Search

The primary role for erythrocytes is oxygen transport that requires the reversible binding of oxygen to hemoglobin. There are, however, secondary reactions whereby the erythrocyte can generate reactive oxygen species (ROS) and nitric oxide (NO). ROS such as superoxide anion and hydrogen peroxide are generated by the autoxidation of hemoglobin. NO can be generated when nitrite reacts with hemoglobin forming an HbNO+ intermediate. Both of these reactions are dramatically enhanced under hypoxic conditions. Within the erythrocyte, interactions of NO with hemoglobin and enzymatic reactions that neutralize ROS are expected to prevent the release of any generated NO or ROS. We have, however, demonstrated that partially- oxygenated hemoglobin has a distinct conformation that enhances hemoglobin-membrane interactions involving Band 3 protein. Autoxidation of the membrane bound partially-oxygenated hemoglobin facilitates the release of ROS from the erythrocyte. NO release is made possible when HbNO+, the hemoglobin nitrite-reduced intermediate, which is not neutralized by hemoglobin, is bound to the membrane and releases NO. Some of the released ROS has been shown to be transferred to the vasculature suggesting that some of the released NO may also be transferred to the vasculature. NO is known to have a major effect on the vasculature regulating vascular dilatation. Erythrocyte generated NO may be important when NO production by the vasculature is impaired. Furthermore, the erythrocyte NO released, may play an important role in regulating vascular function under hypoxic conditions when endothelial eNOS is less active. ROS can react with NO and, can thereby modulate the vascular effects of NO. We have also demonstrated an inflammatory response due to erythrocyte ROS. This reflects the ability of ROS to react with various cellular components affecting cellular function.

The reduction of nitrite by deoxyhemoglobin to nitric oxide (NO) has been proposed as a mechanism for the transfer of NO bioactivity from the red blood cell (RBC) to the vasculature. This transfer can increase vascular dilatation. The major challenge to this hypothesis is the very efficient scavenging of NO by hemoglobin, which prevents the release of NO from RBCs. Previous studies indicate that the reaction of nitrite with deoxyhemoglobin produces two metastable intermediates involving nitrite bound to deoxyhemoglobin and a hybrid intermediate [Hb(II)NO(+) ↔ Hb(III)NO] where the nitrite is reduced, but unavailable to react with hemoglobin. We have now shown how unique properties of these intermediates provide a pathway for the release of NO bioactivity from RBCs. The high membrane affinity of these intermediates (100-fold greater than that of deoxyhemoglobin) places these intermediates on the membrane. Furthermore, membrane-induced conformational changes of the nitrite-reacted intermediates facilitate the release of NO from the hybrid intermediate and nitrite from the nitrite-bound intermediate. Increased membrane affinity, coupled with facilitated dissociation of NO and nitrite from the membrane-bound intermediates, provides the first realistic mechanism for the potential release of NO and nitrite from the RBC and their potential transfer to the vasculature.

There are most important strategic significance in our country as well as the carrier rocket, ballistic missiles, the development of the manned space engineering that GPS signal simulation of satellite navigation system has. The structure and principle of GPS navigation and positioning signal were discussed in detail in this paper, with practicality as the starting point, the navigation message is transmitted by the use of pseudo random noise code phase-modulated signal, and the method of direct sequence spread spectrum modulation system is used to simulate the signal of GPS satellite orbit based on the MATLAB/Simulink platform. Then the simulation research and analysis of C/A code and P code in the frequency domain and time domain with it`s correlation is carried on, at the same time, the C/A code frequency domain is captured by using the fast Fourier transform method (FFT).finally the space transmission characteristics of GPS signal is simulated under Gaussian noise.it is show that the simulation result is close to the theoretical value, and the accuracy is better.

The fractional exhaled concentration of nitric oxide (FENO) has been shown to be reduced in idiopathic pulmonary arterial hypertension (PAH) but has not been adequately studied in PAH associated with systemic sclerosis (SSc). We measured FENO at an expiratory flow rate of 50 mL/s in 21 treatment-naive patients with SSc-associated PAH (SSc-PAH), 94 subjects with SSc without pulmonary involvement, and 84 healthy volunteers. Measurements of FENO at additional flow rates of 100, 150, and 250 mL/s were obtained to derive the flow-independent nitric oxide exchange parameters of maximal airway flux (J'awNO) and steady-state alveolar concentration (CANO). FENO at 50 mL/s was similar (P = 0.22) in the SSc-PAH group (19 ± 12 parts per billion [ppb]) compared with the SSc group (17 ± 12 ppb) and healthy control group (21 ± 11 ppb). No change was observed after 4 months of targeted PAH therapy in 14 SSc-PAH group patients (P = 0.9). J'awNO was modestly reduced in SSc group subjects without lung disease (1.2 ± 0.5 nl/s) compared with healthy controls (1.64 ± 0.9; P < 0.05) but was similar to that in the SSc-PAH group. CANO was elevated in individuals with SSc-PAH (4.8 ± 2.6 ppb) compared with controls with SSc (3.3 ± 1.4 ppb) and healthy subjects (2.6 ± 1.5 ppb; P < 0.001 for both). However, after adjustment for the diffusing capacity of CO, there was no significant difference in CANO between individuals with SSc-PAH and controls with SSc. We conclude that FENO is not useful for the diagnosis of PAH in SSc. Increased alveolar nitric oxide in SSc-PAH likely represents impaired diffusion into pulmonary capillary blood.

Our previous study demonstrated that the peroxisome proliferator-activated receptor (PPAR) γ agonist, pioglitazone (PIO), may be cardioprotective against ischemia-reperfusion injury; however, modulation of p42/p44 extracellular signal-regulated kinases (ERK1/2) and cyclooxygenase (COX)-2 by PIO in the myocardium with respect to ischemia-reperfusion (I/R) is only partially understood. We determined if PIO reduces I/R-induced apoptosis in cardiomyocytes, and whether or not this protective effect is due to modulation of ERK1/2 and COX-2. Sixty male Sprague-Dawley rats were randomized and assigned to 1 of 6 groups: I/R; I/R + PIO (5 mg•kg(-1)•day(-1)); I/R + PIO (10 mg•kg(-1)•day(-1)); I/R + PIO (10 mg•kg(-1)•day(-1)) + the ERK1/2 inhibitor, PD98059; I/R + PIO ( 10 mg•kg(-1)•day(-1)) + GW9662;and I/R + PD98059. Rats underwent 30 min of myocardial ischemia and 120 min of reperfusion, and then hearts were harvested for analysis. RT-PCR and Western blotting were performed to detect expression of ERK1/2 and COX-2. The number of TUNEL-positive cardiomyocytes and NEC in the PIO groups (5 and 10 mg•kg(-1)•day(-1)) was much lower than the I/R group. The cardioprotective effect of PIO was abrogated by PD98059 and GW9662. Phosphorylation of ERK1/2 and COX-2 was increased in the PIO-treated group compared with the I/R group. GW9662 reversed the expression of ERK1/2 and COX- 2 phosphorylation induced by PIO. PD98059 reversed the expression of COX-2 induced by PIO. PIO was shown to be cardioprotective in an I/R injury model in rats via inhibition of cardiomyocyte apoptosis. PIO limited the infarct size in a PPAR-γ-dependent manner. These results show that PIO triggers the MAPK signaling pathway involving ERK1/2 using COX-2 as the downstream target.

A role for nitric oxide (NO) produced during the reduction of nitrite by deoxygenated red blood cells (RBCs) in regulating vascular dilation has been proposed. It has not, however, been satisfactorily explained how this NO is released from the RBC without first reacting with the large pools of oxyhemoglobin and deoxyhemoglobin in the cell. In this study, we have delineated a mechanism for nitrite-induced RBC vasodilation that does not require that NO be released from the cell. Instead, we show that nitrite enhances the ATP release from RBCs, which is known to produce vasodilation by several different methods including the interaction with purinergic receptors on the endothelium that stimulate the synthesis of NO by endothelial NO synthase. This mechanism was established in vivo by measuring the decrease in blood pressure when injecting nitrite-reacted RBCs into rats. The observed decrease in blood pressure was not observed if endothelial NO synthase was inhibited by Nω-nitro-l-arginine methyl ester (l-NAME) or when any released ATP was degraded by apyrase. The nitrite-enhanced ATP release was shown to involve an increased binding of nitrite-modified hemoglobin to the RBC membrane that displaces glycolytic enzymes from the membrane, resulting in the formation of a pool of ATP that is released from the RBC. These results thus provide a new mechanism to explain nitrite-induced vasodilation.

The reduction of nitrite by RBCs producing NO can play a role in regulating vascular tone. This hypothesis was investigated in rats by measuring the effect of nitrite infusion on mean arterial blood pressure (MAP), cerebral blood flow (CBF) and cerebrovascular resistance (CVR) in conjunction with the accumulation of RBC-NO. The nitrite infusion reversed the increase in MAP and decrease in CBF produced by L-NAME inhibition of e-NOS. At the same time there was a dramatic increase in RBC-NO. Correlations of RBC-NO for individual rats support a role for the regulation of vascular tone by this pool of NO. Furthermore, data obtained prior to treatment with L-NAME or nitrite are consistent with a contribution of RBC reduced nitrite in regulating vascular tone even under normal conditions. The role of the RBC in delivering NO to the vasculature was explained by the accumulation of a pool of bioactive NO in the RBC when nitrite is reduced by deoxygenated hemoglobin chains. A comparison of R and T state hemoglobin demonstrated a potential mechanism for the release of this NO in the T-state present at reduced oxygen pressures when blood enters the microcirculation. Coupled with enhanced hemoglobin binding to the membrane under these conditions the NO can be released to the vasculature.

Two groups of rats were used to examine the effect of pioglitazone, a peroxisome proliferator-activated receptor γ (PPARγ) agonist, on rat hearts using an in vivo model of ischemia-reperfusion (I/R) to elucidate potential mechanisms. One group was the 30-min reperfusion group, which was further subdivided into sham (n = 5), vehicle (n = 6) and pioglitazone (3 mg·kg–1, n = 7) treatment groups with 30 min ischemia followed by 30 min reperfusion to detect data related to cardiac function and the area of myocardial infarction. The other group was the 120-min reperfusion group, subdivided into sham (n = 5), vehicle (n = 6), and pioglitazone 0.3 mg·kg–1 (n = 6), 1 mg·kg–1 (n = 7) and 3 mg·kg–1 (n = 6) treatment groups. Immunohistochemistry, in situ hybridization, terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL) and DNA agarose gel electrophoresis were performed to detect apoptosis and expressions of Bax, Bcl-2, caspase 3, MMP-2 and PPARγ protein, and MMP-2 and PPARγ mRNA. We found that, after acute treatment with pioglitazone, the ratio of necrosis to area at risk decreased by 28% (p < 0.01) and that of necrosis to left ventricle was reduced by 32% (p < 0.01), compared with the vehicle group. Heart rate and +dp/dtmax, representing the cardiac systolic function, as well as –dp/dtmax, the indicator of cardiac diastolic function, improved significantly at 1 and 30 min after reperfusion (p < 0.05–0.01). Furthermore, myocardial apoptosis was significantly suppressed by acute treatment with pioglitazone as evidenced by the decreased number of TUNEL-positive myocytes and DNA ladder, enhanced Bcl-2 protein expression, reduced Bax and caspase 3 protein expression in a dose-dependent manner compared with vehicle-treated rats. In addition, acute treatment with pioglitazone dose-dependently increased PPARγ expression and decreased MMP-2 expression at protein and mRNA levels. Our findings demonstrate that a PPARγ agonist may protect the heart from I/R injury. The protective effect is likely to occur by reducing cardiomyocyte apoptosis and inhibiting MMP-2.