摘要:

Abstract—Angiotensin II (Ang II) has profound effects in the central nervous system (CNS), including promotion of thirst, regulation of vasopressin secretion, and modulation of sympathetic outflow. Despite its importance in cardiovascular and volume homeostasis, angiotensinergic mechanisms are incompletely understood in the CNS. Recently, a novel signaling mechanism for Ang II involving reactive oxygen species (ROS) has been identified in a variety of peripheral tissues, but the involvement of ROS as second messengers in Ang II–mediated signaling in the CNS has not been reported. The hypothesis that superoxide is a key mediator of the actions of Ang II in the CNS was tested in mice using adenoviral vector–mediated expression of superoxide dismutase (AdSOD). Changes in blood pressure, heart rate, and drinking elicited by injection of Ang II in the CNS were abolished by prior treatment with AdSOD in the brain, whereas the cardiovascular responses to carbachol, another central vasopressor agent, were unaffected. In addition, Ang II stimulated superoxide generation in primary CNS cell cultures, and this was prevented by the Ang II receptor (Ang II type 1 subtype) antagonist losartan or AdSOD. These results identify a novel signaling mechanism mediating the actions of Ang II in the CNS. Dysregulation of this signaling cascade may be important in hypertension and heart failure triggered by Ang II acting in the CNS.

ISSN:0009-7330    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Abstract—Blood flow to contracting skeletal muscle is tightly coupled to the oxygenation state of hemoglobin. To investigate if ATP could be a signal by which the erythrocyte contributes to the regulation of skeletal muscle blood flow and oxygen (O2) delivery, we measured circulating ATP in 8 young subjects during incremental one-legged knee-extensor exercise under conditions of normoxia, hypoxia, hyperoxia, and CO+normoxia, which produced reciprocal alterations in arterial O2content and thigh blood flow (TBF), but equal thigh O2delivery and thigh O2uptake. With increasing exercise intensity, TBF, thigh vascular conductance (TVC), and femoral venous plasma [ATP] augmented significantly (P<0.05) in all conditions. However, with hypoxia, TBF, TVC, and femoral venous plasma [ATP] were (P<0.05) or tended (P=0.14) to be elevated compared with normoxia, whereas with hyperoxia they tended to be reduced. In CO+normoxia, where femoral venous O2Hb and (O2+CO)Hb were augmented compared with hypoxia despite equal arterial deoxygenation, TBF and TVC were elevated, whereas venous [ATP] was markedly reduced. At peak exercise, venous [ATP] in exercising and nonexercising limbs was tightly correlated to alterations in venous (O2+CO)Hb (r2=0.93 to 0.96;P<0.01). Intrafemoral artery infusion of ATP at rest in normoxia (n=5) evoked similar increases in TBF and TVC than those observed during exercise. Our results in humans support the hypothesis that the erythrocyte functions as an O2sensor, contributing to the regulation of skeletal muscle blood flow and O2delivery, by releasing ATP depending on the number of unoccupied O2binding sites in the hemoglobin molecule.

ISSN:0009-7330    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Abstract—Treatment of rats with monocrotaline (MCT) leads to pulmonary hypertension, right ventricular (RV) hypertrophy, and finally to RV heart failure. This is associated with characteristic changes in right ventricular &bgr;-adrenoceptors (&bgr;-AR), neuronal noradrenaline transporter (NAT) density and activity (uptake1), and G protein–coupled receptor kinase (GRK) activity. This study aimed to find out factors that determine &bgr;-AR, uptake1, and GRK changes. Thus, 6-week-old rats were treated with 50 mg/kg MCT subcutaneous or 0.9% saline. Within 13 to 19 days after MCT application (group A), RV weight (222±6 versus 147±5 mg) and RV/left ventricular (LV) weight ratio (0.42±0.01 versus 0.29±0.01) were significantly increased, whereas plasma noradrenaline, RV &bgr;-AR density, RV NAT density and activity, and RV GRK activity were not significantly altered. Twenty-one to twenty-eight days after MCT (group B), however, not only RV weight (316±4 versus 148±2 mg) and RV/LV weight ratio (0.61±0.01 versus 0.3±0.01) were markedly increased but also plasma noradrenaline (645±63 versus 278±18 pg/mL); now, RV &bgr;-AR density (13.4±1.3 versus 26.5±1.1 fmol/mg protein), RV NAT density (50.9±11.3 versus 79.6±2.9 fmol/mg protein), and RV NAT activity (65.4±7.4 versus 111.8±15.9 pmol [3H]-NA/mg tissue slices/15 min) were significantly decreased and RV-membrane GRK activity (100±15 versus 67±6 [32P]-rhodopsin in cpm) significantly increased. LV parameters of MCT-treated rats were only marginally different from control LV. We conclude that in MCT-treated rats ventricular hypertrophy per se is not sufficient to cause characteristic alterations in the myocardial &bgr;-AR system often seen in heart failure; only if ventricular hypertrophy is associated with neurohumoral activation &bgr;-ARs are downregulated and GRK activity is increased.

ISSN:0009-7330    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Abstract—We previously observed that adenovirus-mediated expression of C-type natriuretic peptide (CNP) markedly inhibits neointima formation after balloon injury in rat carotid arteries, suggesting that CNP has multiple effects over its modest inhibitory effect on cellular proliferation. We hypothesized that local expression of CNP might have antithrombotic and antiinflammatory effects. Balloon-injured rabbit carotid arteries were infected with an adenovirus expressing human CNP (AdCNP), human tissue factor pathway inhibitor (AdTFPI), or bacterial &bgr;-galactosidase (AdLacZ) or infused with saline. Seven days later, shear stress–induced thrombosis was evaluated by cyclic flow variation (CFV), reflecting recurrent cycles of thrombus formation and dislodgment. CFV was observed in all AdLacZ-infected and saline-infused arteries but not in arteries infected with AdCNP or AdTFPI even in the presence of epinephrine. Injury increased the expressions of intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) and infiltration of macrophages. However, these effects were markedly reduced in AdCNP-treated arteries but not in AdTFPI-infected ones. In AdCNP-infected arteries, injury-induced expression of inducible NO synthase (iNOS) was enhanced, leading to increased NO generation. Interestingly, when the enhanced NO production was inhibited, neither inhibitory effect was observed, and suppression of neointima formation by CNP was canceled. Our study demonstrates that overexpression of CNP shows antithrombotic and antiinflammatory effects and reduces neointima formation mainly through enhanced NO production.

ISSN:0009-7330    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Abstract—We examined the hypothesis that ONOO−, a product of the interaction between superoxide (O2·−) and nitric oxide (NO), inhibits calcium-activated K+(KCa) channel activity in vascular smooth muscle cells (VSMCs) of human coronary arterioles (HCAs), thereby reducing hyperpolarization-mediated vasodilation. HCAs were dissected from right atrial appendages. The interaction of ONOO−with microvessels was determined by immunohistochemistry using a nitrotyrosine antibody. Strong staining was observed in arteries exposed to authentic ONOO−or to sodium nitroprusside (SNP)+xanthine (XA)+xanthine oxidase (XO). Dilation to 10−8mol/L bradykinin (BK) was abolished in vessels exposed to ONOO−(−2.5±8%;P<0.05) but not DC-ONOO−(65±8%). Reduced dilation to BK was also observed after application of XO and SNP. Dilation to NS1619 (KCachannel opener) was reduced in endothelial denuded arterioles treated with ONOO−. In isolated VSMCs, whole-cell peak K+current density was reduced by ONOO−(control 65±15 pA/pF; ONOO−42±9 pA/pF;P<0.05). Iberiotoxin had no further effect on whole-cell K+current. In inside-out patches, ONOO−but not DC-ONOO−decreased open state probability (NPo) of KCachannel by 50±12%. O2·−generated by XA+XO had no effect on BK-induced dilation and NPoof KCachannels. These results suggest that ONOO−, but not O2·−, inhibits KCachannel activity in VSMCs possibly by a direct effect. This mechanism may contribute to impaired EDHF-mediated dilation in conditions such as ischemia/reperfusion where increased activity of NO synthase occurs in the presence of excess of O2·−.

ISSN:0009-7330    

出版商:OVID    

年代:2002

数据来源: OVID

ISSN:0009-7330    

出版商:OVID    

年代:2002

数据来源: OVID