摘要:

Vascular smooth muscle cells (VSMCs) from spontaneously hypertensive rats (SHR) show the synthetic phenotype and exaggerated growth in comparison with VSMCs from normotensive Wistar-Kyoto (WKY) rats. We investigated genes associated with the synthetic phenotype and exaggerated growth of VSMCs from SHR by microarray. Expression of 1300 transcripts was evaluated by microarray with total mRNA extracted from mid-layer aortic smooth muscle of 3-week-old SHR/Izumo and WKY/Izumo rats. mRNAs encoding sodium-dependent neurotransmitter transporter, epidermal growth factor precursor, EEF2, leptin receptor long-isoform b, clathrin assembly protein short form, and preprocomplement 3 (pre-pro-C3) were expressed only in aortic smooth muscle from SHR by microarray and by reverse-transcription polymerase chain reaction analysis. Pre-pro-C3 mRNA was detected only in cultured VSMCs from SHR. Exogenous C3 changed VSMCs to the synthetic phenotype. Antisense oligodeoxynucleotides (ODN) to C3 reduced the higher level of DNA synthesis in VSMCs from SHR. Antisense ODN to C3 increased expression of SM22&agr; mRNA and decreased expression of osteopontin and matrix Gla mRNAs. It also decreased expression of growth factor mRNAs in VSMCs from SHR. In conclusion, we have shown that C3, independent of other complement molecules, has direct effects on the phenotype of VSMCs and stimulates growth of these cells. C3 is produced only by VSMCs from SHR. Therefore, C3 may be the gene underlying the synthetic phenotype and exaggerated growth of VSMCs from SHR. C3 may be a new target for the treatment of hypertension.

ISSN:0194-911X    

出版商:OVID    

年代:2004

数据来源: OVID

摘要:

The ECG strain pattern of lateral ST depression and T-wave inversion is a marker for left ventricular hypertrophy (LVH) and adverse prognosis in population studies. However, whether ECG strain is an independent predictor of cardiovascular (CV) morbidity and mortality in the setting of aggressive antihypertensive therapy is unclear. ECGs were examined at study baseline in 8854 hypertensive patients with ECG LVH who were treated in a blinded manner with atenolol- or losartan-based regimens. Strain was defined by the presence of a downsloping convex ST segment with an inverted asymmetrical T wave opposite to the QRS axis in leads V5and/or V6and was present in 971 patients (11.0%). The Losartan Intervention For Endpoint reduction in hypertension (LIFE) study composite end point of CV death or nonfatal myocardial infarction or stroke occurred in 1035 patients (11.7%). In Cox analyses adjusting only for treatment effect, ECG strain was a significant predictor of CV death (hazard ratio [HR] 2.26, 95% confidence interval [CI] 1.78 to 2.86), fatal/nonfatal myocardial infarction (HR 2.16, 95% CI 1.67 to 2.80), fatal/nonfatal stroke (HR 1.76, 95% CI 1.39 to 2.21), and the composite CV end point (HR 1.99, 95% CI 1.70 to 2.33). After further adjusting for standard CV risk factors, baseline blood pressure, and severity of ECG LVH, ECG strain remained a significant predictor of CV mortality (HR 1.53, 95% CI 1.18 to 2.00), myocardial infarction (HR 1.55, 95% CI 1.16 to 2.06), and the composite CV end point (HR 1.33, 95% CI 1.11 to 1.59). Thus, ECG strain is a marker of increased CV risk in hypertensive patients in the setting of aggressive blood pressure lowering, independent of baseline severity of ECG LVH.

ISSN:0194-911X    

出版商:OVID    

年代:2004

数据来源: OVID

摘要:

A unique interaction between the influences of body mass index and blood pressure on left ventricular mass index and geometry may contribute to the higher prevalence of left ventricular hypertrophy in African Americans. This cross-sectional study assessed separate and joint influences of body mass index and blood pressure on left ventricular mass index and geometry in 1729 African American participants of the Atherosclerotic Risk in Communities Study. The association between both left ventricular mass index and relative wall thickness and body mass index in each blood pressure category and between these variables and blood pressure in each body mass index category was assessed adjusting for age, diabetes status, hypertension medication, and smoking status. We found that left ventricular hypertrophy and concentric geometry were highly prevalent and that body mass index and blood pressure were independently associated with left ventricular mass index. The adjusted association between blood pressure and left ventricular mass index was stronger with higher body mass index categories; however, there was no significant interaction suggesting merely an additive relationship (not synergistic/multiplicative as tested for in the interaction analysis). Although relative wall thickness was greater with higher categories of body mass index and blood pressure, the mean difference in relative wall thickness between body mass index and blood pressure categories was not statistically significant. The effect on left ventricular geometry as measured by relative wall thickness supports the theory that there is a pathophysiological component in the mechanism of hypertrophy.

ISSN:0194-911X    

出版商:OVID    

年代:2004

数据来源: OVID

摘要:

Regression of hypertensive left ventricular hypertrophy (LVH) is associated with improved prognosis. The aim of this trial was to compare the effects of irbesartan versus atenolol on LVH in subjects with essential hypertension. Because electrocardiographic and echocardiographic parameters of LVH carry disparate prognostic information, both methods were applied in this trial. In the randomized, double-blind, multicenter trial CardioVascular Irbesartan Project, 240 patients with essential hypertension were treated with irbesartan or atenolol for 18 months. Voltage criteria used for LVH were Sokolow index, Cornell index, Cornell voltage×QRS duration product and Lewis index. In parallel, left ventricular mass (LVM) was determined by 2-dimensional guided M-mode echocardiography. After 6 and 18 months, reductions of LVM and voltage criteria for LVH were only found in subjects treated with irbesartan. However, a reduction of LVM was only detectable in subjects within the highest quartile of baseline LVM but not overall. In contrast, reductions of voltage criteria for LVH were detectable after 6 and 18 months even within commonly used normal limits. In conclusion, treatment of hypertension with irbesartan resulted in a significant reduction in the voltage criteria for LVH, although an effect on LVM was only seen in subjects with high baseline LVM. In contrast, atenolol did not lead to reductions in electrocardiographic or echocardiographic parameters of LVH. Because voltage criteria for LVH have been shown to predict cardiovascular outcome independently from LVM, we suggest that both methods should be used to accurately assess the benefits of antihypertensive treatment.

ISSN:0194-911X    

出版商:OVID    

年代:2004

数据来源: OVID

摘要:

Hypertension and type 2 diabetes are associated with increased aortic pulse wave velocity (PWV), a measure of aortic stiffness and a powerful risk factor for cardiovascular events. The association of hypertension with type 2 diabetes may obscure the degree to which diabetes rather than hypertension contributes to an elevated PWV. The objective of this study was to determine whether the presence of type 2 diabetes is associated with an elevated PWV compared with nondiabetic subjects matched for mean arterial blood pressure. PWV was determined by measuring carotid to femoral transit time using applanation tonometry in 186 subjects (104 women) with (n=93) and without (n=93) type 2 diabetes. Diabetic and nondiabetic subjects were matched for age and mean arterial pressure (to ±5 years and 5 mm Hg, respectively). PWV was strongly correlated with age and mean arterial blood pressure (R=0.59 and 0.29 respectively, eachP<0.0001). PWV increased significantly more with age in women with diabetes (slope of regression line±SE: 0.19±0.03 m · s−1· year−1) than in nondiabetic women (0.08±0.02 m · s−1· year−1,P<0.01 for difference). In men, however, the age-related increase in PWV was similar in diabetic (0.15±0.03 m · s−1· year−1) and nondiabetic subjects (0.13±0.03 m · s−1· year−1, P=NS). The interaction of diabetic status with age and with sex was significant (P=0.01). Type 2 diabetes is associated with a greater age-related stiffening of the aorta in women compared with men, and this is not explained by hypertension.

ISSN:0194-911X    

出版商:OVID    

年代:2004

数据来源: OVID

摘要:

We examined if there is systemic vascular inflammation and neutrophil infiltration in women with preeclampsia. Resistance-sized vessels (10 to 200 μm) of subcutaneous fat were evaluated from normal nonpregnant women, normal pregnant women, and preeclamptic women. Immunohistochemical staining was performed for: (1) interleukin-8 (IL-8), a potent neutrophil chemokine; (2) intercellular adhesion molecule-1 (ICAM-1; CD54), an endothelial cell adhesion molecule; and (3) CD66b, a neutrophil antigen. Vessels of preeclamptic patients had intense IL-8 staining in the endothelium and vascular smooth muscle, as compared with little or no staining for normal pregnant and normal nonpregnant patients. ICAM-1 was expressed on the endothelium of all patient groups. In preeclamptic patients, ICAM-1 was also expressed on vascular smooth muscle. Vessels of preeclamptic patients had significantly more CD66b staining of neutrophils than did normal pregnant or normal nonpregnant patients. There were significantly more vessels stained, more vessels with neutrophils flattened and adhered to endothelium, more vessels with neutrophils infiltrated into the intima, and more neutrophils per vessel. In conclusion, in women with preeclampsia, there was significant infiltration of neutrophils into maternal systemic vasculature associated with inflammation of the vascular smooth muscle indicated by increased expression of IL-8 and ICAM-1. Neutrophil infiltration provides a reasonable explanation for endothelial and vascular smooth muscle dysfunction in preeclampsia because neutrophils produce toxic substances, which may explain clinical symptoms.

ISSN:0194-911X    

出版商:OVID    

年代:2004

数据来源: OVID

摘要:

Postmenopausal estrogen deficiency increases the incidence of cerebrovascular disease. However, hormone replacement therapy is associated with an increased cardiovascular risk. Tamoxifen is a selective estrogen receptor modulator with estrogenic effects on cardiovascular risk factors, but its long-term impacts on cerebral vasculature are unknown. We hypothesized that chronic 17β-estradiol or tamoxifen treatment exerted similar effects in reducing cerebrovascular tension in ovariectomized rats. We therefore determine whether (1) chronic 17β-estradiol treatment could influence vasomotor activities, (2) chronic tamoxifen therapy could exert an estrogen-like or estrogen-antagonistic effect, and (3) acute exposure to estrogen could mimic the effect of 17β-estradiol. Isometric tension was measured in cerebral arteries from female rat groups: control, ovariectomy, ovariectomy plus 17β-estradiol treatment, ovariectomy plus tamoxifen treatment, and ovariectomized rats treated with tamoxifen and 17β-estradiol. Ovariectomy enhanced cerebrovascular contractions to endothelin-1 or CaCl2, but not to U46619 or phenylephrine. 17β-Estradiol therapy reversed these effects. Chronic tamoxifen treatment exerted estrogen-like actions by reversing ovariectomy-induced enhancement of vessel tone without antagonizing the effect of chronic 17β-estradiol treatment. Ovariectomy enhanced the relaxing potency of nicardipine, and 17β-estradiol treatment prevented this effect. Acute exposure to 10−9mol/L 17β-estradiol or 10−8mol/L tamoxifen did not modulate contractions in rings from nonoperated female rats. In conclusion, ovariectomy differentially enhances agonist-induced cerebrovascular tone, an effect that was reversed by estrogen therapy. Tamoxifen does not act as an estrogen antagonist; instead, it functions as an estrogen agonist during estrogen deficiency. Thus, tamoxifen may confer beneficial effects similar to estrogen in cerebrovascular vessels.

ISSN:0194-911X    

出版商:OVID    

年代:2004

数据来源: OVID

摘要:

Embryo cross-transplantation and cross-fostering between spontaneously hypertensive rats (SHR) and normotensive rats (WKY) suggest that perinatal environment modulates the genetically determined phenotype. In SHR the balance between NO and reactive oxygen species (ROS) is disturbed. We hypothesized that increasing NO and diminishing ROS in perinatal life would ameliorate hypertension in adult SHR. Pregnant SHR and WKY and their offspring received L-arginine plus antioxidants (vitamin C, vitamin E, and taurine) during the last 2 weeks of pregnancy and then until either 4 or 8 weeks after birth. Systolic blood pressure (SBP) and urinary excretion of protein, nitrates (NOx), and thiobarbituric acid reactive substances (TBARS) were measured. At 48 weeks of age rats were euthanized for glomerular counts. Perinatal supplements reduced SBP persistently in SHR and prevented the SBP increase observed in aging WKY. Initially NOxexcretion was lower and TBARS excretion higher in SHR than WKY. There was a direct effect on NOxexcretion in supplemented pregnant SHR and their offspring, but no increase was observed after stopping the supplements. TBARS excretion was only depressed up to 14 weeks by the supplements despite persistent differences in SBP. Consistent effects on nephron number were absent. Mild proteinuria, present in control SHR at 48 weeks, was prevented in all supplemented rats. Perinatal supplementation of NO substrate and antioxidants results in persistent reduction of SBP and renal protection in SHR, although effects on NOxand TBARS were only transient. This suggests a critical role for perinatal pro- and antioxidant balance in programming BP later in life.

ISSN:0194-911X    

出版商:OVID    

年代:2004

数据来源: OVID

摘要:

Kidney function is critical in determining the level of arterial pressure and in the pathogenesis of hypertension. Important evidence comes from studies in which the level of blood pressure is dictated by the donor when kidneys are transplanted between genetically hypertensive and normotensive rats. We have hypothesized that pharmacotherapy modifies specific properties of the kidney, particularly the vasculature, such that after kidney transplantation, there are persistent changes in the level of arterial pressure. Consistent with previous studies, a 2-week aggressive treatment of adult (15 weeks) spontaneously hypertensive rats with an angiotensin-converting enzyme inhibitor (enalapril) combined with a low-salt diet induced a persistent change in the kidney and a decrease in arterial pressure (18%). These persistent changes in arterial pressure could be completely transferred to untreated adult spontaneously hypertensive rats by kidney transplantation (ie, pressure in untreated rats was decreased after transplantation of a kidney donated from a previously treated rat). Further, the importance of kidney-specific changes was demonstrated by finding that the treatment-induced lowering of arterial pressure was completely reversed by transferring an untreated kidney into a previously treated rat. The specific treatment-induced changes to the kidney included a decrease in structurally based renal vascular resistance that was similar to the persistent lowering of arterial pressure. These data provide evidence for a link between the treatment-induced changes in kidney vascular structure and the persistent lowering of arterial pressure. The findings also suggest that a key pharmacotherapeutic target in hypertension should be kidney-specific changes, such as renal vascular structure.

ISSN:0194-911X    

出版商:OVID    

年代:2004

数据来源: OVID

摘要:

During early development of hypertension, the spontaneously hypertensive rat (SHR) demonstrates increased proximal tubule sodium reabsorption. Our previous observations of reduced Na+, K+-ATPase catalytic α1 and γ subunit transcript abundance in SHR proximal tubule led us to test the hypothesis that increased proximal tubule sodium reabsorption may be attributable to altered subunit protein abundance, post-translational modification, or a shift in subcellular α1 and γ distribution toward the basolateral membrane. We now extend previous gene expression studies by analyzing total cellular α1 and γ protein abundance in proximal tubule from SHR compared with matched Wistar–Kyoto (WKY) controls. We also used sucrose density-gradient centrifugation to isolate basolateral, early, and late endosomal membrane–enriched fractions as well as cell surface biotinylation to test the hypothesis of altered subunit subcellular distribution in the SHR proximal tubule. At 4 weeks of age, significantly greater amounts of α1 were present in basolateral membrane–enriched fractions of SHR than WKY (21.1±1.8% versus 12.3±1.8%;P< 0.005), and there was a concomitant reduction of α1 in late endosomal membrane–enriched fractions of SHR (63.3±2.7% versus 74.8±4.3%;P< 0.05). This finding was confirmed in cell surface biotinylation studies that showed higher α1 (1.45±0.1-fold greater;P< 0.05) and γ-subunit (3.48±0.7-fold greater;P< 0.01) abundance in 4-week-old SHR proximal tubule plasma membrane compared with matched WKY samples. These studies support the hypothesis that development of hypertension in SHR may involve an altered subcellular distribution of proximal tubule Na+,K+-ATPase subunits.

ISSN:0194-911X    

出版商:OVID    

年代:2004

数据来源: OVID