bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of Smoking Cessation on Changes in Blood Pressure and Incidence of Hypertension
Authors: Lee Duk-Hee , Ha Myung-Hwa , Kim Jang-Rak , Jacobs David R.
Published: June 2012

Abstract
—We performed the present study to investigate the effects of smoking cessation on changes in blood pressure and incidence of hypertension. We evaluated 8170 healthy male employees at a steel manufacturing company who had received occupational health examinations at the company’s health care center in 1994 and were reexamined in 1998. Adjustment covariates were the baseline age, body mass index, cigarette smoking, alcohol consumption, exercise, family history of hypertension, systolic or diastolic blood pressure, and changes in body mass index and alcohol consumption during the follow-up period. The adjusted relative risks of hypertension in those who had quit smoking for <1, 1 to 3, and ≥3 years were 0.6 (95% CI 0.2 to 1.9), 1.5 (95% CI 0.8 to 2.8), and 3.5 (95% CI 1.7 to 7.4), respectively, compared with current smokers. The trends for increased risk of hypertension for longer periods of smoking cessation were observed in subgroups of those who maintained weight as well as those who gained weight after smoking cessation. The adjusted increments in both systolic and diastolic blood pressure were higher in those who had quit for ≥1 year than in current smokers. These trends among weight losers, as well as gainers and maintainers, were similar. We observed progressive increases in blood pressure with the prolongation of cessation in men, although at this time the mechanism remains unknown and must be clarified. This study implies that the cessation of smoking may result in increases in blood pressure, hypertension, or both.
Hypothesis:
β-Adrenergic Receptor Blockers and Weight Gain
Authors: Sharma Arya M. , Pischon Tobias , Hardt Sandra , Kunz Iris , Luft Friedrich C.
Published: June 2012

One of the arguments put forward against the primary use of β-blockers has been concern about adverse metabolic effects, such as unfavorable effects on lipids or insulin sensitivity. Another less-appreciated potential drawback is their propensity to cause weight gain in some patients. In 8 evaluable prospective randomized controlled trials that lasted ≥6 months, body weight was higher in the β-blocker than in the control group at the end of the study. The median difference in body weight was 1.2 kg (range −0.4 to 3.5 kg). A regression analysis suggested that β-blockers were associated with an initial weight gain during the first few months. Thereafter, no further weight gain compared with controls was apparent. There was no relationship between demographic characteristics and changes in body weight. Based on these observations, the first-line use of β-blockers in obese hypertensive patients should be reviewed. Obesity management in overweight hypertensive patients may be more difficult in the face of β-blocker treatment.
Pulse Pressure, Aortic Reactivity, and Endothelium Dysfunction in Old Hypertensive Rats
Authors: Chamiot-Clerc Philippe , Renaud Jean François , Safar Michel E.
Published: June 2012

The reactivity of old hypertensive rat aortas has not been investigated in relation to each phenotype of the blood pressure curve, mean arterial pressure (MAP), and pulse pressure (PP). Aortic reactivities from 3- to 78-week-old Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) were studied with the use of organ chambers and invasive blood pressure, carotid diameter, and histomorphometry. MAP and PP were elevated in SHR, but at 78 weeks, a selective increase of PP without further MAP increase was observed for the same carotid diameter as WKY. Aortic relaxation in response to carbamylcholine decreased similarly with age in both strains. With (+) or without (−) endothelium (E), maximal developed tension (MDT) under KCl increased linearly with age in SHR, proportionally to wall thickness and MAP increase. Under norepinephrine (NE), MDT of E
−
aortas from SHR and controls increased with age and reached plateaus at 12 weeks, whereas MDT of E
+
aortas from SHR increased linearly with age. Because the NE-induced MDT was higher for E
−
than E
+
, the difference estimated endothelial function. This difference reached plateaus from 12 to 78 weeks in WKY but was abolished beyond 12 weeks in SHR, a finding also observed under NO-synthase inhibition. In old hypertensive rats, (1) increased KCl reactivity is endothelium independent but influenced by the MAP-dependent aortic hypertrophy with resulting increased vascular smooth muscle reactivity, whereas (2) increased NE reactivity is endothelium dependent in association with increased PP, altered endothelial function, and extracellular matrix, with resulting enhanced intrinsic arterial stiffness.
Increased Oxidative Stress in Experimental Renovascular Hypertension
Authors: Lerman Lilach O. , Nath Karl A. , Rodriguez-Porcel Martin , Krier James D. , Schwartz Robert S. , Napoli Claudio , Romero J. Carlos
Published: June 2012

The pathophysiological mechanisms responsible for maintenance of chronic renovascular hypertension remain undefined. Excess angiotensin II generation may lead to release of reactive oxygen species and increased vasoconstrictor activity. To examine the potential involvement of oxidation-sensitive mechanisms in the pathophysiology of renovascular hypertension, blood samples were collected and renal blood flow measured with electron-beam computed tomography in pigs 5 and 10 weeks after induction of unilateral renal artery stenosis (n=7) or sham operation (n=7). Five weeks after procedure, plasma renin activity and mean arterial pressure were elevated in hypertensive pigs. Levels of prostaglandin F2α (PGF
2α
)–isoprostanes, vasoconstrictors and markers of oxidative stress, also were significantly increased (157±21 versus 99±16 pg/mL;
P
<0.05) and correlated with both plasma renin activity (
r
=0.83) and arterial pressure (
r
=0.82). By 10 weeks, plasma renin activity returned to baseline but arterial pressure remained elevated (144±10 versus 115±5 mm Hg;
P
<0.05). Isoprostane levels remained high and still correlated directly with the increase in arterial pressure (
r
=0.7) but not with plasma renin activity. Stenotic kidney blood flow was decreased at both studies. In shock-frozen cortical tissue, ex vivo endogenous intracellular radical scavengers were significantly decreased in both kidneys. The present study demonstrates, for the first time, that in early renovascular hypertension, an increase in plasma renin activity and arterial pressure is associated with increased systemic oxidative stress. When plasma renin activity later declines, PGF
2α
-isoprostanes remain elevated, possibly due to local activation or slow responses to angiotensin II, and may participate in sustenance of arterial pressure. Moreover, oxidation-sensitive mechanisms may influence ischemic and hypertensive parenchymal renal injury.
Production and Actions of Superoxide in the Renal Medulla
Authors: Zou Ai-Ping , Li Ningjun , Cowley Allen W.
Published: June 2012

The present study characterized the biochemical pathways responsible for superoxide (O

2

−·

) production in different regions of the rat kidney and determined the role of O

2

−·

in the control of renal medullary blood flow (MBF) and renal function. By use of dihydroethidium/DNA fluorescence spectrometry with microtiter plates, the production of O

2

−·

was monitored when tissue homogenate from different kidney regions was incubated with substrates for the major O

2

−·

-producing enzymes, such as NADH/NADPH oxidase, xanthine oxidase, and mitochondrial respiratory chain enzymes. The production of O

2

−·

via NADH oxidase was greater (P
<0.05) in the renal cortex and outer medulla (OM) than in the papilla. The mitochondrial enzyme activity for O
2
−·
production was higher (
P
<0.05) in the OM than in the cortex and papilla. Compared with NADH oxidase and mitochondrial enzymes, xanthine oxidase and NADPH oxidase produced much less O
2
−·
in the kidney under this condition. Overall, the renal OM exhibited the greatest enzyme activities for O
2
−·
production. In anesthetized rats, renal medullary interstitial infusion of a superoxide dismutase inhibitor, diethyldithiocarbamate, markedly decreased renal MBF and sodium excretion. Diethyldithiocarbamate (5 mg/kg per minute by renal medullary interstitial infusion [RI]) reduced the renal medullary laser-Doppler flow signal from 0.6±0.04 to 0.4±0.03 V, a reduction of 33%, and both urine flow and sodium excretion decreased by 49%. In contrast, a membrane-permeable superoxide dismutase mimetic, 4-hydroxytetramethyl-piperidine-1-oxyl (TEMPOL, 30 μmol/kg per minute RI) increased MBF and sodium excretion by 34% and 69%, respectively. These effects of TEMPOL on renal MBF and sodium excretion were not altered by pretreatment with
N
G
-nitro-
l
-arginine methyl ester (10 μg/kg per minute RI). We conclude that (1) renal medullary O
2
−·
is primarily produced in the renal OM; (2) both NADH oxidase and mitochondrial enzymes are responsible for the O
2
−·
production in this kidney region; and (3) O
2
−·
exerts a tonic regulatory action on renal MBF.
Oxidative Stress in a Rat Model of Obesity-Induced Hypertension
Authors: Dobrian Anca D. , Davies Michael J. , Schriver Suzanne D. , Lauterio Thomas J. , Prewitt Russell L.
Published: June 2012

The mechanisms underlying the development of hypertension in obesity are not yet fully understood. We recently reported the development of hypertension in a rat model of diet-induced obesity. When Sprague-Dawley rats (n=60) are fed a moderately high fat diet (32 kcal% fat) for 10 to 16 weeks, approximately half of them develop obesity (obesity-prone [OP] group) and mild hypertension (158±3.4 mm Hg systolic pressure), whereas the other half (obesity-resistant [OR] group) maintains a body weight equivalent to that of a low fat control group and is normotensive (135.8±3.8 mm Hg). We examined the potential role of oxidative stress in the development of hypertension in this model. Lipid peroxides measured as thiobarbituric acid–reactive substances showed a significant increase in the LDL fraction of OP rats (2.8±0.32 nmol malondialdehyde/mg protein) compared with OR and control rats (0.9±0.3 nmol malondialdehyde/mg protein). Also, aortic and kidney thiobarbituric acid–reactive substances showed a significant (3- and 5- fold) increase in OP rats after 16 weeks of diet. In addition, superoxide generation by aortic rings, measured by lucigenin luminescence, showed a 2-fold increase in the OP group compared with both the OR and control groups. In addition, free isoprostane excretion and nitrotyrosine in the kidney showed an increase in OP rats only. The urine and plasma nitrate/nitrite measured by the LDH method showed a 1.8-fold decrease in OP rats compared with OR rats. However, endothelial NO synthase expression in the kidney cortex and medulla assessed by reverse transcriptase–polymerase chain reaction showed a strong increase in the OP rats versus OR and control rats (endothelial NO synthase/β-actin ratio 1.3±0.04 in OP rats versus 0.44±0.02 in OR rats), suggesting a possible shift toward superoxide production by the enzyme. Collectively, the data show a decreased NO bioavailability in OP animals that is due in part to the increased oxidative stress.
Tyrosine Kinase Involvement in Renal Arteriolar Constrictor Responses to Angiotensin II
Authors: Carmines Pamela K. , Fallet Rachel W. , Che Qi , Fujiwara Keiji
Published: June 2012

Experiments were performed to test the hypothesis that tyrosine kinase activity contributes to renal arteriolar contractile responses to angiotensin (Ang) II. Rats were subjected to short-term enalaprilat treatment to decrease endogenous Ang II formation before tissue was harvested for experiments with the in vitro blood-perfused juxtamedullary nephron technique. Acute surgical papillectomy was used to avoid the indirect afferent arteriolar effect of Ang II that arises through increased tubuloglomerular feedback sensitivity. Arteriolar lumen diameter responses to 1 and 10 nmol/L Ang II were monitored by videomicroscopic methods before and during treatment with various tyrphostin compounds: 100 μmol/L AG18 (broad-spectrum tyrosine kinase inhibitor), 100 nmol/L AG1478 (selective epidermal growth factor receptor tyrosine kinase inhibitor), or 100 μmol/L AG9 (inactive analog). Baseline afferent arteriolar lumen diameter averaged 23.5±1.2 μm and was not influenced by any tyrphostin. Ang II (10 nmol/L) decreased afferent diameter by 11.1±1.0 μm under untreated conditions, a response that was not altered by AG9 but significantly blunted by AG18 (34±9% inhibition) or AG1478 (52±8% inhibition). AG18 did not suppress afferent arteriolar contractile responses to membrane depolarization (20 to 55 mmol/L K
+
bath). Efferent arteriolar baseline diameter averaged 24.1±0.8 μm and was unaltered by AG18 or AG1478; however, efferent diameter responses to 10 nmol/L Ang II were diminished 52±10% by AG18 and 51±13% by AG1478. These observations indicate that Ang II signaling in renal afferent and efferent arteriolar vascular smooth muscle is either mediated or modulated by tyrosine kinase activity, including that of the epidermal growth factor receptor tyrosine kinase.
γ-Aminobutyric Acid (GABA)-A Function and Binding in the Paraventricular Nucleus of the Hypothalamus in Chronic Renal-Wrap Hypertension
Authors: Haywood Joseph R. , Mifflin Steven W. , Craig Teresa , Calderon Alfred , Hensler Julie G. , Hinojosa-Laborde Carmen
Published: June 2012

The goal of this study was to determine whether γ-aminobutyric acid (GABA)ergic transmission and GABA binding are altered in chronic renal-wrap hypertension. Three groups of hypertensive and sham-operated rats were prepared for separate protocols. Four weeks later, the animals were prepared with femoral artery catheters for the measurement of mean arterial pressure. In all groups, blood pressure was significantly higher in the renal-wrapped animals. In the first study, bilateral microinjection of the GABA-A antagonist, bicuculline (50 pmol/site), into the paraventricular nucleus of the hypothalamus (PVN) caused a greater increase in arterial pressure (21.9±1.4 versus 16.7±1.8 mm Hg, P
<0.05) and heart rate (135±15 versus 98±12 bpm,
P
=0.064) in hypertensive rats. [
3
H]Flunitrazepam was used to measure binding to the GABA-A receptor. Magnocellular neurons and the adjacent medial parvicellular neurons had more intense binding compared with the remainder of the PVN. B
max
was greater for the higher density binding area; the
K
d
value was less in the high-density region. There were no differences in these parameters between normotensive and hypertensive animals. Competitive reverse transcription–polymerase chain reaction was used to measure the expression of mRNA for the α
1
subunit of the GABA-A receptor. No difference was observed in the mRNA between renal-wrapped and sham-operated rats. In summary, inhibition of GABA-A receptors in the PVN is augmented in the chronic phase of hypertension and is unrelated to a change in the expression of the number or affinity to the receptor. These findings suggest that the greater GABAergic activity is the result of an increase in GABA release in the PVN in chronic renal-wrap hypertension.
Central Leptin Infusion Attenuates the Cardiovascular and Metabolic Effects of Fasting in Rats
Authors: Overton James Michael , Williams Todd Dennis , Chambers James Bradley , Rashotte Michael Edward
Published: June 2012

The role of reduced leptin signaling in the regulation of cardiovascular responses to negative energy balance is not known. We tested the hypothesis that central infusion of leptin would attenuate the cardiovascular and metabolic responses to fasting. Male Sprague-Dawley rats, instrumented with telemetry devices and intracerebroventricular cannulas, were housed in metabolic chambers for continuous (24 hours) measurement of dark-phase (active) and light-phase (inactive) mean arterial pressure, heart rate, oxygen consumption, and respiratory quotient. Rats received central infusions of either saline (0.5 μL/h) or leptin (42 ng/h) for 6 days through osmotic pumps and were either fed ad libitum or were fasted for 48 hours followed by refeeding for 4 days. In ad lib animals, continuous intracerebroventricular leptin infusion significantly reduced caloric intake, body weight, and respiratory quotient compared with saline controls while having no effect on mean arterial pressure or heart rate. Fasting reduced mean arterial pressure, heart rate, oxygen consumption, and respiratory quotient in rats receiving saline infusions. Fasting-induced reductions in mean arterial pressure were specific to the active phase and were not attenuated by central leptin infusion. In contrast, intracerebroventricular leptin, at a dose that had no cardiovascular effects in ad lib control animals, completely prevented fasting-induced decreases in light-phase heart rate and oxygen consumption and blunted fasting-induced reductions in dark-phase heart rate and oxygen consumption. The results are consistent with the hypothesis that reductions in central leptin signaling contribute to the integrated cardiovascular and metabolic responses to acute caloric deprivation.
C825T Polymorphism of the G Protein β
3
-Subunit and Antihypertensive Response to a Thiazide Diuretic
Authors: Turner Stephen T. , Schwartz Gary L. , Chapman Arlene B. , Boerwinkle Eric
Published: June 2012

The T allele of the C825T polymorphism of the gene encoding the β
3
-subunit of G proteins has been associated with increased sodium-hydrogen exchange and low renin in patients with essential hypertension. To assess its association with blood pressure response to diuretic therapy, we measured the C825T polymorphism in 197 blacks (134 men, 63 women) and 190 non-Hispanic whites (76 men, 114 women) with essential hypertension (mean±SD age 48±7 years), who underwent monotherapy with hydrochlorothiazide for 4 weeks. Mean declines in systolic and diastolic blood pressures were 6±2 (
P
<0.001) and 5±1 (
P
<0.001) mm Hg greater, respectively, in TT than in CC homozygotes. Responses in heterozygotes were intermediate between the homozygous groups. Other univariate predictors of greater blood pressure responses included black race, female gender, higher pretreatment blood pressure, older age, lower waist-to-hip ratio, and measures of lower renin-angiotensin-aldosterone system activity. After the effects of the other predictors were considered, the TT genotype remained a significant predictor of greater declines in systolic and diastolic blood pressures. Thus, the C825T polymorphism of the G protein β
3
-subunit may help identify patients with essential hypertension who are more responsive to diuretic therapy.
Workshop:
Hypertension and Cardiovascular Risk Factors
Authors: Raij Leopoldo
Published: June 2012

Vascular upregulation of nitric oxide (NO) is an adaptive response to increased blood pressure that may help in the prevention of end-organ damage. Differences in cardiovascular and renal morbidity and mortality in hypertensive patients may result, at least in part, from individual variations in endothelial function in response to the hemodynamic workload of hypertension. A functional feedback balance exists between both angiotensin (Ang) II and NO under normal conditions. The NO-Ang II imbalance may not explain all the vascular pathophysiology of hypertension, but it certainly appears to be an important component. In hypertension, salt sensitivity, whether primary (ie, certain populations in the United States and Japan) or secondary (ie, aging, type II diabetes), appears to be a marker of increased cardiovascular and renal risk that is often linked to a decreased bioactivity of NO. In diabetes and atherosclerosis, NO-dependent vascular relaxation is impaired and can be restored by decreasing the synthesis and/or blocking the action of Ang II. An understanding of the relations between hypertension, cardiovascular risk factors, end-organ damage, and the NO-Ang II axis leads one to believe that the combination of therapeutic agents capable of reinstating the homeostatic balance of these vasoactive molecules within the vessel wall would be most effective in preventing or arresting end-organ disease.
Mineralocorticoid Receptor Affects AP-1 and Nuclear Factor-κB Activation in Angiotensin II–Induced Cardiac Injury
Authors: Fiebeler Anette , Schmidt Folke , Müller Dominik N. , Park Joon-Keun , Dechend Ralf , Bieringer Markus , Shagdarsuren Erdenechimeg , Breu Volker , Haller Hermann , Luft Friedrich C.
Published: June 2012

Aldosterone is implicated in cardiac hypertrophy and fibrosis. We tested the role of the mineralocorticoid receptor in a model of angiotensin II–induced cardiac injury. We administered spironolactone (SPIRO; 20 mg · kg
−1
· d
−1
), valsartan (VAL; 10 mg · kg
−1
· d
−1
), or vehicle to rats double transgenic for the human renin and angiotensinogen genes (dTGR). We investigated basic fibroblast growth factor (bFGF), platelet-derived growth factor, transforming growth factor-β
1
, and the transcription factors AP-1 and nuclear factor (NF)-κB. We used immunohistochemistry, electrophoretic mobility shift assays, and TaqMan RT-PCR. Untreated dTGR developed hypertension, cardiac hypertrophy, vasculopathy, and fibrosis with a 50% mortality rates at 7 weeks. SPIRO and VAL prevented death and reversed cardiac hypertrophy, while only VAL normalized blood pressure. Both drugs prevented vasculopathy. bFGF was markedly upregulated in dTGR, whereas platelet-derived growth factor-B and transforming growth factor-β
1
were little changed. VAL and SPIRO suppressed this upregulation. Both AP-1 and NF-κB were activated in dTGR compared with controls. VAL and SPIRO reduced both transcription factors and reduced bFGF, collagen I, fibronectin, and laminin in the interstitium. These findings show that aldosterone promotes hypertrophy, cardiac remodeling, and fibrosis, independent of blood pressure. The effects involve AP-1, NF-κB, and bFGF. Mineralocorticoid receptor blockade downregulates these effectors and reduces angiotensin II–induced cardiac damage.
Aldosterone Receptor Antagonism Normalizes Vascular Function in Liquorice-Induced Hypertension
Authors: Quaschning Thomas , Ruschitzka Frank , Shaw Sidney , Lüscher Thomas F.
Published: June 2012

The enzyme 11β-hydroxysteroid dehydrogenase (11β-HSD2) provides mineralocorticoid receptor specificity for aldosterone by metabolizing glucocorticoids to their receptor-inactive 11-dehydro derivatives. The present study investigated the effects of the aldosterone receptor antagonists spironolactone and eplerenone on endothelial function in liquorice-induced hypertension. Glycyrrhizic acid (GA), a recognized inhibitor of 11β-HSD2, was supplemented to the drinking water (3 g/L) of Wistar-Kyoto rats over a period of 21 days. From days 8 to 21, spironolactone (5.8±0.6 mg · kg
−1
· d
−1
), eplerenone (182±13 mg · kg
−1
· d
−1
), or placebo was added to the chow (n=7 animals per group). Endothelium-dependent or -independent vascular function was assessed as the relaxation of preconstricted aortic rings to acetylcholine or sodium nitroprusside, respectively. In addition, aortic endothelial nitric oxide synthase (eNOS) protein content, nitrate tissue levels, and endothelin-1 (ET-1) protein levels were determined. GA increased systolic blood pressure from 142±8 to 185±9 mm Hg (
P
<0.01). In the GA group, endothelium-dependent relaxation was impaired compared with that in controls (73±6% versus 99±5%), whereas endothelium-independent relaxation remained unchanged. In the aortas of 11β-HSD2–deficient rats, eNOS protein content and nitrate tissue levels decreased (1114±128 versus 518±77 μg/g protein,
P
<0.05). In contrast, aortic ET-1 protein levels were enhanced by GA (308±38 versus 497±47 pg/mg tissue,
P
<0.05). Both spironolactone and eplerenone normalized blood pressure in animals on GA (142±9 and 143±9 mm Hg, respectively, versus 189±8 mm Hg in the placebo group;
P
<0.01), restored endothelium-dependent relaxation (96±3% and 97±3%, respectively,
P
<0.01 versus placebo), blunted the decrease in vascular eNOS protein content and nitrate tissue levels, and normalized vascular ET-1 levels. This is the first study to demonstrate that aldosterone receptor antagonism normalizes blood pressure, prevents upregulation of vascular ET-1, restores NO-mediated endothelial dysfunction, and thus, may advance as a novel and specific therapeutic approach in 11β-HSD2–deficient hypertension.
Predominance of Isolated Systolic Hypertension Among Middle-Aged and Elderly US Hypertensives
Authors: Franklin Stanley S. , Jacobs Milagros J. , Wong Nathan D. , L’Italien Gilbert J. , Lapuerta Pablo
Published: June 2012

The purpose of the present study was to examine patterns of systolic and diastolic hypertension by age in the nationally representative National Health and Nutrition Examination Survey (NHANES) III and to determine when treatment and control efforts should be recommended. Percentage distribution of 3 blood pressure subtypes (isolated systolic hypertension, combined systolic/diastolic hypertension, and isolated diastolic hypertension) was categorized for uncontrolled hypertension (untreated and inadequately treated) in 2 age groups (ages <50 and ≥50 years). Overall, isolated systolic hypertension was the most frequent subtype of uncontrolled hypertension (65%). Most subjects with hypertension (74%) were ≥50 years of age, and of this untreated older group, nearly all (94%) were accurately staged by systolic blood pressure alone, in contrast to subjects in the untreated younger group, who were best staged by diastolic blood pressure. Furthermore, most subjects (80%) in the older untreated and the inadequately treated groups had isolated systolic hypertension and required a greater reduction in systolic blood pressure than in the younger groups (-13.3 and -16.5 mm Hg versus -6.8 and -6.1 mm Hg, respectively;
P
=0.0001) to attain a systolic blood pressure treatment goal of <140 mm Hg. Contrary to previous perceptions, isolated systolic hypertension was the majority subtype of uncontrolled hypertension in subjects of ages 50 to 59 years, comprised 87% frequency for subjects in the sixth decade of life, and required greater reduction in systolic blood pressure in these subjects to reach treatment goal compared with subjects in the younger group. Better awareness of this middle-aged and older high-risk group and more aggressive antihypertensive therapy are necessary to address this treatment gap.
Tissue Angiotensin and Pathobiology of Vascular Disease
Authors: Dzau Victor J.
Published: June 2012

Abstract
—There is increasing evidence that direct pathobiological events in the vessel wall play an important role in vascular disease. An important mechanism involves the perturbation of the homeostatic balance between NO and reactive oxygen species. Increased reactive oxygen species can inactivate NO and produce peroxynitrite. Angiotensin II is a potent mediator of oxidative stress and stimulates the release of cytokines and the expression of leukocyte adhesion molecules that mediate vessel wall inflammation. Inflammatory cells release enzymes (including ACE) that generate angiotensin II. Thus, a local positive-feedback mechanism could be established in the vessel wall for oxidative stress, inflammation, and endothelial dysfunction. Angiotensin II also acts as a direct growth factor for vascular smooth muscle cells and can stimulate the local production of metalloproteinases and plasminogen activator inhibitor. Taken together, angiotensin II can promote vasoconstriction, inflammation, thrombosis, and vascular remodeling. In this article, we propose a model that unifies the interrelationship among cardiovascular risk factors, angiotensin II, and the pathobiological mechanisms contributing to cardiovascular disease. This model may also explain the beneficial effects of ACE inhibitors on cardiovascular events beyond blood pressure reduction.
Prognostic Significance of Serum Creatinine and Uric Acid in Older Chinese Patients With Isolated Systolic Hypertension
Authors: Wang Ji-Guang , Staessen Jan A. , Fagard Robert H. , Birkenhäger Willem H. , Gong Lansheng , Liu Lisheng
Published: June 2012

Abstract
—We examined the relation of serum creatinine and uric acid to mortality and cardiovascular disease in older (aged ≥60 years) Chinese patients with isolated systolic hypertension (systolic/diastolic blood pressure ≥160/<95 mm Hg). We used Cox regression to correlate outcome with baseline serum creatinine and uric acid measured in 1880 and 1873, respectively, of the 2394 patients enrolled in the placebo-controlled Systolic Hypertension in China (Syst-China) Trial. Median follow-up was 3 years. In multiple Cox regression analysis with adjustment for gender, age, active treatment, and other significant covariates, serum creatinine was significantly associated with a worse prognosis. The relative hazard rates (95% CIs) associated with a 20-μmol/L increase in serum creatinine for all-cause, cardiovascular, and stroke mortality were 1.16 (1.05 to 1.27,
P
=0.003), 1.15 (1.01 to 1.31,
P
=0.03), and 1.37 (1.13 to 1.65,
P
=0.001), respectively. In a similar analysis, which also accounted for serum creatinine, serum uric acid was also significantly and independently associated with excess mortality of cardiovascular disease and stroke. The relative hazard rates associated with a 50-μmol/L increase of serum uric acid were 1.14 (1.02 to 1.27,
P
=0.02) for cardiovascular mortality and 1.34 (1.14 to 1.57,
P
<0.001) for fatal stroke. In conclusion, in older Chinese patients with isolated systolic hypertension, serum creatinine and serum uric acid were predictors of mortality.
Alcohol Consumption and the Incidence of Hypertension
Authors: Fuchs Flávio Danni , Chambless Lloyd E. , Whelton Paul Kieran , Nieto F. Javier , Heiss Gerardo
Published: June 2012

Abstract
—A close relationship between alcohol consumption and hypertension has been established, but it is unclear whether there is a threshold level for this association. In addition, it has infrequently been studied in longitudinal studies and in black people. In a cohort study, 8334 of the Atherosclerosis Risk in Communities (ARIC) Study participants, aged 45 to 64 years at baseline, who were free of hypertension and coronary heart disease had their blood pressures ascertained after 6 years of follow-up. Alcohol consumption was assessed by dietary interview. The type of alcoholic beverage predominantly consumed was defined by the source of the largest amount of ethanol consumed. Incident hypertension was defined as a systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg or use of antihypertensive medication. There was an increased risk of hypertension in those who consumed large amounts of ethanol (≥210 g per week) compared with those who did not consume alcohol over the 6 years of follow-up. The adjusted odds ratios (95% confidence interval) were 1.2 (0.85 to 1.67) for white men, 2.02 (1.08 to 3.79) for white women, and 2.31 (1.11 to 4.86) for black men. Only 4 black women reported drinking >210 g ethanol per week. At low to moderate levels of alcohol consumption (1 to 209 g per week), the adjusted odds ratios (95% confidence interval) were 0.88 (0.71 to 1.08) in white men, 0.89 (0.73 to 1.09) in white women, 1.71 (1.11 to 2.64) in black men, and 0.88 (0.59 to 1.33) in black women. Systolic and diastolic blood pressures were higher in black men who consumed low to moderate amounts of alcohol compared with the nonconsumers but not in the 3 other race-gender strata. Models with polynomial terms of alcohol exposure suggested a nonlinear association in white and black men. Higher levels of consumption of all types of alcoholic beverages were associated with a higher risk of hypertension for all race-gender strata. The consumption of alcohol in amounts ≥210 g per week is an independent risk factor for hypertension in free-living North American populations. The consumption of low to moderate amounts of alcohol also appears to be associated with a higher risk of hypertension in black men.
Enhancement of Angiotensinogen Expression in Angiotensin II–Dependent Hypertension
Authors: Kobori Hiroyuki , Harrison-Bernard Lisa M. , Navar L. Gabriel
Published: June 2012

Abstract
—Chronic infusion of angiotensin (Ang) II leads to the development of hypertension and enhances intrarenal Ang II content to levels greater than can be explained from the circulating concentrations of the peptide. We previously reported that renal angiotensinogen (Ao) mRNA is enhanced in Ang II–dependent hypertension and may contribute to augmented intrarenal Ang II levels, but the Ao protein levels were not significantly increased. Because a high-salt diet (H/S) has been shown to suppress renal expression of Ao mRNA, we examined the effects of chronic Ang II infusion on kidney and liver Ao mRNA and protein levels in male Sprague-Dawley rats (n=12) maintained on an 8% salt diet. Ang II was administered via osmotic minipumps (40 ng/min) to 1 group (n=6) while the remaining rats were sham-operated. A H/S diet alone did not alter systolic blood pressure in sham animals (109±6 mm Hg at day 12); however, Ang II infusions to the H/S rats significantly increased systolic blood pressure (167±7 at day 12) and intrarenal Ang II content (459±107 fmol/g versus 270±42) despite a marked suppression of plasma renin activity (0.9±0.2 ng Ang I · mL
−1
· h
−1
versus 2.8±1.3). Ang II infusions significantly increased kidney Ao mRNA compared with the H/S diet alone by 1.9±0.1-fold. Western blot analysis of kidney protein extracts showed that the Ang II–infused rats had increased kidney Ao protein levels compared with the H/S diet alone (1.9±0.1-fold). Liver Ao mRNA and protein and plasma Ao protein were also significantly increased by Ang II infusions. These data demonstrate the effects of Ang II infusion to stimulate Ao mRNA and protein. Thus, the augmented intrarenal Ang II in Ang II–dependent hypertension may result, in part, by a positive amplification mechanism to activate renal expression of Ao.
Angiotensin II and Its Metabolites Stimulate PAI-1 Protein Release From Human Adipocytes in Primary Culture
Authors: Skurk Thomas , Lee Yu-Mi , Hauner Hans
Published: June 2012

Abstract
—Plasminogen activator inhibitor (PAI)-1 is the main inhibitor of the fibrinolytic system and was recently shown to be produced by adipose cells. Obesity is associated with an increased production and release of PAI-1 protein. The aim of this study was to investigate the role of angiotensin (Ang) II and its degradation products for PAI-1 release from human adipose cells. For this purpose, we used the model of in vitro differentiated human adipocytes in primary culture. Exposure of human adipocytes to Ang II resulted in a dose- and time-dependent stimulation of PAI-1 release into the culture medium. The maximum effect of Ang II was found at a concentration of 10
−5
mol/L for 48 hours, increasing PAI-1 release by 276±53% compared with control cultures (
P
<0.05). This stimulation was preceded by an increase in specific PAI-1 mRNA copies by 65±12% (
P
<0.05), with a maximum after 6 hours. Incubation of adipocytes with 10
−5
mol/L Ang III and Ang IV, respectively, also resulted in a stimulation of PAI-1 release into the medium by 195±60% (
P
<0.05) and 142±24% (
P
<0.05), respectively, compared with control cultures. Addition of the angiotensin-receptor subtype 1 (AT
1
) blocker candesartan abolished the stimulatory action of Ang II and its metabolites, indicating that this effect is mediated by AT
1
. Addition of the AT
1
blocker alone to unstimulated cultures reduced PAI-1 release by 41%±25% (
P
<0.05), suggesting that endogenous Ang II synthesis contributes to PAI-1 secretion from adipose tissue in an autocrine/paracrine manner. In conclusion, Ang II and its metabolites promote PAI-1 production and release by human fat cells and may contribute to the impairment of the fibrinolytic system typical for obesity. AT
1
receptor blockade reduces basal and abolishes Ang II–stimulated PAI-1 release from human adipocytes.
Autonomic Function in Hypertensive and Normotensive Subjects
Authors: Sevre Knut , Lefrandt Johan D. , Nordby Gudmund , Os Ingrid , Mulder Marieke , Gans Reinold O. B. , Rostrup Morten , Smit Andries J.
Published: June 2012

Abstract
—Baroreceptor reflex sensitivity (BRS) has been found lower and heart rate variability (HRV) parasympathetic markers have been found higher in healthy women than in healthy men. Thus, in the present study we hypothesized gender differences in the autonomic function among hypertensive subjects. Forty-one hypertensive patients and 34 normotensive subjects, age 53±1 years, were examined. Four weeks after cessation of antihypertensive therapy, HRV was assessed in 24-hour Holter ECGs, and BRS was calculated with the transfer technique. A
t
test was performed after log transformation of spectral values. Resting blood pressure and heart rate in the hypertensive and the normotensive groups were 150±2/100±1 (mean±SEM) and 121±2/81±1 mm Hg, respectively, and 68±1 and 60±1 bpm, respectively (
P
<0.0005). Compared with normotensive controls, hypertensive patients had lower total power (1224±116 versus 1797±241 ms
2
;
P
=0.03), lower low frequency power (550±57 versus 813±115 ms
2
;
P
=0.04), lower high frequency power (141±23 versus 215±38 ms
2
;
P
=0.06), lower root mean square successive difference (28.7±2.7 versus 35.7±3.0 ms;
P
=0.03), and PNN50 (4.9±0.6% versus 9.8±1.5%;
P
=0.003). BRS was also lower in the hypertensive subjects (7.6±0.6 versus 10.4±0.8 ms/mm Hg;
P
=0.005). When comparing the same parameters between normotensive subjects and hypertensive subjects within the same gender group, we found significant reduction (
P
<0.05) only within the female group. The difference in BRS within the female group was twice that within the male group. Stepwise multiple regression analysis revealed gender, age, HDL cholesterol, and blood pressure as independent explanatory variables of BRS and HRV. Our results suggest that gender is an important determinant of BRS and HRV. Autonomic function parameters were especially impaired in hypertensive women compared with hypertensive men.
Animal Model of Neuropathic Tachycardia Syndrome
Authors: Carson Robert P. , Appalsamy Martin , Diedrich André , Davis Thomas L. , Robertson David
Published: June 2012

Abstract
—Clinically relevant autonomic dysfunction can result from either complete or partial loss of sympathetic outflow to effector organs. Reported animal models of autonomic neuropathy have aimed to achieve complete lesions of sympathetic nerves, but incomplete lesions might be more relevant to certain clinical entities. We hypothesized that loss of sympathetic innervation would result in a predicted decrease in arterial pressure and a compensatory increase in heart rate. Increased heart rate due to loss of sympathetic innervation is seemingly paradoxical, but it provides a mechanistic explanation for clinical autonomic syndromes such as neuropathic postural tachycardia syndrome. Partially dysautonomic animals were generated by selectively lesioning postganglionic sympathetic neurons with 150 mg/kg 6-hydroxydopamine hydrobromide in male Sprague-Dawley rats. Blood pressure and heart rate were monitored using radiotelemetry. Systolic blood pressure decreased within hours postlesion (Δ>20 mm Hg). Within 4 days postlesion, heart rate rose and remained elevated above control levels. The severity of the lesion was determined functionally and pharmacologically by spectral analysis and responsiveness to tyramine. Low-frequency spectral power of systolic blood pressure was reduced postlesion and correlated with the diminished tyramine responsiveness (
r
=0.9572,
P
=0.0053). The tachycardia was abolished by treatment with the β-antagonist propranolol, demonstrating that it was mediated by catecholamines acting on cardiac β-receptors. Partial lesions of the autonomic nervous system have been hypothesized to underlie many disorders, including neuropathic postural tachycardia syndrome. This animal model may help us better understand the pathophysiology of autonomic dysfunction and lead to development of therapeutic interventions.
HMG-CoA Reductase Inhibitors Improve Endothelial Dysfunction in Normocholesterolemic Hypertension via Reduced Production of Reactive Oxygen Species
Authors: Wassmann Sven , Laufs Ulrich , Bäumer Anselm T. , Müller Kirsten , Ahlbory Katja , Linz Wolfgang , Itter Gabi , Rösen Renate , Böhm Michael , Nickenig Georg
Published: June 2012

Abstract
—3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) significantly reduce cardiovascular mortality associated with hypercholesterolemia. There is evidence that statins exert beneficial effects in part through direct effects on vascular cells independent of lowering plasma cholesterol. We characterized the effect of a 30-day treatment with atorvastatin in normocholesterolemic, spontaneously hypertensive rats (SHR). Systolic blood pressure was significantly decreased in atorvastatin-treated rats (184±5 versus 204±6 mm Hg for control). Statin therapy improved endothelial dysfunction, as assessed by carbachol-induced vasorelaxation in aortic segments, and profoundly reduced angiotensin II–induced vasoconstriction. Angiotensin type 1 (AT
1
) receptor, endothelial cell NO synthase (ecNOS), and p22phox mRNA expression were determined with quantitative reverse transcription–polymerase chain reaction. Atorvastatin treatment downregulated aortic AT
1
receptor mRNA expression to 44±12% of control and reduced mRNA expression of the essential NAD(P)H oxidase subunit p22phox to 63±7% of control. Aortic AT
1
receptor protein expression was consistently decreased. Vascular production of reactive oxygen species was reduced to 62±12% of control in statin-treated SHR, as measured with lucigenin chemiluminescence assays. Accordingly, treatment of SHR with the AT
1
receptor antagonist fonsartan improved endothelial dysfunction and reduced vascular free-radical release. Moreover, atorvastatin caused an upregulation of ecNOS mRNA expression (138±7% of control) and an enhanced ecNOS activity in the vessel wall (209±46% of control). Treatment of SHR with atorvastatin causes a significant reduction of systolic blood pressure and a profound improvement of endothelial dysfunction mediated by a reduction of free radical release in the vasculature. The underlying mechanism could in part be based on the statin-induced downregulation of AT
1
receptor expression and decreased expression of the NAD(P)H oxidase subunit p22phox, because AT
1
receptor activation plays a pivotal role for the induction of this redox system in the vessel wall.
Centrally Mediated Effects of Bromocriptine on Cardiac Sympathovagal Balance
Authors: Franchi Franco , Lazzeri Chiara , Barletta Giuseppe , Ianni Lucia , Mannelli Massimo
Published: June 2012

Bromocriptine, a dopamine agonist, is known to lower cardiovascular mortality in
l
-dopa-treated patients with Parkinson’s disease, probably by reducing the cardiac sympathetic activity. We aimed at unmasking the central effects of bromocriptine on the heart by power spectrum analysis. Ten healthy subjects (aged 31±2 years) in supine and sitting positions were evaluated after the administration of bromocriptine (2.5 mg) alone and after pharmacological peripheral D
2
-like blockade by domperidone (20 mg). We calculated (autoregressive method) the following: the low-frequency (LF) component (an index of cardiac sympathetic tone), the high-frequency (HF) component (an index of cardiac vagal tone), and the LF/HF ratio (an index of cardiac sympathovagal balance). With subjects in the supine position, bromocriptine alone induced a significant increase in the LF component and the LF/HF ratio, together with a reduction in norepinephrine plasma levels and blood pressure values. These conflicting effects can be explained as the combined result of direct and indirect (reflex-mediated) actions of bromocriptine in vivo. No changes in cardiac autonomic drive were observed with subjects in the sitting position. After domperidone pretreatment, bromocriptine induced a reduction in the LF component and in the LF/HF ratio. The sitting position caused an increase in heart rate and in the LF/HF ratio. We demonstrated both peripheral and central effects of bromocriptine. In particular, pretreatment with a peripheral antagonist (domperidone) allowed us to unmask the central effect of bromocriptine on cardiac sympathetic drive.
Inhibition of Baroreflex by Angiotensin II via Fos Expression in Nucleus Tractus Solitarii of the Rat
Authors: Luoh Sophie H.F. , Chan Samuel H.H.
Published: June 2012

We evaluated the modulatory action of angiotensin II at the nucleus tractus solitarii on spontaneous baroreceptor reflex response, the angiotensin subtype receptors involved, and the role of Fos protein in this process, using Sprague-Dawley rats anesthetized with pentobarbital sodium. Microinjection bilaterally of angiotensin (Ang ) II (5, 10, 20, or 40 pmol) into the nucleus tractus solitarii significantly suppressed the spontaneous baroreceptor reflex, as represented by the magnitude of transfer function between systemic arterial pressure and heart rate signals. There also was a concomitant increase in Fos-like immunoreactivity in the nucleus tractus solitarii. Both the suppression of spontaneous baroreceptor reflex and Fos expression in nucleus tractus solitarii neurons elicited by Ang II were discernibly attenuated by pretreatment with or comicroinjection into the bilateral nucleus tractus solitarii of a 15-mer antisense c-
fos
oligonucleotide that targets against the initiation codon of c-
fos
mRNA. In addition, those 2 actions of Ang II were reversed by the coadministration of the nonpeptide Ang II type 1 (AT
1
) receptor antagonist losartan (1.6 nmol) but not by the nonpeptide AT
2
receptor antagonist PD 123,319 (1.6 nmol). Control treatments with artificial cerebrospinal fluid, sense cDNA, or antisense oligonucleotide with a scrambled sequence were ineffective. We conclude that under minimal cardiovascular perturbation, Fos expression mediated via activation of AT
1
subtype receptors may underlie the inhibitory modulation of beat-to-beat baroreflex control of blood pressure by Ang II at the nucleus tractus solitarii.
Endothelial Apoptosis Induced by Oxidative Stress Through Activation of NF-κB
Authors: Aoki Motokuni , Nata Toshie , Morishita Ryuichi , Matsushita Hidetsugu , Nakagami Hironori , Yamamoto Kei , Yamazaki Keita , Nakabayashi Mari , Ogihara Toshio , Kaneda Yasufumi
Published: June 2012

Injury of endothelial cells has been assumed to be an initial trigger of the development of atherosclerosis. In this study, we investigated the molecular mechanisms of endothelial cell death induced by hypoxia, which leads to oxidative stress. To study the relation between hypoxia-induced cell death and activation of nuclear factor-κB (NF-κB) in a hypoxic state, we evaluated the effect of 2 antioxidant drugs, probucol and pyrrolidine dithiocarbamate (PDTC), on human endothelial apoptosis. Although hypoxic treatment of human aortic endothelial cells resulted in a significant decrease in cell number and a significant increase in apoptotic cells compared with that of cells under normoxia (
P
<0.01), treatment with probucol (50 μmol/L) or PDTC (100 μmol/L) significantly attenuated the decrease in cell number (
P
<0.01) and was accompanied by inhibition of NF-κB activation. Furthermore, downregulation of bcl-2 caused by hypoxia was inhibited by these drugs. We further investigated the translocation of bax protein from the cytoplasm to the mitochondrial heavy fraction membrane, as translocation of bax protein is considered to be a determinant of apoptosis. Interestingly, we found that antioxidant treatment inhibited the translocation of bax protein caused by hypoxia. Moreover, upregulation of p53, a proapoptotic molecule, was observed in hypoxia, whereas treatment with probucol attenuated the expression of p53 accompanied by suppression of NF-κB activation. These data suggest functional links between p53 and endothelial apoptosis through the activation of NF-κB. Overall, the current study demonstrated that oxidative stress induced apoptosis in human aortic endothelial cells through the downregulation of bcl-2, translocation of bax, and upregulation of p53, probably through NF-κB activation. Oxidative stress may play an important role in endothelial apoptosis mediated by hypoxia, through the activation of NF-κB.