Hypertension
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Podocyte Injury Underlies the Glomerulopathy of Dahl Salt-Hypertensive Rats and Is Reversed by Aldosterone Blocker Recent clinical studies implicate proteinuria as a key prognostic factor for renal and cardiovascular complications in hypertensives. The pathogenesis of proteinuria in hypertension is, however, poorly elucidated. Podocytes constitute the final filtration barrier in the glomerulus, and their dysfunction may play a pivotal role in proteinuria. In the present study, we examined the involvement of podocyte injury in Dahl salt-hypertensive rats, an animal model prone to hypertensive glomerulosclerosis, and explored the effects of inhibition of aldosterone. Four-week–old Dahl salt-resistant and salt-sensitive rats were fed a 0.3% or 8.0% NaCl diet. Some salt-loaded Dahl salt-sensitive rats were treated with a selective aldosterone blocker eplerenone (1.25 mg/g diet) or hydralazine (0.5 mmol/L). After 6 weeks, salt-loaded Dahl salt-sensitive rats developed severe hypertension, proteinuria, and glomerulosclerosis. Immunostaining for nephrin, a constituent of slit diaphragm, was attenuated, whereas expressions of damaged podocyte markers desmin and B7-1 were upregulated in the glomeruli of salt-loaded Dahl salt-sensitive rats. Electron microscopic analysis revealed podocyte foot process effacement. Podocytes were already impaired at as early as 2 weeks of salt loading in Dahl salt-sensitive rats, when proteinuria was modestly increased. Both eplerenone and hydralazine partially reduced systemic blood pressure as measured by indirect and direct methods in salt-loaded Dahl salt-sensitive rats, but only eplerenone dramatically improved podocyte damage and retarded the progression of proteinuria and glomerulosclerosis. Our findings suggest that podocyte injury underlies the glomerulopathy of Dahl salt-hypertensive rats and that inhibition of aldosterone by eplerenone is protective against podocyte damage, proteinuria, and glomerulosclerosis in this hypertensive model.
Hypertension - Tập 47 Số 6 - Trang 1084-1093 - 2006
Evidence for a difference in vitamin D metabolism between spontaneously hypertensive and Wistar-Kyoto rats. It has been contended that the metabolism of vitamin D in spontaneously hypertensive rats (SHR) is different from that in Wistar-Kyoto rats (WKY). To investigate this possibility, the plasma concentration of 1,25-dihydroxycholecalciferol (1,25[OH]2D) and several known determinants of its production rate were measured in SHR and WKY given normal and restricted amounts of dietary phosphorus. In 12-week-old male SHR given a normal amount of dietary phosphorus, the mean plasma concentration of 1,25(OH)2D (72 +/- 5 pg/ml) was significantly lower than that in age-matched WKY (129 +/- 6 pg/ml; p less than 0.001). The lower plasma concentration of 1,25(OH)2D in the SHR could not be attributed to higher circulating levels of inorganic phosphorus or ionized calcium, lower plasma concentrations of 25-hydroxycholecalciferol, or acidosis. However, in the SHR, urinary excretion of cyclic adenosine 3',5'-monophosphate (12.5 +/- 0.4 nmol/mg creatinine) was significantly lower than that in WKY (15.2 +/- 0.3 nmol/mg creatinine; p less than 0.001). In both SHR and WKY, restriction of dietary phosphorus for 1 week induced an increase in the plasma concentration of 1,25(OH)2D without affecting blood pressure. The current findings indicate that in 12-week-old male SHR, 1,25(OH)2D metabolism is different from that in age-matched WKY. The activity of 25-hydroxyvitamin D-1 alpha-hydroxylase, however, appears to be at least partially responsive to short-term restriction of dietary phosphorus. In SHR, the activity of 25-hydroxyvitamin D-1 alpha-hydroxylase may be lower than that in WKY, perhaps due in part to some impairment in the renal metabolism of, or responsiveness to, cyclic adenosine 3',5'-monophosphate.
Hypertension - Tập 8 Số 11 - Trang 1015-1020 - 1986
Crucial Role of NO and Endothelium-Derived Hyperpolarizing Factor in Human Sustained Conduit Artery Flow-Mediated Dilatation
Whether NO is involved or not in sustained conduit artery flow-mediated dilatation in humans remains unclear. Moreover, the role of endothelium-derived hyperpolarizing factor (EDHF), synthesized by cytochrome epoxygenases and acting through calcium-activated potassium channels, and its relationship with NO during flow-mediated dilatation have never been investigated previously. In 12 healthy subjects we measured radial artery diameter (echotracking) and blood flow (Doppler) during flow-mediated dilatation induced by gradual distal hand skin heating (34 to 44°C), during the local infusion of saline and inhibitors of NO synthase (
N
G
-monomethyl-
l
-arginine [
l
-NMMA]: 8 to 20 μmol/min per liter), calcium-activated potassium channels (tetraethylammonium chloride: 9 μmol/min per liter), and cytochrome epoxygenases (fluconazole: 0.4 to 1.6 μmol/min per liter), alone and in combination. Mean wall shear stress, the flow-mediated dilatation stimulus, was calculated at each level of flow, and the diameter–wall shear stress relationship was constructed. During heating, compared with saline, the diameter–shear stress relationship was shifted downward by
l
-NMMA, tetraethylammonium, fluconazole, and, in a more pronounced manner, by the combinations of
l
-NMMA with tetraethylammonium or with fluconazole. Therefore, maximal radial artery flow-mediated dilatation, compared with saline (0.62±0.03 mm), was decreased under our experimental conditions by
l
-NMMA (−39±4%), tetraethylammonium chloride (−14±4%), fluconazole (−18±6%), and to a greater extent, by the combinations of
l
-NMMA with tetraethylammonium (−64±4%) or with fluconazole (−71±3%). This study demonstrates that NO and a cytochrome-related EDHF are involved in peripheral conduit artery flow-mediated dilatation in humans during sustained flow conditions. Moreover, the synergistic effects of the inhibitors strongly suggest a functional interaction between NO and EDHF pathways.
Hypertension - Tập 48 Số 6 - Trang 1088-1094 - 2006
Is There a Rationale for Angiotensin Blockade in the Management of Obesity Hypertension? Obesity, currently affecting >20% of the adult population in most Western countries, is a major risk factor for the development of hypertension. Hypertension in obese patients is, in the majority of instances, further complicated by the concomitant presence of dyslipidemia and insulin resistance. The latter is reflected by derangement of glucose homeostasis, ranging from hyperinsulinemia to frank type 2 diabetes. Hypertension in obese patients is also associated with an increased risk for left ventricular hypertrophy, endothelial dysfunction, renal hyperfiltration, microalbuminuria, and elevated markers of inflammation. Sodium retention, volume expansion, and increased cardiac output are common findings in obese individuals. These changes are largely attributable to increased activity of the sympathetic nervous system and insufficient suppression of the renin-angiotensin system. Recent data show increased expression of angiotensin II–forming enzymes in adipose tissue, and increased activity of the renin-angiotensin system has recently been implicated in the development of insulin resistance and type 2 diabetes. Accordingly, antihypertensive agents that block the renin-angiotensin system might be a beneficial strategy for treatment of obesity-related hypertension. Both angiotensin-converting enzyme inhibitors and angiotensin type-1 receptor blockers have been associated with favorable metabolic properties and end-organ protection in addition to their antihypertensive effects. Data from ongoing large trials will provide an indication of the protective and preventive effects of these treatment strategies while offering insights into the mechanisms linking obesity, hypertension, and other facets of the metabolic syndrome.
Hypertension - Tập 44 Số 1 - Trang 12-19 - 2004
Long-Term Burden of Higher Body Mass Index and Adult Arterial Stiffness Are Linked Predominantly Through Elevated Blood Pressure
Obesity and hypertension are important risk factors of arterial stiffness. However, the complex relationship between increased body mass index (BMI), elevated blood pressure (BP), and arterial stiffness is largely unknown. We aim to examine the mediation effect of elevated BP on the association of early life BMI, long-term burden, and trend of BMI with arterial stiffness in midlife. The longitudinal study cohort consisted of 1190 participants (829 whites and 361 blacks, 518 males, mean age=40.0 years at follow-up) who had been examined for BMI and BP 4 to 15 times from childhood and aortic-femoral pulse wave velocity (afPWV) in adulthood, with a mean follow-up period of 30.3 years. Total area under the curve (AUC
t
) and incremental AUC (AUC
i
) were calculated in random-effects models and used as long-term measures of BMI and BP. Total effects of BMI measures on adult afPWV, adjusted for covariates were all significant without adult BMI and systolic BP (SBP) measures included in the models. The mediation effects of adult SBP (20.2%) and SBP AUC
i
(16.9%) were significant on the childhood BMI-afPWV association. Adult SBP showed significant mediation effects of 36.7% on the BMI AUC
i
-afPWV association and 36.4% on the BMI AUC
t
-afPWV association. The mediation effect of SBP AUC
i
was estimated at 63.3% (
P
<0.01) on the BMI AUC
i
-afPWV association. Diastolic BP had similar total and mediation effects. These findings suggest that the association of increased childhood BMI and its cumulative burden with adult arterial stiffness measured as afPWV is predominantly mediated through the long-term and increasing trend of BP.
Hypertension - Tập 73 Số 1 - Trang 229-234 - 2019
Pulsatile versus steady component of blood pressure: a cross-sectional analysis and a prospective analysis on cardiovascular mortality. Studies on the prognostic significance of blood pressure on cardiovascular disease have essentially investigated the levels of diastolic or systolic blood pressure. However, blood pressure may also be divided into two other components: steady (mean arterial pressure) and pulsatile (pulse arterial pressure). The relations of these two components with cardiovascular risk factors and cardiovascular mortality were investigated in 18,336 men and 9,351 women aged 40-69 years, who were followed up for a mean period of 9.5 years. However, the interpretation of the relations is complicated by the strong correlation existing between these two components. A principal component analysis was performed to obtain two independent parameters: a steady and a pulsatile component index, strongly correlated with mean and pulse arterial pressure, respectively. In the cross-sectional analysis, relations were stronger with the steady component index than with the pulsatile component index; an association was found between left ventricular hypertrophy and the pulsatile component index in both sexes. The survival analysis was not performed in women under 55 as only 11 cardiovascular deaths occurred in this group. The steady component index was a strong prognostic factor of all types of cardiovascular death in both sexes. In women, the pulsatile component index was positively correlated to death from coronary artery disease and inversely correlated to stroke. In conclusion, the steady component of blood pressure is a strong risk factor for cardiovascular death in both sexes; the pulsatile component could be a risk factor independent of the steady component in women older than 55 years.
Hypertension - Tập 13 Số 4 - Trang 392-400 - 1989
Suy giảm nhận thức ở Chuột được tiêm Amyloid-β đã được cải thiện bởi điều trị trước với một liều thấp Telmisartan Phần nào nhờ Kích hoạt Thụ thể-γ Kích hoạt Hoạt động Proliferoxyme Dấu hiệu bệnh lý của bệnh Alzheimer là sự lắng đọng của protein amyloid-β (Aβ) trong não. Telmisartan là một chất độc độc quyền của thụ thể angiotensin II với hoạt động kích hoạt thụ thể-γ kích hoạt hoạt động proliferoxyme. Kích hoạt thụ thể-γ được kỳ vọng để ngăn ngừa viêm và sự tích tụ Aβ trong não. Chúng tôi đã nghiên cứu hiệu quả phòng ngừa có thể của telmisartan lên sự suy giảm nhận thức trong một mô hình chuột bệnh Alzheimer thông qua kích hoạt thụ thể-γ. Ở đây, các con chuột ddY đực đã trải qua tiêm ICV Aβ 1-40. Chức năng nhận thức được đánh giá bằng bài kiểm tra mê nước Morris. Một liều thấp telmisartan (0,35 mg/kg mỗi ngày) được sử dụng bằng nước uống có hoặc không có GW9662, một chất đối kháng thụ thể-γ. Dòng máu não sọ được đánh giá bằng lưu lượng kế laser speckle. Mức độ cytokine viêm được đo bằng RT-PCR định lượng. Tiêm ICV Aβ 1-40 đã làm suy giảm nghiêm trọng chức năng nhận thức. Điều trị trước bằng telmisartan cải thiện sự suy giảm nhận thức này đến mức tương tự như ở các con chuột đối chứng. Sự điều trị kết hợp với GW9662, một chất đối kháng thụ thể-γ, đã làm suy giảm sự cải thiện nhận thức do telmisartan điều hòa. Điều trị bằng telmisartan làm tăng dòng máu não và giảm biểu hiện gia tăng cytokine gây viêm Aβ, chẳng hạn như yếu tố hoại tử khối u-α và NO synthase có thể gây ra trong não. Điều thú vị là sự kết hợp sử dụng GW9662 đã hủy bỏ các tác dụng có lợi của telmisartan. Nồng độ Aβ 1-40 trong não đã giảm đáng kể bởi điều trị bằng telmisartan, trong khi sự cho dùng GW9662 đã làm suy yếu sự giảm nồng độ Aβ 1-40 liên quan đến telmisartan. Tổng thể, những phát hiện của chúng tôi cho thấy rằng ngay cả một liều thấp của telmisartan đã có một tác dụng phòng ngừa sự suy giảm nhận thức trong một mô hình chuột bệnh Alzheimer, một phần là do sự kích hoạt thụ thể-γ.
Hypertension - Tập 54 Số 4 - Trang 782-787 - 2009
#Alzheimer #telmisartan #thụ thể-γ kích hoạt hoạt động proliferoxyme #Aβ #suy giảm nhận thức #ddY mice
β-2 Adrenergic Receptor Variants Affect Resting Blood Pressure and Agonist-Induced Vasodilation in Young Adult Caucasians
Abstract
—Recent evidence suggests that the prodownregulatory Gly16 allele of the β-2 adrenergic receptor (β-2 AR) is associated with essential hypertension in African Caribbeans. To further investigate the effect of the glycine (Gly)16 and arginine (Arg)16 β-2 AR variants on hemodynamics, we investigated the agonist-mediated in vivo vasodilation in normotensive Austrian Caucasians and analyzed the results with respect to the Gly16/Arg16 polymorphism. Fifty-seven normotensive men, 20 to 32 years of age with body mass index of 18.7 to 29.9 kg/m
2
, were genotyped for the Arg16/Gly16 β-2 AR alleles. All 15 Gly16/Gly16 subjects, all 12 Arg16/Arg/16 subjects, and 27 of 30 heterozygous subjects underwent hemodynamic measurements while supine after an overnight fast. The observers were unaware of the subjects’ genotypes. The subjects received a graded infusion of the selective β-2 AR agonist salbutamol (0.07, 0.14, and 0.21 μg/kg per minute, respectively), each dose over 8 minutes. Stroke volume and blood pressure were determined continuously by means of impedance cardiography and oscillometry, respectively. The last 4 minutes of each infusion were evaluated statistically. Basal mean blood pressure was higher in the Gly16/Gly16 subjects compared with Arg16/Arg16 subjects (mean±SD: 81.6±6.14 versus 75.2±4.93 mm Hg,
P
<0.01). Homozygous Gly16 subjects showed a significantly decreased vasodilation during the first dose of salbutamol infusion compared with Arg16/Arg16 subjects (Δtotal peripheral resistance index −17.9±14.4 versus −30.6±8.3%,
P
<0.01) despite increased sympathetic counterregulation in the Arg16/Arg16 group (Δheart rate +16.9±7.0% versus +8.6±7.0%,
P
<0.01; Δcardiac index +39.5±18.5% versus 21.4±18.8%,
P
<0.05). Our results provide additional evidence that the Gly16/Arg16 alleles of the β-2 AR are intimately related to blood pressure regulation and deserve further studies in the pathogenesis of essential hypertension.
Hypertension - Tập 33 Số 6 - Trang 1425-1430 - 1999
Effect of chronic sodium loading on cardiovascular response in young blacks and whites. The effect of long-term oral sodium loading on blood pressure and on stress-induced cardiovascular response was studied in normotensive and marginally hypertensive young adults. The 121 subjects, 18-23 years old, included 38 whites and 83 blacks. Blood pressure and heart rate response to the stress of mental arithmetic was measured before and after 14 days of sodium load, which consisted of 10 g NaCl/day added to the usual diet. A sodium-sensitive response to sodium load occurred in 18.4% of whites and 37.3% of blacks. Sodium-insensitive subjects had a higher rate of sodium excretion (p less than 0.001). Sodium-sensitive hypertensive subjects had a significantly greater weight gain (p less than 0.001). A significant correlation between blood pressure change and sodium excretion (r = -0.28, p less than 0.01) occurred in the sodium-sensitive group. The high sodium intake did not augment the blood pressure or heart rate response to the beta-adrenergic-mediated stimulus of mental arithmetic in the population when grouped by blood pressure, race, or sodium sensitivity. These results suggest that blood pressure increase in response to sodium load, particularly in blacks, is related to functional changes in peripheral vascular resistance.
Hypertension - Tập 15 Số 1 - Trang 36-43 - 1990
Salt sensitivity and resistance of blood pressure. Age and race as factors in physiological responses. To identify characteristics that may contribute to salt sensitivity, we conducted studies of normal subjects who are at risk for hypertension, namely blacks, subjects older than 40 years of age, and first-degree relatives of subjects with essential hypertension. We also formulated definitions for salt sensitivity and resistance with a short-term volume expansion and contraction protocol and additionally from data derived from studies of long-term reduced dietary salt intake. We examined the effects of augmented potassium and calcium intake and also those of sodium as the chloride or the bicarbonate salt. Finally, we sought genetic markers that are associated with salt sensitivity. We found that salt sensitivity is a function of age and is more common in blacks than whites. These groups also have relatively delayed acute salt excretion compared with controls. We were unable to identify effects of gender. Haptoglobin phenotypes (HP 1-1) may facilitate identification of salt-sensitive individuals. A high potassium intake may make individuals less salt sensitive. Sodium chloride and sodium bicarbonate differ in their effects on blood pressure. Sodium chloride augments urinary calcium excretion, but sodium bicarbonate does not. Differences between susceptible and nonsusceptible groups, together with improved knowledge of electrolyte interactions, may facilitate our understanding of salt-sensitive hypertension.
Hypertension - Tập 17 Số 1_supplement - 1991
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