摘要:

BackgroundIncreased serum urate concentrations is a frequent finding in patients with hypertension. Since hyperuricaemia is associated with obesity, renal disease, hyperlipidaemia, and atherosclerosis the question as to whether serum urate is a cardiovascular risk factorper sehas remained elusive. In considering the relationship between uric acid and hypertension three aspects should be answered: (a) the significance of hyperuricaemia; (b) the pathophysiological mechanism of the association; and (c) whether hyperuricaemia is deleterious.Significance of hyperuricaemiaSeveral arguments favour the concept that increased serum urate in hypertensive patients most likely reflects renal vascular involvement.Pathophysiological mechanismHyperuricaemia is accompanied by a relatively diminished uric acid excretion rate in hypertensive patients. Selective insulin resistance and hyperinsulinism estimulates the tubular sodium—hydrogen exchanger and facilitates the active reabsorption of urate.Is hyperuricaemia deleterious?In addition to the renal (urolithiasis) and articular disturbances that hyperuricaemia may cause, vascular damage due to arterial hypertension may limit the availability of oxygen for ATP synthesis. Tissue hypoxia determines increased adenine nucleotide degradation which ends in uric acid overproduction. The formation of uric acid is accompanied by an enhanced synthesis of reactive oxygen species which play a significant role in tissue damage. The hypothesis that hyperuricaemia indicates hypertensive vascular damage is plausible and if unequivocally demonstrated may contribute to delineate evidence-based therapeutic strategies for hypertensive-hyperuricaemic patients.

ISSN:0263-6352    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Angiotensin II (Ang II) acts at the cellular level on two receptor subtypes: the AT1 receptor which can be blocked by losartan and its analogues (the ‘sartan family’), and the AT2 receptor that does not react with the above antagonists but which can be blocked by different compounds, such as PD123319. AT1 receptor blockade has proven to be a highly effective means of interference with the renin—angiotensin system (RAS) and hence of reducing high blood pressure. As a result of the terminal blockade of the RAS cascade, circulating Ang II levels tend to rise two-to threefold. The free access of such enhanced levels to uninhibited AT2 receptors may be clinically relevant, as argued in the present review. The most extensive experimental and clinical experience with AT1 receptor blockade so far has been obtained with the pioneer drug losartan, although major contributions have also been made on candesartan cilexetil, irbesartan and valsartan. All of these four drugs have been instrumental in substantial clinical trials, serving as sources of information in the clinically oriented part of this review. AT1 receptor blocking drugs generally provide a relatively gradual decrease in blood pressure, which is comparable to that obtained with conventional anti-hypertensive drugs. Clinical trials reveal an astounding lack of drug-related adverse effects, scoring even better than placebo in terms of frequencies and sometimes patterns. The trough/peak ratio on single dosages seems to have been mastered, particularly with the second generation of AT1 receptor blockers, as is evident from 24 h ambulatory blood pressure monitoring. Combination with low-dose thiazide regimens is well established. Intermediate endpoints (micro-albuminuria and left ventricular hypertrophy) appear to be controllable. Morbid cardiovascular sequelae are currently under study in comparison with β-and calcium channel blockade.

ISSN:0263-6352    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

ObjectiveTo investigate relationships between birth characteristics and blood pressure at age 20 years and to assess whether effects of birth weight on blood pressure are amplified from childhood to adulthood.DesignA longitudinal study of 584 men and women from Adelaide, Australia, examined previously at 8 years and followed up at age 20 years.ResultsBirth weight was negatively associated with systolic pressure at age 20 years in men (regression coefficient 2.6 mmHg per kg; 95% confidence interval 0.7, 4.4) and women (regression coefficient 4.6 mmHg per kg; 95% confidence interval 2.9, 6.4), after adjustment for current weight. There was an interaction with current size (P= 0.05 for men andP= 0.09 for women), such that effects were enhanced among individuals with relatively high weight or weight for height. Shortness at birth, thinness at birth, and low birth weight relative to placental weight were also associated with elevated systolic pressure at age 20 years. Effects of birth weight on blood pressure were stronger at age 20 than at age 8 years (P< 0.01 for men andP= 0.03 for women). This was not due simply to increased variability of blood pressure in adulthood. There were greater rises in blood pressure with age among individuals of relatively low birth weight.ConclusionsThese findings are further evidence that poor fetal growth is associated with elevated blood pressure in later life. The results support the hypothesis that the relationship is amplified with increasing age.

ISSN:0263-6352    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

ObjectiveTo determine the qualitative and quantitative differences of blood pressure measured at home (home measurement) in the morning versus the evening.MethodsOf 3744 participants, aged 20 years or older in the Ohasama population, more than 14 home measurements in the morning and in the evening, respectively, were obtained in each of 1207 individuals (881 untreated, 56.1 ± 11.4 years and 326 treated, 66.0 ± 9.2 years). A casual/screening measurement was also obtained in these individuals.ResultsThe home measurements in the morning were significantly higher than those in the evening. The bivariate linear regression analysis demonstrated that the difference between diastolic home measurement in the morning and that in the evening increased with an increase in diastolic home measurements. The multiple step-wise linear regression analysis, however, demonstrated that male sex, the use of antihypertensive medication, and SD of home measurements in individuals (blood pressure variability), but not level of home measurements, were positively associated with the difference between home measurement in the morning and that in the evening. The SD of home measurement in the evening in individuals was significantly larger than that in the morning, and the SD in treated individuals was significantly larger than that in untreated individuals. The correlations between casual and home measurements were moderate in untreated individuals (r= 0.509–0.567) but poor in treated subjects (r= 0.223–0.384). The correlations between home systolic measurements in the morning and in the evening were very close in both treated and untreated subjects (r= 0.814–0.902). The correlations between the SD of home measurements in the morning and in the evening were moderate in both treated and untreated individuals (r= 0.585–0.657).ConclusionsQualitative and quantitative differences in home blood pressure measurement, due to the differential time of measurement, should be taken into consideration in clinical use of home blood pressure measurements.

ISSN:0263-6352    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

ObjectiveA silencer within the renin first intron (intron A) was identified using Calu-6 cells, a pulmonary carcinoma cell line which produced renin. In the present study, a dissection of the first intron was performed to determine precisely thecis-regulatory elements involved in the silencer transcriptional effects.Materials and methodsIntron A was completely sequenced to characterize potential binding sites for known transcription factors. Partial portions of intron A were subcloned upstream the 892 bp of the renin promoter and transfected in different models of renin-producing cells: primary culture of human chorionic cells, human Calu-6 cells and mouse As4.1 cells.ResultsThere is significant DNA homology (67%) between the 3′ and 5′ ends of the human and rat renin first intron. Several transcription factor binding sites identified in human first intron, but not in rat intron, do not contribute to the reported silencer activity. Transfections of renin/luciferase constructs containing partial portions of first intron inserted upstream of the 892 bp in both renin-producing cells do not allow the precise characterization of cis-elements involved in the silencer effect.ConclusionsThe silencer located renin intron A is cell specific. The integrity of the human first intron seems necessary for its repressor activity on renin proximal promoter in renin-producing cells.

ISSN:0263-6352    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

ObjectiveThis study investigates the growth effects and associated signaling pathways of angiotensin II (Ang II) in human vascular smooth muscle cells.MethodsCultured vascular smooth muscle cells derived from resistance arteries (< 300 μm diameter) from subcutaneous gluteal biopsies of healthy subjects (n= 6) and human aortic vascular smooth muscle cells were used. Cells were studied between passages 3 and 6. Both3H-thymidine and3H-leucine incorporation were measured as indices of vascular smooth muscle cell hyperplasia (DNA synthesis) and cell hypertrophy (protein synthesis), respectively. Growth effects of Ang II (10−12= 10−6mol/l), in the absence and presence of 10−5mol/l losartan (AT1antagonist) and PD123319 (AT2antagonist), were determined. Ang II-induced effects were compared to those of endothelin-1. To determine whether extracellular signal-regulated kinase (ERK)-dependent pathways play a role in Ang II-mediated growth, cells were pretreated with the selective ERK kinase (MEK) inhibitor, PD98059 (10−5mol/l). ERK activation was determined by Western blot in the absence and presence of PD98059.ResultsAng II dose-dependently increased3H-thymidine incorporation in cells from aorta (Emax= 276 ± 10.4% of control) and resistance arteries (Emax= 284 ± 5.1% of control). Ang II also stimulated3H-leucine incorporation in cells from aorta (Emax= 162 ± 11.6 of control) and resistance arteries (Emax175 ± 10% of control). Unlike Ang II, endothelin-1 failed to significantly alter cellular growth, except at high concentrations (> 10−7mol/l), where it had a weak stimulatory effect. Losartan, but not PD123319, blocked Ang II-stimulated growth responses. Ang II significantly increased phosphorylation of ERK-1 and ERK-2, with maximum responses obtained at 5 min. PD98059 inhibited Ang II-stimulated ERK activity and abrogated agonist-induced DNA and protein synthesis. Losartan, but not PD123319 inhibited Ang II-induced phosphorylation of ERK-1 and ERK-2.ConclusionsAng II stimulates both hyperplasia and hypertrophy in vascular smooth muscle cells from human arteries. These growth effects are mediated via Ang II receptors of the AT1subtype that are linked to ERK-dependent signaling pathways.

ISSN:0263-6352    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

ObjectiveTo examine whether chronic oral treatment with an angiotensin-converting enzyme inhibitor imidapril and an angiotensin II type 1 receptor antagonist TCV-116 would alter the response to angiotensin II in the rostral ventrolateral medulla.MethodsTwelve-week-old spontaneously hypertensive rats (SHR) were treated with imidapril (20 mg/kg per day,n= 7), TCV-116 (5 mg/kg per day,n= 8) or vehicle (n= 8) for 4 weeks. Wistar–Kyoto rats (WKY) (n= 8) served as normotensive controls. At 16 weeks of age, angiotensin II (100 pmol) was microinjected into the rostral ventrolateral medulla of anaesthetized rats.ResultsBlood pressure decreased significantly in the rats treated with either imidapril or TCV-116. Pressor responses to angiotensin II microinjected into the rostral ventrolateral medulla were comparable in the untreated SHR, the imidapril-treated SHR and WKY (12 ± 2, 15 ± 4 and 10 ± 1 mmHg, respectively), but were abolished in SHR treated with TCV-116 (0 ± 2 mmHg,P> 0.01). Angiotensin-converting enzyme activity in the brain stem was significantly lower in SHR treated with imidapril (0.70 ± 0.06 nmol/mg per h), but significantly higher in SHR treated with TCV-116 (1.62 ± 0.04 nmol/mg per h) than in the untreated SHR (1.37 ± 0.05 nmol/mg per h).ConclusionsChronic oral treatment with imidapril and TCV-116 may have divergent influences on the renin-angiotensin system within the brain stem. TCV-116, but not imidapril, abolishes the pressor effect of angiotensin II in the rostral ventrolateral medulla.

ISSN:0263-6352    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

ObjectiveWe recently reported that the renin-angiotensin system plays an important role in the progression of vascular and kidney injuries, even in Dahl salt-sensitive rats with volume-dependent hypertension. In this study, we investigated whether a high-salt diet increases susceptibility to kidney injury induced by angiotensin II in normotensive, uni-nephrectomized Sprague-Dawley rats, which mimics the condition of salt-volume repletion and blunted renin-angiotensin system.MethodsThe rats were fed either a low-salt (0.3% NaCl) or a high-salt (4% NaCl) diet and divided into five groups: two control groups with a low-salt or a high-salt diet without angiotensin II infusion (saline infusion), and three angiotensin II groups (angiotensin II infusion, 10 or 50 ng/ kg per min with high-salt diet, 50 ng/kg per min with low-salt diet, subcutaneously). The rats were kept on these regimes for 8 weeks. The blood pressure was measured every week. Functional and morphological alterations in the kidney were assessed at the end of the experiment.ResultsThere were no differences in the arterial blood pressures of the five experimental groups. However, angiotensin II infusion increased the weights of the heart and aortic walls in a dose-dependent manner in the high-salt groups. There was also a dose-dependent increase in proteinuria, N-acetyl-β-D-glucosaminidase activity (NAG) excretion, and additional glomerular and arterial injuries in the kidney, associated with angiotensin II infusion in the high-salt groups. In the rats given a higher dose of angiotensin II, the high-salt diet significantly increased the weights of the heart and aortic walls and exacerbated the renal function and morphological injuries, compared to the low-salt group. High-salt diet alone increased the kidney and heart weights. However, it did not significantly influence the results of the morphological and functional study. On the other hand, angiotensin II infusion on a low-salt diet showed a trend towards glomerular damage; however, the effects were small and not significant. Similarly, there were few effects of angiotensin II infusion on morphology and functional study on a low-salt diet.ConclusionThese data clearly show that a high-salt intake increases susceptibility of the kidney to injuries induced by low doses of angiotensin II in normotensive, uninephrectomized rats.

ISSN:0263-6352    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

ObjectivePrevious studies indicate that the adrenal gland plays a compensatory role in the maintenance of blood pressure in chemically sympathectomized rats. However, the mechanisms responsible for compensatory adrenal responses are poorly understood. This study examined the regulation of adrenal growth and type 1A, 1B, and type 2 angiotensin II (Ang II) receptor (AT1A, AT1B and AT2) expression in the adrenal gland induced by sympathectomy.MethodsFive-week-old male Sprague-Dawley rats were treated with either guanethidine (50 mg/kg per day, intraperitoneally) or vehicle for 5 weeks. Norepinephrine and epinephrine levels in the atrium of the heart were measured by high-pressure liquid chromatography. Plasma renin activity was determined by radioimmunoassay. Adrenal AT1 and AT2 receptor density was determined by radioligand binding assay. Adrenal AT1A, AT1B and AT2 mRNA levels were determined by Northern blot analysis.ResultsNorepinephrine and epinephrine levels in the atrium of the heart were decreased 86% (P < 0.0001) and 58% (P < 0.05) by guanethidine treatment, respectively. Plasma renin activity was decreased 71% (P < 0.001) in guanethidine-treated rats compared with vehicle. In contrast, the ratio of adrenal to body weight was increased 38% in guanethidine-treated rats compared with vehicle (P < 0.001). Adrenal AT1 and AT2 receptor density was increased by guanethidine treatment (P < 0.05). Adrenal mRNA levels for AT2 (P < 0.001) and AT1A (P < 0.01), but not AT1B (P >0.05), were increased in guanethidine-treated rats compared with vehicle (P < 0.01). There were positive correlations between adrenal weight and AT2 (r = 0.9, P < 0.001) and AT1A (r = 0.6, P < 0.05) but not AT1B (r = 20.01, P > 0.05) expression.ConclusionsImpairment of the sympathetic nervous system with guanethidine withdraws the normal stimulation of this system on the circulating renin-angiotensin system, but upregulates the expression of adrenal Ang II receptors. Increased expression of adrenal AT2 and AT1A receptors may play an important role in adaptive adrenal hypertrophy and hormonal responses to sympathectomy.

ISSN:0263-6352    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

ObjectiveRecent studies showed that smoking four cigarettes per hour impairs baroreflex sensitivity in humans. In this study, baroreceptor function was qualified more precisely by 24 h measurements using the new portable Portapres®system, allowing a continuous noninvasive registration of blood pressure curves.MethodsTwenty-four smoking individuals (12 male/12 female) who smoked more than 10 cigarettes per day for more than 6 years were investigated. Thirty non-smokers (15 male/15 female) served as controls. Data were evaluated separately for the 08:00–22:00 h and 22:00–08:00 h periods.ResultsWithin one 24 h period, smokers showed a higher blood pressure [female: mean arterial blood pressure (MAP) 85.5 mmHg; male: MAP 93 mmHg] compared to non-smokers (female: MAP 80 mmHg; male: MAP 90 mmHg). During daytime (08:00–22:00 h), this difference reached a level of statistical significance (P < 0.05) in female subjects. Heart rate was significantly higher in smokers (female: 86 bpm; male: 80 bpm) compared to non-smokers (female: 77 bpm; male: 70 bpm) during the 24 h observation period. The number of sequences (seq) in smokers surpassed the number of sequences in non-smokers by about 53 seq/day, which corresponds to a significant difference of 4.5 %. At night the sympathetic-systolic blood pressure/-pulse interval (−SBP/−PI) sequences of the smoking group predominated over the −SBP/−PI sequences in the non-smoking group. On the other hand, the parasympathetic +SBP/+PI sequences were significantly less in smokers between 22:00 and 08:00 h. The regressions (i.e. D pulse interval/D SBP [ms/mmHg]), which represent the baroreceptor sensitivity, were clearly smaller in smokers.ConclusionsThe present study provides evidence that chronic tobacco (nicotine) abuse causes pathological alterations of autonomic nervous blood pressure regulation which can be measured under normal living conditions and may be described as sympathovagal dysbalance and decreased baroreceptor sensitivity. Taken together with processes such as elevated catecholamine blood levels, these alterations may explain the higher risk of cardiovascular diseases.

ISSN:0263-6352    

出版商:OVID    

年代:1999

数据来源: OVID