ISSN:0194-911X    

出版商:OVID    

年代:2004

数据来源: OVID

摘要:

Abstract—Peroxisome proliferator-activated receptor &ggr; (PPAR&ggr;) is a ligand-activated transcription factor belonging to the nuclear hormone receptor superfamily. PPAR&ggr; is expressed by macrophages, endothelial cells, and vascular smooth muscle cells. It regulates gene expression of key proteins involved in lipid metabolism, vascular inflammation, and proliferation contributing to atherogenesis and postangioplasty restenosis. The discovery of synthetic ligands for PPAR&ggr; has led to significant enhancement of our understanding of the mechanism of their ligand-dependent activation and subsequent biological effects, particularly with respect to the role of PPAR&ggr; in vascular pathophysiology. The thiazolidinedione PPAR&ggr; agonists not only improve insulin resistance in patients with type II diabetes but also exert a broad spectrum of antiatherogenic effects in vitro and in animal models of atherosclerosis. In this review, we summarize the important role of PPAR&ggr; as a molecular target for thiazolidinediones and its implications for the control of vascular inflammation and proliferation for the cardiovascular system.

ISSN:0194-911X    

出版商:OVID    

年代:2004

数据来源: OVID

摘要:

Abstract—The role of baroreflexes in long-term control of arterial pressure is unresolved. To determine whether chronic activation of the baroreflex produces sustained hypotension, we developed a method for prolonged activation of the carotid baroreflex in conscious dogs. This was achieved by chronically implanting electrodes around both carotid sinuses and using an externally adjustable pulse generator to electrically activate the carotid baroreflex. Control values for mean arterial pressure (MAP) and heart rate were 93±3 mm Hg and 64±4 bpm, respectively. After control measurements, the carotid baroreflex was activated bilaterally for 7 days at a level that produced a prompt and substantial reduction in MAP, and for day 1 MAP was reduced to 75±4 mm Hg. Moreover, this hypotensive response was sustained throughout the entire 7 days of baroreflex activation (day 7, MAP=72±5 mm Hg). During prolonged baroreflex activation, heart rate decreased in parallel with MAP, although the changes were not as pronounced (day 7, heart rate=51±3 bpm). Prolonged baroreflex activation was also associated with ≈35% reduction in plasma norepinephrine concentration (control=87±15 pg/mL). After baroreflex activation, hemodynamic measures and plasma levels of norepinephrine returned to control levels. Interestingly, despite the pronounced fall in MAP, plasma renin activity did not increase during prolonged baroreflex activation. These data indicate that prolonged baroreflex activation can lead to substantial reductions in MAP by suppressing the sympathetic nervous system. Furthermore, sustained sympathoinhibitory effects on renin secretion may play an important role in mediating the long-term hypotensive response.

ISSN:0194-911X    

出版商:OVID    

年代:2004

数据来源: OVID

摘要:

Abstract—In addition to central nervous system actions, angiotensin (Ang) II may increase sympathetic nerve activity (SNA) via a direct action on sympathetic ganglia. We hypothesized that sympathetic ganglionic actions of endogenous Ang II contribute to SNA in transgenic mice that overexpress renin and angiotensinogen (R+A+mice). Renal SNA and arterial pressure were recorded in anesthetized R+A+and littermate control mice before and after ganglionic blockade, and after additional blockade of angiotensin type 1 (AT1) receptors with losartan. Ganglionic blockade essentially abolished SNA in control mice, but only reduced SNA to 47±18% of baseline in R+A+mice. The residual SNA remaining after ganglionic blockade in R+A+mice was reduced from 47±18% to 8±6% of baseline by losartan (P<0.05). The sympathoinhibitory response to losartan was accompanied by an enhanced decrease in arterial pressure in R+A+mice compared with that observed in control mice. AT1receptor expression in sympathetic ganglia, as measured by real-time reverse transcription–polymerase chain reaction, was increased ≈3-fold in R+A+versus control mice. The results demonstrate that, as anticipated, essentially all of the renal postganglionic SNA in control mice is driven by preganglionic input. The major new finding is that Ang II–evoked ganglionic activity accounts for ≈40% of total SNA in R+A+mice. The significant contribution of the direct ganglionic action of Ang II in R+A+mice likely reflects both increased levels of Ang II and upregulation of AT1receptors in sympathetic ganglia.

ISSN:0194-911X    

出版商:OVID    

年代:2004

数据来源: OVID

摘要:

Abstract—In the coarctation hypertension model, we showed both dissociation of plasma renin activity from cardiovascular-induced effects and the reversal of hypertension-induced responses by losartan. In this study, we investigated the effects of hypertension on the expression of brain renin-angiotensin system components and the simultaneous functional responses and effects of long-term angiotensin II (AT) receptor blockade on these responses. Rats were given vehicle or losartan for 9 days and subjected to subdiaphragmatic aortic constriction or sham surgery after 4 days of treatment. On the fifth postsurgical day, pressure and heart rate were measured in the conscious state; the brain was perfused and removed afterward. Sequential slices of brainstem were hybridized with35S-oligodeoxynucleotide probes for angiotensinogen, AT1A, and AT1Breceptors and processed for autoradiography and densitometry. In vehicle-treated rats, hypertension was accompanied by tachycardia and marked increments in angiotensinogen and AT1AmRNA expression in the cardiovascular system–controlling brainstem areas. In the nucleus tractus solitarii, AT1Adensity was correlated with both pressure and heart rate values (P<0.01), whereas angiotensinogen levels were correlated with pressure only (P<0.05). Losartan did not change the pressure of hypertensive rats (142±4 versus 146±2 mm Hg, losartan versus vehicle) and the hypertension-induced angiotensinogen mRNA expression but did block both tachycardic response and hypertension-induced AT1AmRNA expression. Hypertension and losartan did not change AT1BmRNA expression. The hypertension-induced positive feedback on angiotensinogen and AT1AmRNA expression supports the concept of a permissive role for brain angiotensin II in orchestrating circulatory responses during the development of hypertension. These data also explain the efficacy of long-term AT1receptor blockade to reverse hypertension-induced effects.

ISSN:0194-911X    

出版商:OVID    

年代:2004

数据来源: OVID

摘要:

Abstract—We have previously shown that a decrease in hypothalamic gamma adducin (&ggr;-adducin) is associated with hypertension in the spontaneously hypertensive rat (SHR). In view of many inherent issues with SHR, our objective in the present study was to provide proof of this concept with the use of 2 nongenetic rat models of hypertension. Subcutaneous angiotensin II (Ang II) infusion for 2 weeks (55 ng/kg per day) resulted in an increase in blood pressure (BP) of 18 mm Hg. This was associated with a 70% decrease in hypothalamic &ggr;-adducin. Concomitant administration of losartan attenuated the development of hypertension and a decrease in &ggr;-adducin. Deoxycorticosterone acetate salt-induced hypertension also caused a 70% decrease in hypothalamic &ggr;-adducin. Finally, neuronal cultures from neonatal rat brains were incubated with 100 nmol/L Ang II for 4 hours to mimic the in vivo Ang II infusion rat model. This chronic incubation with Ang II resulted in a 60% decrease in the neuronal &ggr;-adducin. Taken together, these observations strengthen our hypothesis that a decrease in hypothalamic &ggr;-adducin is linked to hypertension.

ISSN:0194-911X    

出版商:OVID    

年代:2004

数据来源: OVID

摘要:

Abstract—This study tested the hypothesis that depressor responses caused by tempol are not associated with reductions in vascular O2−levels in urethane-anesthetized deoxycorticosterone acetate (DOCA)-salt hypertensive rats. We compared the effects of intravenous (IV) administration of tempol, apocynin, superoxide dismutase-polyethylene glycol (PEG-SOD), and SOD on mean arterial blood pressure (MAP), heart rate (HR), and renal sympathetic nerve activity (RSNA). In DOCA-salt rats, tempol (30 to 300 &mgr;mol/kg) dose-dependently decreased RSNA, MAP, and HR. Tempol (300 &mgr;mol/kg) decreased MAP from 140±5 to 83±4 mm Hg (P<0.05). HR decreased from 435±15 to 390±12 bpm (P<0.05). RSNA was reduced by 54%±6% from baseline. However, in the same rats, tempol did not reduce dihydroethidium-induced fluorescent signals in the aorta and vena cava. Apocynin (200 &mgr;mol/kg) did not lower MAP (142±5 mm Hg versus 140±6 mm Hg) or HR (428±15 bpm versus 420±13 bpm) and apocynin did not potentiate depressor responses caused by tempol. PEG-SOD (10 000 U/kg, bolus or 5000 U/kg bolus followed by a 30-minutes infusion of 500 U/kg/min) or SOD (25 000 U/kg, bolus or 10 000 U/kg bolus followed by a 30-minutes infusion of 1000 U/kg per minute) did not alter MAP or HR. It is concluded that depressor responses and decreases in HR and RSNA caused by acute tempol treatment are caused by direct sympathetic nerve activity inhibition that is not accompanied by SOD-mimetic action in the aorta or vena cava.

ISSN:0194-911X    

出版商:OVID    

年代:2004

数据来源: OVID

摘要:

Abstract—To determine the role of endogenous superoxide (O2−) in the kidney, we assessed renal hemodynamics and excretory function in gp91PHOX(a NAD(P)H oxidase subunit) gene knockout (KO) mice and compared these findings with those of wild-type (WT) strain C57BL/6 mice. Renal blood flow (RBF) and glomerular filtration rate (GFR) were determined by PAH and inulin clearances respectively in anesthetized mice (n=8 in each group). There were higher baseline RBF (4.3±0.4 versus 2.5±0.2 mL/min per gram;P<0.002) and lower renal vascular resistance (RVR) (16±1.4 versus 29±2.3 mm Hg/mL/min per gram;P<0.0001) in KO compared with WT without a significant difference in mean arterial pressure (MAP) (67±2 versus 71±2 mm Hg) and GFR (0.66±0.09 versus 0.73±0.05 mL/min per gram) between the strains. Intravenous infusion of angiotensin II (Ang II) (2 ng/min per gram of body weight) for 30 minutes caused a lesser degree of decreases in RBF (−8% versus −33%) and of increases in RVR (+73% versus +173%) in KO compared with WT. GFR was increased (43%) in KO but not in WT during Ang II infusion. Urinary excretion of nitrate/nitrite was higher in conscious KO (n=5) than in WT (n=5), indicating an increase in nitric oxide bioavailability that could be the cause of high RBF and low RVR in KO. These data indicate that gp91PHOX, a subunit of NAD(P)H oxidase, plays a regulatory role in the maintenance of renal vascular tone. These results also suggest that the mechanism of Ang II-mediated renal vascular action involves concomitant generation of O2−.

ISSN:0194-911X    

出版商:OVID    

年代:2004

数据来源: OVID

摘要:

Abstract—The effects of NaCl, glucose, and thyroid hormone on the production of superoxide (O2·−) within the renal medulla of Sprague-Dawley rats were examined. Responses of intracellular superoxide [O2·−]iin isolated medullary thick ascending limbs (mTALs) were studied using real-time fluorescent microscopy with measurement of the dehydroethidium (DHE) to ethidium (Eth) conversion ratio (Eth/DHE ratio unit). The results demonstrated that elevations of extracellular NaCl (from 152 to 252 mmol/L), d-glucose (from 5 to 25 mmol/L), and triiodo-thyronine (T3; 10 &mgr;mol/L) significantly increased [O2·−]ilevels. Preincubation with superoxide scavenger 4,5-dihydroxy-1,3-benzene-disulfonic acid (1 mmol/L) significantly inhibited these responses. Stimulation with equamolar amounts of choline chloride or l-glucose failed to increase [O2·−]i, indicating that these O2·−responses were not determined by changes in osmolality. The responses to NaCl, d-glucose, and T3 were abolished by pretreatment with the Na+/K+-ATPase pump inhibitor ouabain (4 mmol/L) and with Na+/H+-exchanger inhibitor dimethylamiloride (100 &mgr;mol/L). We conclude that elevations of extracellular NaCl, d-glucose, or T3 levels can activate both the Na+/K+-ATPase pump and Na+/H+exchanger in mTAL, which, in turn, is associated with increased intracellular concentrations of superoxide.

ISSN:0194-911X    

出版商:OVID    

年代:2004

数据来源: OVID

摘要:

Abstract—We tested the hypothesis that the status of NO synthesis influences the renal heme-heme oxygenase system. Studies were conducted in untreated rats and rats treated with the NO synthesis inhibitorNG-nitro-l-arginine methyl ester for 2 days. Treated and untreated rats were contrasted in terms of renal expression of heme oxygenase-1 and -2, renal carbon monoxide (CO)-generating activity, and urinary CO concentration and excretion rate. Heme oxygenase-1 and -2 proteins were similarly expressed in the kidneys of untreated and treated rats. In contrast, the NADPH-dependent component of the CO-generating activity of renal homogenates incubated with heme (a measure of heme oxygenase activity) was higher (P<0.05) in kidneys from rats treated with the NO synthesis inhibitor relative to corresponding data in untreated rats (1015±95 versus 379±111 pmol CO/mg per hour). Similarly, relative to corresponding data in untreated rats, rats treated with the NO synthesis inhibitor displayed increased (P<0.05) urinary CO concentration (920±174 versus 2286±472 pmol/mL) and urinary CO excretion (4.7±0.4 versus 14.3±2.7 pmol/min). This study demonstrates that NO synthesis inhibition upregulates the urinary concentration and excretion rate of CO, and the HO-dependent generation of CO by renal homogenates, without affecting the expression of renal heme oxygenase isoforms. Our findings imply that endogenous NO is an inhibitory regulator of renal CO generation by HO.

ISSN:0194-911X    

出版商:OVID    

年代:2004

数据来源: OVID