate and soot emissions relative to petroleum diesel. Higher nitric oxide (NO) emissions for biodiesel, however, are of primary concern in biodiesel-fueled engines. Search for an in-cylinder technique to reduce NO emissions for biodiesel has motivated studies to gain an improved understanding of fundamental factors that drive increase in NO emissions with biodiesel. Potential factors include fuel-bound oxygen, fuel-bound nitrogen and post-flame gas temperature. The role of fuel-bound oxygen however is debated in the literature. The research objective of this study is to computationally determine if biodiesel and petroleum diesel yield equivalent concentrations of NO with the same oxygen equivalence ratio in a 0-D homogeneous reactor, to explain the role of fuel-bound oxygen in biodiesel on increases in NO emissions with biodiesel. The results from this study indicate that the biodiesel surrogate yields higher NO emissions than the n-heptane because of its lower oxygen consumption efficiency. The lower oxygen consumption efficiency for biodiesel is likely because of the slower decomposition of the individual components and the blending ratios of the biodiesel surrogate blend. The relative differences in combustion efficiency of individual components of the biodiesel blend suggest this conclusion. The more efficient burning of the methyl esters relative to the n-heptane in biodiesel surrogate perhaps indicates the favorable role of fuel-bound oxygen in the fuel’s combustion. The low utilization of oxygen by the biodiesel surrogate could not be explained in this study. The dominance of NO2 H ↔ NO OH and N NO ↔ N2 O mechanisms during biodiesel combustion however explain the high NO emissions for the biodiesel surrogate relative to the n-heptane. The biodiesel may yield lower NO emissions than the petroleum diesel if the blending ratios for the biodiesel are adjusted such that combustion efficiency of biodiesel and petroleum diesel is same or the NO2 H ↔ NO OH and N NO ↔ N2 O mechanisms are suppressed during biodiesel combustion.

Environmental factors such as ambient temperature and oxygen availability are variation in different altitude. Individuals within a species, living in variable environments often display phenotypic plasticity by changing morphology, behavior, reproduction, and physiology to meet the individual¡¦s ability to survive demanding conditions. This study was aimed to investigate the expression of angiotensin receptor and nitric oxide synthase genes of individuals resided at differential altitude, in an attempt to find the role of these molecules in cardiovascular adaptation to altitude. Spiny rats (Niviventer coxingi) are widely elevational distributed in Taiwan. They were studied under more natural conditions to provide an ecological context data on physiological plasticity between the different altitudes. I examined the body weight, blood pressure, heart rate and the expression of angiotensin type 1 or type 2 (ATI or ATII) receptor and nitric oxide synthase (NOS) genes in tissues (cortex, hypothalamus, medulla, lung, heart, aorta, adrenal gland and kidney) of spiny rats resided at differential altitude and during the domesticated period. The results of the study showed that spiny rats resided at higher altitudes were lighter than that at lower altitudes (750 m: 178.6¡Ó35.8 g and 1600 m: 122.3¡Ó29.3 g). Spiny rats resided at 1600 m did not change their body weight during the domesticated period, but rats resided at 750 m gradually reduced their body weight. Blood pressure and heart rate were similar between rats resided at different altitudes, and did not change during the domesticated period. ATI receptor, endothelelial NOS (eNOS), inducible NOS (iNOS) and neuronal NOS (nNOS) mRNA expression in these tissues were similar between rats resided at different altitudes. ATII receptor mRNA expressed in these tissues under our detection limit. Rats resided at 750 m declined the level of nNOS in heart, when they were domesticated at 100 m. ATI receptor in kidney reduced at first, but subsequently increase to same level like native. Moreover, rats resided at 1600 m declined the level of iNOS in heart, when they were domesticated at 100 m. Together, these results indicate that heart rate, blood pressure, ATI receptor, eNOS, iNOS and nNOS mRNA expressions in these tissues were similar between rats resided at different altitudes. If there was no other compensatory mechanism, individuals resided at higher altitude were limited in low available oxygen. A reduced body weight could help in adaptation to high-altitude.

Abstract The phospholipid PI(3,4,5)P3 works as a second messenger in PI3K signaling pathway. The PI3K signaling pathway is involved in insulin stimulated nitric oxide (NO) production in vascular endothelium, leading to vasodilation and increased blood flow. However, the production of NO also has been reported in neurons as a neurotransmitter and in nucleus tractus solitarii (NTS), NO plays a role in central cardiovascular regulation. Previously, microinjection of insulin into the NTS of rats produces prominent depressor and bradycardic and activates the PI3K downstream Akt. Therefore, to investigate the detail downstream signaling of insulin stimulated NO production in NTS, the effects of PI(3,4,5)P3 on NO production were determined in neuronal cell lines PC12 and GH3 and in NTS of SD rats. The GH3 and differentiated PC12 exposed to 10

Neurogenic inflammatory responses can be induced by antidromic electrical stimulation or intravenous capsaicin injection. These responses were thought to be caused by neuropeptides released from the sensory axon of C-fiber nerve endings. The relation of tachykinins, reactive oxygen species (ROS) and reactive nitrogen species (RNS) on electrical stimulation of thoracic vagus nerve (TVNS) or capsaicin-evoked neurogenic inflammation in respiratory tract of atropine-treated rats was not clear. In the present studies, the role of ROS and RNS on neurogenic inflammation were investigated in TVNS and capsaicin injected rats. The experiments were divided into two parts. In the first part, TVNS was performed by thoracotomy, non-cholinergic regulation of neurogenic plasma extravasation in the trachea and bronchi were examined, and whether TVNS via NK receptor facilitates neurogenic inflammation by nuclear factor-kappaB (NF-£eB) activation and ROS production were expored. Our results in this part showed that TVNS evoked substance P release, hypotension, bronchoconstriction (as shown by increases in smooth muscle electromyographic activity and total pulmonary resistance), trachea plasma extravasation as well as increases in blood O2- and H2O2 ROS amount in a frequency-dependent manner. Histopathological examination demonstrated silver-stained leaky venules, India-ink labeled plasma extravasation, and accumulations of inflammatory cells in the right lower trachea after TVNS. L-732138 (NK1 receptor antagonist), SR-48968 (NK2 receptor antagonist), dimethylthiourea (H2O2 scavenger) or catechins (O2- and H2O2 scavenger) pretreatment reduced TVNS-enhanced hypotension, bronchoconstriction, and plasma extravasation. TVNS upregulated the expression of NF-£eB in nuclear protein and intercellular adhesion molecule-1 (ICAM-1) in total protein of the lower respiratory tract tissue in a frequency-dependent manner. The upregulation of NF-£eB and ICAM-1 was attenuated by NK receptor antagonist and antioxidants. In the second part, the contribution of nitric oxide (NO) to capsaicin-evoked airway responses was investigated in rats. The measurement of plasma NO level, airway dynamics, airway smooth muscle electromyogram, and plasma extravasation by India ink and Evans blue leakage technique was adapted. Our results in this part showed that capsaicin injection evoked hypotension, bronchoconstriction, trachea plasma extravasation as well as increases in plasma NO level in a dose-dependent manner. L-732138 or SR-48968 pretreatment reduced capsaicin-enhanced hypotension, bronchoconstriction, plasma extravasation, and plasma NO level. Inhibition of a non-selective NO synthase (NOS) inhibitor (NG-nitro-L-Arginine methyl ester, L-NAME), or a selective inducible NO synthase (iNOS) inhibitor (aminoguanidine), reduced capsaicin-induced increases in plasma NO level and protected against capsaicin-induced plasma extravasation, whereas L-arginine (a NO precursor), enhances capsaicin-evoked plasma NO level and plasma extravasation. L-Arginine pretreatment ameliorated capsaicin-induced bronchoconstriction, whereas L-NAME and aminoguanidine exaggerated capsaicin-induced bronchoconstriction. In summary, both TVNS and capsaicin injection may increase oxidative stress responses. TVNS enhances proinflammatory NF-£eB and ICAM-1 expression, increases the production of O2- and H2O2 activity in the respiratory tract of atropine-treated rats. Pretreatment with antioxidants and selective NK receptor antagonists attenuate TVNS evoked airway hyperactivity, proinflammatory response, and oxidative stress. Capsaicin injection stimulates the release of tachykinins, which act on NK1 and NK2 receptors located on the smooth muscles of airways and blood vessels. The interaction of NK receptors with tachykinin enhances furtherly the NO formation, bronchoconstriction, vasodilation, and plasma extravasation in the trachea. The released tachykinins also increase the production of NO via iNOS, and iNOS -evoked NO counteracts tachykinin-mediated bronchoconstriction, but exacerbates tachykinin-mediated plasma extravasation.

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