摘要:

With advancing age, arterial stiffness and wave reflections increase and elevate systolic and pulse pressures. An elevated central pulse pressure is generally ascribed to increased wave reflection and portends an unfavorable prognosis. Using arterial tonometry, we evaluated central (carotid-femoral) and peripheral (carotid-brachial) pulse wave velocity, amplitudes of forward and reflected pressure waves, and augmentation index in 188 men and 333 women in the Framingham Heart Study offspring cohort who were free of clinical cardiovascular disease, hypertension, diabetes, smoking within the past 12 months, dyslipidemia, and obesity. In multivariable linear regression models, advancing age was the predominant correlate of higher carotid-femoral pulse wave velocity; other correlates were higher mean arterial pressure, heart rate, and triglycerides and walk test before tonometry (modelR2= 0.512,P< 0.001). A similar model was obtained for carotid-brachial pulse wave velocity (modelR2= 0.227,P< 0.001), although the increase with advancing age was smaller. Owing to different relations of age to central and peripheral stiffness measures, carotid-femoral pulse wave velocity was lower than carotid-brachial pulse wave velocity before age 50 years but exceeded it thereafter, leading to reversal of the normal central-to-peripheral arterial stiffness gradient. In this healthy cohort with a minimal burden of cardiovascular disease risk factors, an age-related increase in aortic stiffness, as compared with peripheral arterial stiffness, was associated with increasing forward wave amplitude and pulse pressure and reversal of the arterial stiffness gradient. This phenomenon may facilitate forward transmission of potentially deleterious pressure pulsations into the periphery.

ISSN:0194-911X    

出版商:OVID    

年代:2004

数据来源: OVID

摘要:

Oxidative stress contributes to the pathogenesis of atherosclerosis. p22phox-based NAD(P)H oxidases exist in the vessel wall, acting as important superoxide-generating systems in the vasculature. Some studies have identified reduced atherosclerosis in the presence of the C242TCYBApolymorphism, whereas others have not. Because vascular p22phoxis identical to neutrophil p22phox, we studied the association between the C242T, A640G, and −930A/GCYBApolymorphisms and the quantity of superoxide produced from neutrophils isolated from healthy adults to determine if these polymorphisms had any functional impact on NADPH oxidase function. Neutrophils were isolated from 90 subjects by Percoll density gradient centrifugation. Genotypes were determined by polymerase chain reaction (PCR) and restriction mapping, as well as real-time PCR. The oxidative burst was stimulated with phorbol 12-myristate 13-acetate. Superoxide was quantified using the superoxide dismutase inhibitable oxidation of the spin probe hydroxylamine 1-hydroxy-3-carboxy-pyrrolidine, detected by electron paramagnetic resonance. Superoxide production was significantly affected by the C242T polymorphism, being 8.7±0.7, 7.9±0.6, and 5.9±1.2 μmol/L per minute per 106neutrophils for the C242T CC, CT, and TT genotypes, respectively (P<0.05). In contrast, the A640G and the −930A/Gpolymorphisms did not alter the neutrophil respiratory burst. Phagocytic respiratory burst activity in homozygous individuals with the T allele of the C242TCYBApolymorphism is significantly lower than of wild-type carriers and heterozygous individuals. Because p22phoxexists in both the neutrophil and vessel wall, vascular oxidative stress is likely diminished in individuals with this polymorphism.

ISSN:0194-911X    

出版商:OVID    

年代:2004

数据来源: OVID

摘要:

We examined the effect of different levels of salt intake on the role of aldosterone on cardiac and vascular changes in salt-loaded stroke-prone spontaneously hypertensive rats (SHRSP). Eleven-week-old SHRSP were fed high-salt (4.2% NaCl), normal-salt (0.28%), or low-salt (0.03%) diets with or without eplerenone (100 mg/kg per day, in food) for 5 weeks. A group of high-salt SHRSP was also treated with hydralazine (25 mg/kg per day). Blood pressure increased more in high-salt rats than in other groups (P< 0.001). Eplerenone prevented further blood pressure rise in salt-loaded rats, with little effect on control and low-salt SHRSP. Increased media-to-lumen ratio of mesenteric resistance arteries induced by salt (P< 0.01) was prevented by eplerenone (P< 0.01). Maximal acetylcholine-induced vasodilation was impaired under salt loading (P< 0.01), but improved under eplerenone (P< 0.01). Eplerenone prevented (P< 0.01) increased heart weight and left and right ventricular collagen deposition induced by high salt. Blood pressure lowering by hydralazine in high-salt SHRSP did not influence endothelial function or left ventricular collagen. Our study demonstrates salt-dependency of aldosterone effects on severity of hypertension, endothelial dysfunction, and cardiac and vascular remodeling in SHRSP. These effects were attenuated by eplerenone, particularly in the salt-loaded state, underlining the pathophysiological role of aldosterone in salt-sensitive hypertension.

ISSN:0194-911X    

出版商:OVID    

年代:2004

数据来源: OVID

摘要:

Abdominal aortic banding induces upregulation of the angiotensin II (Ang II) type-2 (AT2) receptor, thereby decreasing the contractile response to Ang II in the thoracic aorta of the rat. The aim of this study was to use a mouse model to clarify the mechanisms by which the banding elicits upregulation of the aortic AT2receptor and the subsequent attenuation of Ang II responsiveness. Concomitantly with the elevation in blood pressure and plasma renin concentration after banding, AT2-receptor mRNA levels in the thoracic aorta rapidly increased in mice within 4 days. Upregulation of the AT2receptor, as well as blood pressure elevation after banding, was abolished by losartan administration. The contractile response to Ang II was depressed in aortic rings of banding mice but not of sham mice, and was restored by either the AT2-receptor antagonist PD123319 or the bradykinin B2-receptor antagonist icatibant. cGMP content in the thoracic aorta of banding mice was 9-fold greater than that of sham mice, and the elevation was reduced to sham levels 1 hour after intravenous injection of PD123319 or icatibant. When aortic rings were incubated with Ang II, cGMP content increased in banding rings but not in sham rings; the pretreatment with PD123319 or icatibant inhibited Ang II-induced cGMP production. These results suggest that aortic banding induces upregulation of the AT2receptor through increased circulating Ang II via the AT1receptor, thereby activating a vasodilatory pathway in vessels through the AT2receptor via the kinin/cGMP system.

ISSN:0194-911X    

出版商:OVID    

年代:2004

数据来源: OVID

摘要:

The influence of cyclooxygenase pathway activation following thromboxane-endoperoxide (TP) receptor stimulation was studied in rat mesenteric resistance arteries (n=6 to 10 per group). We studied isolated, perfused, and pressurized mesenteric resistance arteries (mean internal diameter 214 μm) using an arteriograph, enabling us to study arteries in physiological conditions of flow and pressure. Changes in diameter were continuously recorded, and contractions measured as internal diameter reduction. Release of cyclooxygenase pathway metabolites was also assessed by enzyme immunoassay (EIA) analysis of mesenteric bed perfusions. The thromboxane A2 (TxA2) analog U-46619 (1 μmol/L) induced a significant contraction (108 μm maximal diameter reduction). Inhibition by 3 chemically different cyclooxygenase inhibitors (ie, flurbiprofen, indomethacin, and aspirin) potently reduced the contraction to 27%, 25%, and 6% of control, respectively. The selective cyclooxygenase-1 inhibitor SC-58560 inhibited U-46619 contraction, whereas selective cyclooxygenase-2 inhibition (SC-58236) had no effect. Thromboxane synthase inhibition (furegrelate) did not affect U-46619 –induced contraction, but it was reduced by cytosolic phospholipase A2 inhibition. Measurement of cyclooxygenase derivatives produced by the isolated mesenteric bed showed that PGE2was produced after TxA2-receptor stimulation with U-46619. Exogenous prostaglandin E2(in the presence of the TxA2receptor antagonist SQ 29 548) and U-46619 contracted mesenteric arteries with a similar potency (EC50: 0.30 and 0.48 μmol/L, respectively). This study provides the first evidence that TxA2-receptor– dependent contraction in a resistant artery involved cyclooxygenase stimulation and, at least in part, a PGE2formation. This mechanism of TxA2-dependent contraction in resistant arteries might be of importance in the understanding of diseases affecting resistant arteries and involving TxA2, such as hypertension.

ISSN:0194-911X    

出版商:OVID    

年代:2004

数据来源: OVID

摘要:

Previous studies have shown that atrial natriuretic peptide (ANP) can inhibit transcription of its receptor, guanylyl cyclase A, by a mechanism dependent on cGMP and have suggested the presence of a putative cGMP-response element (cGMP-RE) in theNpr1gene promoter. To localize and characterize the putativecis-acting element, we have subcloned a 1520-bp fragment of the ratNpr1promoter in an expression vector containing the luciferase reporter gene. Several fragments, generated by exonuclease III-directed deletions, were transiently transfected into cells to measure their promoter activity. Deletion from −1520 to −1396 of a 1520-bp-longNpr1promoter led to a 5-fold increase in luciferase activity. Subsequent deletion to the position −1307 resulted in a decrease of luciferase activity by 90%. Preincubation of cells with 100 nM of ANP or 100 μM 8-bromo-cGMP inhibited luciferase activity of the 1520-bp and 1396-bp-long fragments, but not the activity of the 1307-bp fragment, suggesting that the cGMP-RE is localized between positions −1396 and −1307. The cGMP regulatory region was narrowed by gel shift assays and footprinting to position −1372 to −1354 from the transcription start site ofNpr1and indicated its interaction with transcriptional factor(s). Cross-competition experiments with mutated oligonucleotides led to the definition of a consensus sequence (−1372AaAtRKaNTTCaAcAKTY −1354) for the novel cGMP-RE, which is conserved in the human (75% identity) and mouse (95% identity)Npr1promoters.

ISSN:0194-911X    

出版商:OVID    

年代:2004

数据来源: OVID

摘要:

Black women have an increased risk of preeclampsia compared with white women. Plasma homocysteine is increased in preeclampsia. Homocysteine concentrations are affected by nutritional deficiencies, particularly decreased folic acid and B12, leading to increased homocysteine. Previous studies have reported racial differences in nutritional intake including folic acid. Therefore, we investigated whether there were racial differences in plasma homocysteine, folic acid, and vitamin B12 among women with preeclampsia. We tested for an association between homocysteine and folic acid and B12, and we hypothesized an inverse relationship of homocysteine and folic acid in preeclampsia, more so in black women in whom preeclampsia developed. Black women with preeclampsia (n= 26) had elevated homocysteine concentrations (8.7±1.4 μmol/L) compared with black women with normal pregnancy (n= 52, 7.6±0.5 μmol/L), white women with preeclampsia (n= 34, 7.5±0.6 μmol/L), and white women with normal pregnancy (n= 48, 5.5±0.3 μmol/L). Folic acid concentrations were lower in black women (14.1±0.8 ng/mL) compared with white women (18.5±0.9 ng/mL,P< 0.01). However, plasma homocysteine was inversely related to folic acid only among black women with preeclampsia (r= −0.23,P= 0.01). These racial differences may have implications for the higher rates of preeclampsia in this group and may have long-term implications for future cardiovascular risk. Racial differences in diet, adherence to folic acid supplementation, or interactions of nutritional and maternal factors warrant further study by race and pregnancy status.

ISSN:0194-911X    

出版商:OVID    

年代:2004

数据来源: OVID

摘要:

Fetal malnutrition and hypoxia may modify organ system maturation and result in cardiovascular diseases in the adult. We tested whether intrauterine stress (IUS) leads to persistent alterations of renal biology. In rats, intrauterine stress was induced by ligation of the uterine arteries at day 17 of pregnancy. Renal arteries of the 21-day-old male offspring were isolated to study pharmacological reactivity. Kidneys were dissected to analyze renal structure and β-adrenoceptor expression. At 21 days of age, half of the animals underwent unilateral left nephrectomy. At the age of 12 weeks, rats were instrumented for blood pressure monitoring, blood sampling, and renal function measurements. After IUS, litter size and birth weight were reduced, whereas the hematocrit was increased. Renal arterial responses to β-adrenergic stimulation and sensitivity to adenylyl cyclase activation were increased, along with the renal expression of β2-adrenoceptors. At 21 days and at 6 months of age, the number and density of the glomeruli were reduced, whereas their size was increased. The filtration fraction and urinary albumin concentration were increased 12 weeks after intrauterine stress. In control rats, removal of the left kidney at 21 days of age did not affect kidney function and blood pressure. However, after IUS, the remaining right kidney failed to compensate for the loss of the left kidney, and blood pressure was increased. In conclusion, prenatal stress transiently modifies renal arterial reactivity and results in long-lasting adverse effects on renal structure and function and on renal compensatory mechanisms.

ISSN:0194-911X    

出版商:OVID    

年代:2004

数据来源: OVID

摘要:

An adverse environment around conception and implantation influences later fetal growth and development to term in humans and sheep. Indeed, preimplantation undernutrition of rats elevated the systolic blood pressure of the resultant adult offspring. In this study, adult cardiovascular function is examined in a slower growing, non–litter-bearing species after peri-implantation undernutrition. Eight ewes were fed to 50% equivalent food intake of 12 control ewes from 1 to 30 days (term ≈147 days) only. Following consumption of an adequate diet to term, natural lambing, and then weaning, resting cardiovascular status and baroreflex function were examined in the resultant young adult offspring. Birth weight and postnatal growth to 1 year of age were unaffected by early undernutrition; however, nutrient-restricted sheep had increased pulse pressure, a reduced rate pressure product, and a leftward shift in their baroreflex function curve. Baroreflex sensitivity during angiotensin II infusion was also blunted in early nutrient-restricted sheep but the tachycardia following a reduction in central blood pressure appeared potentiated, relative to controls. The data suggest that peri-implantation undernutrition may program long-term cardiovascular dysfunction that ultimately increases the risk of hypertension later in life. An increase in regional angiotensin II activity during this critical early phase of development is a likely candidate mechanism for the effects observed. The data have broad implications for the health outcome of those offspring from mothers who were poorly nourished during early, often unknown pregnancy and for embryos artificially manipulated because of infertility treatment.

ISSN:0194-911X    

出版商:OVID    

年代:2004

数据来源: OVID

摘要:

Tooth loss has been associated with an increased risk of vascular diseases such as coronary heart disease and cerebrovascular disease. Little is known whether hypertension is an important factor linking 2 phenomena in postmenopausal women. We compared an incidence of hypertension and traditional risk factors for vascular diseases between 2 age-matched groups: 67 postmenopausal women with missing teeth and 31 without missing teeth. In addition to blood pressure, serum concentration of total cholesterol, high- and low-density lipoprotein cholesterol and triglycerides, plasma angiotensin-converting enzyme activity, plasma angiotensin II concentration, plasma renin activity, and resting heart rate were measured as traditional risk factors for vascular diseases. Subjects without missing teeth had significantly lower diastolic blood pressure than did subjects with missing teeth (P= 0.021). The former tended to have lower systolic blood pressure than did the latter (P= 0.058). There were no significant differences in other variables between subjects with and without missing teeth. The odds ratio of having hypertension in subjects with missing teeth was 3.59 (95% confidence interval, 1.10 to 11.7) after adjustment of obesity, hypercholesterolemia, and hypertriglyceridemia. Our results suggest that hypertension may be an important factor linking tooth loss and an increased risk of vascular diseases in postmenopausal women.

ISSN:0194-911X    

出版商:OVID    

年代:2004

数据来源: OVID