摘要:

Most existing risk prediction models have not considered the joint contribution of systolic and diastolic blood pressure to cardiovascular risk, and some suggest that there are thresholds below which further reductions of blood pressure yield no additional benefit. We developed multivariate risk prediction models that quantify the risk associated with both systolic and diastolic blood pressure and that can be used to infer the benefits of antihypertensive therapy in populations. Two large clinical trial cohorts, the Physicians’ Health Study, composed of 22 071 males (mean age, 53.2 years; median follow-up, 13.0 years), and the Women’s Health Study, composed of 39 876 females (mean age, 53.8 years; median follow-up, 6.2 years), were used to develop gender-specific predictive models via Cox regression. End points included myocardial infarction, stroke, coronary artery bypass, angioplasty, and cardiovascular death. Risk reduction estimates were derived by computing reductions associated with incremental lowering of systolic and diastolic blood pressures. In both populations, lower levels of blood pressure predicted lower event rates, with no evidence of a plateau or a J-shaped curve. In males, both systolic and diastolic blood pressures were significantly associated with events (P<0.001), whereas in females, only systolic blood pressure (P<0.001) predicted outcome after multivariate adjustment. Correction for measurement error in blood pressure increased risk estimates by ≈50%. Differences in systolic blood pressure yielded greater relative risk reductions than did differences in diastolic blood pressure in a combined population of males and females. These predictive models may be useful for risk estimation associated with hypertension in similar populations and may also be used to infer the benefits of antihypertensive therapy.

ISSN:0194-911X    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Fawn-Hooded rats possess an increased risk to develop glomerular damage. Both an impaired control of preglomerular resistance and an elevated postglomerular resistance have been implicated. In the present study, we directly assessed the myogenic reactivity of distal interlobular arteries and afferent arterioles from hypertensive and normotensive Fawn-Hooded rats compared with Sprague-Dawley and Wistar rats, which are known to be resistant for developing renal disease. Pressure-response curves were made in isolated perfused hydronephrotic kidneys from these rats. In addition, increasing concentrations of angiotensin II were added to the perfusate to determine the reactivity of interlobular arteries, afferent arterioles, and efferent arterioles to this peptide. Preglomerular vessels from hypertensive and normotensive Fawn-Hooded rats exhibited an impaired reactivity to both pressure and angiotensin II compared with that of Sprague-Dawley and Wistar rats. Basal efferent arteriolar diameters were similar among the 4 strains of rat. In addition, efferent arterioles from hypertensive and normotensive Fawn-Hooded rats displayed a reduced sensitivity to angiotensin II. Our observations demonstrate that in Fawn-Hooded rats, 2 components of preglomerular resistance control are impaired: the myogenic and the angiotensin II response. In addition, efferent arteriolar reactivity to angiotensin II is not elevated but lowered in these rats. Therefore, a deficit in preglomerular resistance control is the most important intrinsic factor involved in the increased susceptibility of Fawn-hooded rats to develop renal disease.

ISSN:0194-911X    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Hypertension induced by long-term infusion of angiotensin II (Ang II) is associated with augmented intrarenal Ang II levels to a greater extent than can be explained on the basis of the circulating Ang II levels. Although part of this augmentation is due to AT1receptor–dependent internalization, the intracellular compartments involved in this Ang II accumulation remain unknown. In the present study, we sought to determine whether Ang II trafficking into renal cortical endosomes is increased during Ang II hypertension, and if so, whether the AT1receptor antagonist, candesartan, prevents this accumulation. Compared with controls (n=12; 114±2 mm Hg), Ang II-infused rats (n=12; 80 ng/kg/min, SC, for 13 days) developed hypertension with systolic blood pressure rising to 185±4 mm Hg by Day 12. In Ang II hypertensive rats, plasma renin activity was suppressed, whereas plasma and kidney Ang II levels were increased by 3-fold (348±58 versus 119±16 fmol/mL) and 2-fold (399±39 versus 186±26 fmol/g). Intracellular endosomal Ang II levels were increased by more than 10-fold (1100±283 versus 71±12 fmol/mg protein), whereas intermicrovillar cleft Ang II levels were increased by more than 2-fold (88±22 versus 37±7 fmol/mg protein). Flow cytometric analysis detected significant increases in AT1Areceptor antibody binding in endosomal and intermicrovillar clefts of Ang II–infused rats. The hypertension induced by Ang II was prevented in rats treated concurrently with candesartan (2 mg/kg/d, 119±3 mm Hg). Candesartan treatment (n=8) also prevented increases in kidney (215±19 fmol/g), endosomal (96±29 fmol/mg protein), and intermicrovillar cleft Ang II levels (11±2 fmol/mg protein). These results indicate that there is substantial intracellular accumulation of angiotensin peptides in renal cortical endosomes during Ang II–dependent hypertension via an AT1receptor–mediated process.

ISSN:0194-911X    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Various renal insults result in induction of heat shock protein (HSP) expression within the kidney. Some of the HSPs induced in that manner are postulated to have renoprotective effects via either chaperoning actions or antioxidative properties. We have previously reported that long-term angiotensin (Ang) II administration induces the expression of renal HSP32, also known as heme oxygenase-1 (HO-1). Here, we investigated the regulation of expression and localization of other HSPs, including HSP70, HSP25, and &agr;B-crystallin, in the kidney of rats undergoing long-term administration of Ang II (0.7 mg · kg−1· d−1). Immunoblot analysis demonstrated that Ang II increased renal expression of HSP70 and HSP25, as well as HO-1, but that expression of &agr;B-crystallin was unaffected by this treatment. The Ang II–induced increase in renal HSP70 and HSP25 was dependent on the angiotensin type 1 receptor activation but not on hypertension per se. Immunohistochemistry revealed that HSP70 and HSP25 were expressed in the medullar regions and in the renal arterial wall in the kidney of control rats. After Ang II infusion, signals for HSP70, HSP25, and HO-1 proteins increased in intensity in the endothelium and medial smooth muscle of the renal artery. In addition, all of these HSPs were induced in proximal renal tubular epithelial cells from the same segments, suggesting that similar mechanisms are responsible for upregulating these HSPs. Our data show that Ang II infusion induces renal HSP70 and HSP25, as well as HO-1, and that Ang II can induce expression of these HSPs in renal cells in a pressor-independent manner.

ISSN:0194-911X    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Previous studies have indicated that angiotensin II (Ang II) concentrations in renal interstitial fluid are much higher than plasma levels. In the present study, we performed experiments to explore renal interstitial fluid concentrations of Ang I and Ang II further and to determine whether these levels are altered by acute arterial infusion of an ACE inhibitor (enalaprilat) or by volume expansion. Microdialysis probes (molecular weight cutoff point: 30 000 Da) were implanted in the renal cortex of anesthetized rats and were perfused at a rate of 2 &mgr;L/min. Using relative equilibrium rates, the basal renal interstitial fluid Ang II concentration averaged 3.07±0.43 nmol/L, a value much higher than the plasma Ang II concentration of 107±8 pmol/L (n=7). Interstitial fluid Ang I concentrations (0.84±0.04 nmol/L) were consistently lower than the Ang II concentrations but higher than the plasma Ang I concentrations (112±14 pmol/L). Intra-arterial infusion of enalaprilat (7.5 &mgr;mol/kg/min, n=5) for 120 minutes resulted in a significant decrease in mean arterial pressure (from 114±4 to 68±4 mm Hg) along with reductions in plasma and renal ACE activity (by −99% and −52%, respectively). Enalaprilat resulted in a significant increase in plasma Ang I from 133±21 to 1167±328 pmol/L and a decrease in plasma Ang II from 110±12 to 67±9 pmol/L. During enalaprilat infusion, interstitial fluid concentration of Ang I was significantly increased from 0.78±0.06 to 0.97±0.08 nmol/L; however, Ang II concentrations were not altered significantly (3.67±0.28 versus 3.67±0.25 nmol/L). Acute volume loading with Ringer’s solution containing 1% bovine serum albumin at a rate of 150 &mgr;L/min for 2 hours (6% to 7% of body weight) lowered plasma concentrations of Ang I from 110±23 to 16±2 pmol/L and Ang II from 100±23 to 36±6 pmol/L; however, renal interstitial fluid concentrations of Ang I and Ang II were not altered significantly during volume expansion (Ang I, from 0.77±0.05 to 0.69±0.03 nmol/L; Ang II, from 3.76±0.43 to 3.59±0.39 nmol/L, n=5). These data indicate that renal interstitial fluid concentrations of Ang I and Ang II are substantially higher than the corresponding plasma concentrations. Furthermore, the fact that the high interstitial fluid concentrations of Ang II are not responsive to acute ACE inhibition or volume expansion suggests the compartmentalization and independent regulation of renal interstitial fluid Ang II.

ISSN:0194-911X    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Chronic renal failure (CRF) is associated with oxidative stress which promotes production of reactive carbonyl compounds and lipoperoxides leading to the accumulation of advanced glycation and lipoxidation end products. Reactive oxygen species (ROS) avidly reacts with nitric oxide (NO) producing cytotoxic reactive nitrogen species capable of nitrating proteins and damaging other molecules. This study tested the hypothesis that CRF results in enhanced ROS-mediated NO inactivation and protein nitration which can be ameliorated with antioxidant therapy. Male Sprague Dawley rats were randomized to CRF (5/6 nephrectomy) and sham-operated controls and fed either a regular diet (vitamin E, 40 U/Kg food) or an antioxidant-fortified diet (vitamin E, 5000 U/Kg food) for 6 weeks. Blood pressure, plasma malondialdehyde (MDA), tissue NO synthase (NOS) isoforms, tissue nitrotyrosine (the footprint of NO interaction with ROS), and vascular tissue NO production were determined. CRF resulted in marked elevations of blood pressure, plasma MDA, and tissue nitrotyrosine abundance, but did not change plasma L-arginine level. This was coupled with depressed vascular tissue NO production and reduced immunodetectable NOS proteins in the vascular, renal, and cardiac tissues. Antioxidant therapy ameliorated the CRF-induced hypertension, improved vascular tissue NO production, lowered tissue nitrotyrosine burden, and reversed downregulations of NOS isoforms. In contrast, antioxidant therapy had no effects in the controls. CRF is associated with oxidative stress which promotes NO inactivation by ROS leading to functional NO deficiency, hypertension, and widespread accumulation of protein nitration products. Amelioration of oxidative stress by high-dose vitamin E enhances NO availability, improves hypertension, lowers protein nitration products, and increases NOS expression and vascular NO production in CRF animals.

ISSN:0194-911X    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

We previously showed that CGP 42112 (an angiotensin type 2 [AT2] agonist) markedly reduces catecholamine biosynthesis by decreasing cGMP production mediated by AT2, a subtype of Ang II receptor that is dominantly expressed in cultured porcine chromaffin cells. To elucidate the relationship of the 2 types of Ang II receptors, angiotensin type 1 (AT1) and AT2, in the synthesis of catecholamine in adrenal medullary cells, we have examined the effect of Ang II plus CV-11974 (an AT1antagonist that selectively simulates AT2stimulation) and the effect of Ang II plus PD 123319 (an AT2antagonist that selectively simulates AT1stimulation) on catecholamine synthesis. We found that Ang II reduced cGMP production via AT2, in a similar manner to that found with CGP 42112. Stimulation of AT1significantly upregulated protein kinase C activity. Tyrosine hydroxylase (TH) is a rate-limiting enzyme involved in the biosynthesis of catecholamine, and this catecholamine synthesis depends both on TH enzyme activity and on the levels of TH protein after TH gene transcription. We found that AT2stimulation significantly inhibited TH enzyme activity, whereas AT1stimulation significantly upregulated TH enzyme activity. The stimulatory effect of AT1was completely inhibited by Ro-32-0432 (a protein kinase C inhibitor) and PD 98059 (a MAP kinase kinase-1 [MEK-1] inhibitor). Pretreatment of cells with either 8-Br-cGMP (a membrane-permeable cGMP analog) or Zaprinast (a phosphodiesterase inhibitor) abolished the inhibitory effect of AT2on TH enzyme activity, indicating that the stimulatory effect of AT2may be mediated through a reduction in cGMP concentration. Similar to the effect on TH enzyme activity, AT2stimulation significantly reduced TH mRNA and protein levels and net catecholamine content below basal levels, whereas AT1stimulation increased them. We confirmed these findings by gel mobility shift assay. Our results show that stimulation of AT2reduces catecholamine biosynthesis via a decrease in cGMP levels. In contrast, stimulation of AT1stimulates catecholamine biosynthesis through activation of PKC. Thus, we conclude that AT1and AT2have counter-regulatory roles in the synthesis of catecholamine in adrenal medullary chromaffin cells.

ISSN:0194-911X    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

We investigated the extent of oxidative stress evoked in the hypertensive rat by measuring plasma levels of 8-epi-prostaglandin F2&agr;(8-epi-PGF2&agr;), a marker of in vivo oxidative stress. Administration of angiotensin (Ang) II and norepinephrine at doses of 0.7 and 2.8 mg · kg−1· d−1, respectively, resulted in similar significant elevations in plasma levels of 8-epi-PGF2&agr;. A 7-day infusion of Ang II at a nonpressor dose, but not norepinephrine at a nonpressor dose, also increased plasma levels of 8-epi-PGF2&agr;. The norepinephrine-induced increase in 8-epi-PGF2&agr;levels could be completely normalized by 3 different classes of antihypertensive drugs: prazosin, an &agr;-adrenergic receptor blocker; hydralazine, a nonspecific vasodilator; and losartan, a specific angiotensin type 1 (AT1) receptor antagonist. This finding suggests that the norepinephrine-induced increase is a pressor-dependent event. In contrast, among these antihypertensive drugs, only losartan was effective in inhibiting the Ang II–induced increase in plasma 8-epi-PGF2&agr;, suggesting that Ang II increases plasma levels of 8-epi-PGF2&agr;in both a pressor-independent and an AT1receptor–dependent manner. In summary, continuous infusion of both Ang II and norepinephrine potently increases plasma levels of 8-epi-PGF2&agr;and thus in vivo oxidative stress. Ang II and norepinephrine seem to induce this increase in 8-epi-PGF2&agr;via mechanisms with different pressor dependencies.

ISSN:0194-911X    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Endothelial dysfunction and inflammation appear to play a major role in the pathogenesis of preeclampsia. We hypothesize that a chronic inflammation in the decidua and placenta during preeclampsia may lead to a local leukocyte activation in this compartment. Venous blood was sampled simultaneously from antecubital and uterine veins during cesarean sections in 30 women with preeclampsia, 29 with uncomplicated pregnancies, and from 17 nonpregnant women. The expression of adhesion molecules and complement-related markers on neutrophils and monocytes was analyzed by flow cytometry. In patients with preeclampsia, neutrophil expression of the integrins CD11a, CD11b, and CD11c and of the complement related markers CD35 and CD59 was significantly higher in samples fromuterinethan fromantecubital veins. No differences were found in nonpregnant women. On monocytes the expression of the Sialyl Lewisxantigen, the integrins CD11a, CD11c, and CD49d, and the complement-related markers CD46 and CD59 was higher in samples fromuterinethan fromantecubital veinsduring preeclampsia, but not in uncomplicated pregnancies, whereas in nonpregnant women CD31 was decreased. Our findings suggest activation of neutrophils and monocytes taking place during the uteroplacental passage in preeclamptic, but not in normal pregnancies. Such a local inflammatory response involving enhanced leukocyte/endothelial interaction may contribute to the pathogenesis of this disorder.

ISSN:0194-911X    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

A body of evidence indicates that the production of adrenomedullin (ADM) in vivo is activated in states of inflammation. Our aim was to characterize the intracellular signaling pathways along which inflammation leads to a stimulation of ADM expression. For this purpose, we characterized the effects of inflammatory cytokines, tumor necrosis factor-&agr; (100 &mgr;g/L), interleukin-1&bgr; (20 &mgr;g/L), and interferon-&ggr; (0.5 U/L) on ADM gene expression in rat aortic vascular smooth muscle cells (AVSMCs). We found that inflammatory cytokines induced a time-dependent 12-fold upregulation of ADM mRNA in AVSMCs that was paralleled by a substantial increase in inducible NO synthase mRNA expression. The stimulatory effect of cytokines on ADM gene expression was attenuated by NO deprivation induced byN&ohgr;-nitro-l-arginine methyl ester (1 mmol/L) and was in part mimicked by the NO donorS-nitroso-N-acetylpenicillamine (100 &mgr;mol/L). The cGMP analog 8-bromo-cGMP (100 &mgr;mol/L) had no effect on ADM gene expression, and inhibition of cGMP production by 1H-oxodiazolo-quinoxalin-1 (ODQ, 200 &mgr;mol/L) was not able to abrogate the increase of ADM mRNA induced by NO donation usingS-nitroso-N-acetylpenicillamine (100 &mgr;mol/L). The significant induction of ADM gene expression by inflammatory cytokines and NO donation was also observed in mesangial cells, endothelial cells, and hepatocytes. These findings suggest that NO is a direct activator of ADM gene expression in a variety of cell types and that inflammatory cytokines stimulate ADM expression via both NO-dependent and -independent mechanisms. The stimulatory effect of NO appears to not be related to the classic guanylate cyclase–cGMP pathway.

ISSN:0194-911X    

出版商:OVID    

年代:2002

数据来源: OVID