bluuebunny/crossref_metadata_2025 huggingface dataset:
Chronic AT
1
Blockade Stimulates Extracellular Collagen Type I Degradation and Reverses Myocardial Fibrosis in Spontaneously Hypertensive Rats
Authors: Varo Nerea , Iraburu María J. , Varela Marta , López Begoña , Etayo Juan C. , Díez Javier
Published: June 2012

Abstract
—It has been suggested that left ventricular fibrosis in spontaneously hypertensive rats (SHR) is the result of both exaggerated collagen synthesis and insufficient collagen degradation. We have shown previously that chronic treatment with the angiotensin II type 1 receptor antagonist losartan results in diminished synthesis of collagen type I molecules and reversal of myocardial fibrosis in SHR. This study was designed to investigate whether losartan also affects the extracellular degradation of collagen type I fibers in the left ventricle of SHR. The study was performed in 30-week-old normotensive Wistar-Kyoto rats (WKY), untreated SHR, and SHR treated with orally administered losartan (20 mg/kg per day) for 14 weeks before they were killed. Ventricular collagenase activity was determined by degradation of [
14
C]collagen with tissue extracts. Ventricular expression of tissue inhibitor of metalloproteinases 1 (TIMP-1) mRNA was analyzed by Northern blot. A histomorphometric study of the left ventricle was performed in all rats. Compared with WKY, SHR exhibited left ventricular hypertrophy, increased (
P
<0.05) blood pressure, left ventricular collagen volume fraction and TIMP-1 mRNA, and diminished (
P
<0.05) collagenase activity. After the treatment period, blood pressure was higher (
P
<0.05) in losartan-treated SHR than in WKY, and no significant differences were noted in the remaining parameters between the 2 strains of rats. Compared with untreated SHR, treated SHR showed no left ventricular hypertrophy, diminished (
P
<0.05) blood pressure, left ventricular collagen volume fraction and TIMP-1 mRNA, and increased (
P
<0.05) collagenase activity. These results suggest that the transcription of the TIMP-1 gene is upregulated in the hypertrophied and fibrotic left ventricle of adult SHR. Upregulation of TIMP-1 may account for diminished collagenase activity in the myocardium of those rats. Chronic angiotensin II type 1 receptor blockade with losartan resulted in inhibition of TIMP-1 expression and stimulation of collagenase activity in the left ventricle of SHR. It is proposed that angiotensin II may facilitate myocardial fibrosis in SHR by depressing the collagenase-mediated extracellular degradation of collagen fibers.
Interactions Between Nitric Oxide and Endothelin in the Regulation of Vascular Tone of Human Resistance Vessels In Vivo
Authors: Cardillo Carmine , Kilcoyne Crescence M. , Cannon Richard O. , Panza Julio A.
Published: June 2012

Abstract
—Endothelial release of nitric oxide (NO) contributes to the regulation of vascular tone by inducing vascular relaxation. In addition, NO may inhibit the synthesis and hemodynamic effects of endothelin-1 (ET-1), a powerful endothelium-derived vasoconstrictor peptide that may stimulate NO production. However, whether NO and ET-1 physiologically interact to regulate vascular tone in humans has not been defined. In this study, the interactions between the
l
-arginine NO pathway and the ET-1 system in the regulation of vascular tone in human forearm resistance vessels were examined in vivo. Vasomotor response to the NO synthase inhibitor
N
G
-monomethyl-
l
-arginine (L-NMMA, 4 μmol/min for 30 minutes) was measured during either saline infusion or blockade of ET-1 receptors. Endothelin-A (ET
A
) and endothelin-B (ET
B
) receptor blockade was achieved by infusion of BQ-123 (100 nmol/min) and BQ-788 (50 nmol/min), respectively, separately and in combination. Drugs were infused into the brachial artery, and the forearm blood flow (FBF) response was measured by strain-gauge plethysmography. During saline infusion, L-NMMA administration significantly decreased FBF (25%,
P
<0.01 versus baseline). This effect was significantly blunted during nonselective blockade of ET-1 receptors (7% decrease in FBF,
P
=0.02 versus the effect of L-NMMA during saline infusion). Selective ET
A
blockade did not modify the vasoconstrictor response to L-NMMA (26% decrease in FBF,
P
=0.66 versus the effect of L-NMMA during saline infusion), but selective ET
B
receptor antagonism caused significant diminution of the hemodynamic response to NO inhibition (8% decrease in FBF,
P
=0.04 versus the effect of L-NMMA during saline infusion). Thus ET-1 contributes to the regulation of vascular tone by stimulating NO activity. This effect is mediated through endothelial ET
B
receptors and may be relevant in conditions associated with endothelial dysfunction.
Lack of Association of 3 Functional Gene Variants With Hypertension in African Americans
Authors: Larson Nicole , Hutchinson Richard , Boerwinkle Eric
Published: June 2012

Abstract
—African Americans are a critical population in which to study the impact of physiologically important candidate gene mutations on the occurrence of hypertension. African Americans not only have a higher prevalence of hypertension, but the disease strikes earlier, with greater severity, and often results in death at an earlier age compared with whites in the United States. In this study, 3 physiologically important candidate gene mutations (angiotensinogen A[−6], α-Adducin Gly460Trp, and G-Protein β
3
-subunit C825T) were examined for their association with hypertension status in a sample of 904 African Americans from Jackson, Mississippi. Tests of simple association and multivariate logistic regression analyses revealed no association between hypertension status and any of the studied polymorphisms. This lack of association persisted after stratification of the sample by gender and body size. These data indicate that these polymorphisms do not contribute in a significant way to interindividual variation in the risk of hypertension in this sample of African Americans, and further genome-wide studies should be performed to identify genes that may influence blood pressure levels in this population.
Role of Tumor Necrosis Factor-α Gene Locus in Obesity and Obesity-Associated Hypertension in French Canadians
Authors: Pausova Zdenka , Deslauriers Benoit , Gaudet Daniel , Tremblay Johanne , Kotchen Theodore A. , Larochelle Pierre , Cowley Allen W. , Hamet Pavel
Published: June 2012

Abstract
—Obesity represents a serious risk factor for the development of cardiovascular diseases, including hypertension. Segregation studies suggest that obesity and obesity-associated hypertension may share some genetic determinants. The results of the present candidate gene investigation suggest that in hypertensive pedigrees of French-Canadian origin, one such determinant is the tumor necrosis factor (TNF)-α gene locus. Gender-pooled quantitative sib-pair analysis demonstrated a significant effect of the gene locus on 3 global and 7 regional measures of obesity (
P
=0.05 to 0.0004). Gender-separate quantitative sib-pair analyses showed that the impact of the locus on obesity is most significant in the abdominal region in men and in the thigh region in women. Furthermore, the haplotype relative-risk test demonstrated a significant association between the TNF-α gene locus and both obesity (
P
=0.006) and obesity-associated hypertension (
P
=0.02). These effects were most significant in individuals with nonmorbid obesity. In conclusion, the results of linkage and association analyses suggest that in hypertensive pedigrees of French-Canadian origin, the TNF-α gene locus contributes to the determination of obesity and obesity-associated hypertension. In addition, the data indicate that gender modifies the effect of the locus on the regional distribution of body fat.
Performance of Classic Electrocardiographic Criteria for Left Ventricular Hypertrophy in an African Population
Authors: Jaggy Christian , Perret François , Bovet Pascal , van Melle Guy , Zerkiebel Nic , Madeleine George , Kappenberger Lukas , Paccaud Fred
Published: June 2012

Abstract
—ECG criteria for left ventricular hypertrophy (LVH) have been almost exclusively elaborated and calibrated in white populations. Because several interethnic differences in ECG characteristics have been found, the applicability of these criteria to African individuals remains to be demonstrated. We therefore investigated the performance of classic ECG criteria for LVH detection in an African population. Digitized 12-lead ECG tracings were obtained from 334 African individuals randomly selected from the general population of the Republic of Seychelles (Indian Ocean). Left ventricular mass was calculated with M-mode echocardiography and indexed to body height. LVH was defined by taking the 95th percentile of body height–indexed LVM values in a reference subgroup. In the entire study sample, 16 men and 15 women (prevalence 9.3%) were finally declared to have LVH, of whom 9 were of the reference subgroup. Sensitivity, specificity, accuracy, and positive and negative predictive values for LVH were calculated for 9 classic ECG criteria, and receiver operating characteristic curves were computed. We also generated a new composite time-voltage criterion with stepwise multiple linear regression: weighted time-voltage criterion=(0.2366R
aVL
+0.0551R
V5
+0.0785S
V3
+ 0.2993T
V1
)×QRS duration. The Sokolow-Lyon criterion reached the highest sensitivity (61%) and the R
aVL
voltage criterion reached the highest specificity (97%) when evaluated at their traditional partition value. However, at a fixed specificity of 95%, the sensitivity of these 10 criteria ranged from 16% to 32%. Best accuracy was obtained with the R
aVL
voltage criterion and the new composite time-voltage criterion (89% for both). Positive and negative predictive values varied considerably depending on the concomitant presence of 3 clinical risk factors for LVH (hypertension, age ≥50 years, overweight). Median positive and negative predictive values of the 10 ECG criteria were 15% and 95%, respectively, for subjects with none or 1 of these risk factors compared with 63% and 76% for subjects with all of them. In conclusion, the performance of classic ECG criteria for LVH detection was largely disparate and appeared to be lower in this population of East African origin than in white subjects. A newly generated composite time-voltage criterion might provide improved performance. The predictive value of ECG criteria for LVH was considerably enhanced with the integration of information on concomitant clinical risk factors for LVH.
Hypertension in Black Patients
Authors: Ergul Adviye
Published: June 2012

Abstract
—The prevalence of essential hypertension in blacks is much higher than that in whites. In addition, the pathogenesis of hypertension appears to be different in black patients. For example, black patients present with a salt-sensitive hypertension characterized by low renin levels. Racial differences in renal physiology and socioeconomic factors have been suggested as possible causes of this difference, but reasons for this difference remain unclear. Endothelial cells are important in the regulation of vascular tonus and homeostasis, in part through the secretion of vasoactive substances. One of these factors, endothelin-1 (ET-1), is a 21 amino acid residue peptide with potent vasopressor actions. In addition to its contractile effects, it has been shown to stimulate mitogenesis in a number of cell types. Moreover, ET-1 displays modulatory effects on the endocrine system, including stimulation of angiotensin II and aldosterone production and inhibition of antidiuretic hormone in the kidney. Recent data from several laboratories indicate that ET-1 is overexpressed in the vasculature in several salt-sensitive models of experimental hypertension. Moreover, circulating plasma ET-1 levels are significantly increased in black hypertensives compared with white hypertensives. Thus, the ET system might be particularly important in the development or maintenance of hypertension in this population.
Telomere Length Inversely Correlates With Pulse Pressure and Is Highly Familial
Authors: Jeanclos Elisabeth , Schork Nicholas J. , Kyvik Kirsten O. , Kimura Masayuki , Skurnick Joan H. , Aviv Abraham
Published: June 2012

Abstract
—There is evidence that telomeres, the ends of chromosomes, serve as clocks that pace cellular aging in vitro and in vivo. In industrialized nations, pulse pressure rises with age, and it might serve as a phenotype of biological aging of the vasculature. We therefore conducted a twin study to investigate the relation between telomere length in white blood cells and pulse pressure while simultaneously assessing the role of genetic factors in determining telomere length. We measured by Southern blot analysis the mean length of the terminal restriction fragments (TRF) in white blood cells of 49 twin pairs from the Danish Twin Register and assessed the relations of blood pressure parameters with TRF. TRF length showed an inverse relation with pulse pressure. Both TRF length and pulse pressure were highly familial. We conclude that telomere length, which is under genetic control, might play a role in mechanisms that regulate pulse pressure, including vascular aging.
Repair of Coronary Arterioles After Treatment With Perindopril in Hypertensive Heart Disease
Authors: Schwartzkopff Bodo , Brehm Michael , Mundhenke Markus , Strauer Bodo E.
Published: June 2012

Abstract
—In hypertensive heart disease, no data are available on the repair of coronary resistance vessels in patients after long-term ACE inhibitor treatment. Fourteen patients with essential hypertension were studied with coronary flow reserve and with transvenous endomyocardial biopsy before and after 12 months of antihypertensive treatment with perindopril (4 to 8 mg/d, mean 5.9±2.3 mg/d). Left ventricular muscle mass index decreased by 11% (from 145±41 to 128±36 g/m
2
,
P
=0.04). Maximal coronary blood flow was increased by 54% (from 170±46 to 263±142 mL · min
−1
· 100 g
−1
,
P
=0.001), and minimal coronary vascular resistance was diminished by 33% (from 0.67±0.21 to 0.45±0.19 mm Hg · min · 100 g · mL
−1
,
P
=0.001); consequently, coronary reserve increased by 67% from 2.1±0.6 to 3.5±1.9 (
P
=0.001). Structural analysis revealed regression of periarteriolar collagen area by 54% (from 558±270 to 260±173 μm
2
,
P
=0.04) and of total interstitial collagen volume density by 22% (from 5.5±3.8 Vv% to 4.3±3.2 Vv%,
P
=0.04), whereas arteriolar wall area was slightly but not significantly reduced. Long-term therapy with the ACE inhibitor perindopril induces structural repair of coronary arterioles that is mainly characterized by the regression of periarteriolar fibrosis and associated with a marked improvement in coronary reserve. These findings indicate the beneficial reparative effects of ACE inhibition on coronary microcirculation in hypertensive heart disease.
Angiotensin II Activates Collagen I Gene Through a Mechanism Involving the MAP/ER Kinase Pathway
Authors: Tharaux Pierre-Louis , Chatziantoniou Christos , Fakhouri Fadi , Dussaule Jean-Claude
Published: June 2012

Abstract
—Vascular remodeling and rearrangement of the extracellular matrix formation are among the major adaptive mechanisms to chronic increase in blood pressure. In previous studies we have found that angiotensin II (Ang II) participates in the hypertension-associated aortic and renal vascular fibrosis by stimulating collagen type I formation. The purpose of the present study was to gain insight into the molecular events that lead from the Ang II receptor to collagen I gene activation. To this end, we used a novel strain of transgenic mice harboring the luciferase gene under the control of the collagen I-α
2
chain promoter [procolα
2
(I)]. Ang II produced an early (1 hour) 2- to 3-fold stimulation of procolα
2
(I) activity in freshly isolated aortas and renal cortical slices (
P
<0.01) followed by similar increase in procolα
2
(I) mRNA aortic levels. This effect of Ang II was inhibited by AT1-receptor antagonism (candesartan) and blockade of the MAPK/ERK cascade (PD98059); in contrast, inhibition of the P38 kinase pathway (SB202190) and blockade of the release of the transcription factor NFκB (PDTC) did not have any effect in the Ang II–induced activation of the collagen I gene. In addition, Ang II induced a rapid (5 minutes) increase of the MAPK/ERK activity that was accompanied by increased expression (3-fold) of the c-
fos
proto-oncogene. This increase of c-
fos
mRNA expression was blocked by PD98059; in addition, curcumin, a blocker of the transcriptional factor AP-1, canceled the effect of Ang II on the collagen I gene. Decorin, a scavenger of the active form of transforming growth factor-β (TGF-β), canceled the Ang II effect on collagen I gene, whereas inhibition of the MAPK/ERK pathway had no effect on the TGF-β–induced activation of procolα
2
(I). These data indicate that the cellular events after AT1 receptor stimulation and leading to activation of collagen I gene expression require activation of both the MAPK/ERK and TGF-β signaling pathways.
Mammalian Bufadienolide Is Synthesized From Cholesterol in the Adrenal Cortex by a Pathway That Is Independent of Cholesterol Side-Chain Cleavage
Authors: Dmitrieva Renata I. , Bagrov Alexei Y. , Lalli Enzo , Sassone-Corsi Paolo , Stocco Douglas M. , Doris Peter A.
Published: June 2012

Abstract
—An increasing body of evidence suggests that an endogenous mammalian bufadienolide (BD) may be involved in the regulation of Na
+
,K
+
-ATPase activity and the pathogenesis of arterial hypertension. We developed a purification scheme for marinobufagenin (MBG), an amphibian cardiotonic BD, and applied it to purify and characterize material in human plasma, culture medium conditioned by Y-1 adrenocortical cells, and rat adrenal tissue. MBG immunoreactivity purified from plasma and measured by ELISA showed important similarities (chromatography and antibody cross-reactivity) to material secreted into cell culture medium by Y-1 cells. This observation indicates that circulating mammalian BD may have an adrenocortical origin. Release of mammalian BD from adrenocortical cells grown in the absence of exogenous cholesterol was reduced by treatment of cultures with mevastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor. Supplementation of the serum and cholesterol-free cell culture medium with the LDL fraction of human plasma increased the production of MBG material in the presence of mevastatin, supporting its origin from cholesterol. We used Y-1 cell lines transfected with genes shown to inhibit steroidogenesis through cholesterol side-chain cleavage (Y-1/DAX and Y-1/RIAB) to investigate the dependence of MBG biosynthesis on side-chain cleavage. Our results indicate that the mammalian BD is synthesized in the adrenal cortex from cholesterol and shares important similarities with the amphibian BD MBG, that its biosynthesis is independent of transfer of cholesterol to the side-chain cleavage enzyme complex mediated by steroidogenic acute regulatory protein, and that neither cAMP nor protein kinase A appears to be a critical component of the pathway controlling its biosynthesis.
Arterial Stiffness as Underlying Mechanism of Disagreement Between an Oscillometric Blood Pressure Monitor and a Sphygmomanometer
Authors: van Popele Nicole M. , Bos Willem Jan W. , de Beer Nicole A. M. , van der Kuip Deirdre A. M. , Hofman A. , Grobbee Diederick E. , Witteman Jacqueline C. M.
Published: June 2012

Abstract
—Oscillometric blood pressure devices tend to overestimate systolic blood pressure and underestimate diastolic blood pressure compared with sphygmomanometers. Recent studies indicate that discrepancies in performance between these devices may differ between healthy and diabetic subjects. Arterial stiffness in diabetics could be the underlying factor explaining these differences. We studied differences between a Dinamap oscillometric blood pressure monitor and a random-zero sphygmomanometer in relation to arterial stiffness in 1808 healthy elderly subjects. The study was conducted within the Rotterdam Study, a population-based cohort study of subjects aged 55 years and older. Systolic and diastolic blood pressure differences between a Dinamap and a random-zero sphygmomanometer were related to arterial stiffness, as measured by carotid-femoral pulse wave velocity. Increased arterial stiffness was associated with higher systolic and diastolic blood pressure readings by the Dinamap compared with the random-zero sphygmomanometer, independent of age, gender, and average mean blood pressure level of both devices. The β-coefficient (95% CI) was 0.25 (0.00 to 0.50) mm Hg/(m/s) for the systolic blood pressure difference and 0.35 (0.20 to 0.50) mm Hg/(m/s) for the diastolic blood pressure difference. The results indicate that a Dinamap oscillometric blood pressure device, in comparison to a random-zero sphygmomanometer, overestimates systolic and diastolic blood pressure readings in subjects with stiff arteries.
Important Role of Angiotensin II–Mediated c-Jun NH
2
-Terminal Kinase Activation in Cardiac Hypertrophy in Hypertensive Rats
Authors: Izumi Yasukatsu , Kim Shokei , Zhan Yumei , Namba Masashi , Yasumoto Hideo , Iwao Hiroshi
Published: June 2012

Abstract
—In vitro studies on the role of the mitogen-activated protein (MAP) kinase family (extracellular signal-regulated kinase [ERK], c-Jun NH
2
-terminal kinase [JNK], and p38) in cardiac hypertrophic response have produced confusing and contradictory results. We examined the in vivo role of the angiotensin II type 1 (AT
1
) receptor in cardiac MAP kinase activities during both the onset and development of cardiac hypertrophy in stroke-prone spontaneously hypertensive rats (SHRSP). In both the acute and chronic phases of cardiac hypertrophy in SHRSP, cardiac JNK activities were significantly increased compared with those in normotensive rats, whereas there was no prominent increase in cardiac ERK or p38 activities in SHRSP. Losartan, an AT
1
receptor antagonist, prevented the onset of cardiac hypertrophy and regressed the progression of cardiac hypertrophy in SHRSP, being accompanied by the reduction of JNK activity and activator protein-1 (AP-1) activity in SHRSP. However, in spite of the normalization of blood pressure, hydralazine did not prevent or regress cardiac hypertrophy and did not decrease JNK or AP-1 activity in SHRSP. Inversely, hydralazine significantly increased the cardiac ERK activity in SHRSP by enhancing its phosphorylation. In conclusion, we have obtained the first evidence that the AT
1
receptor is involved in the enhanced cardiac JNK activity in both the onset and development of cardiac hypertrophy of hypertensive rats. We propose that JNK is involved in AT
1
receptor–mediated cardiac hypertrophy in vivo, in part mediated by the activation of AP-1.
Hemodynamic, Hormone, and Urinary Effects of Adrenomedullin Infusion in Essential Hypertension
Authors: Troughton Richard W. , Lewis Lynley K. , Yandle Timothy G. , Richards A. Mark , Nicholls M. Gary
Published: June 2012

Abstract
—We examined the effects of the vasodilator peptide adrenomedullin (AM) infused intravenously into subjects with essential hypertension. Eight men 39 to 58 years old with uncomplicated hypertension (147/96±5/3 mm Hg at baseline) were studied in a placebo-controlled, crossover design. Each subject received intravenous AM in a low and a high dose (2.9 and 5.8 pmol · kg
−1
· min
−1
for 2 hours each) or vehicle-control (Hemaccel) infusion in a random order on day 4 of a controlled metabolic diet (80 mmol/d Na
+
, 100 mmol/d K
+
). Plasma AM reached pathophysiological levels during infusion (18±4 pmol/L in low dose, 34±9 pmol/L in high dose) with a concurrent rise in plasma cAMP (+8.4±1.2 pmol/L,
P
<0.05 compared with control). Compared with control, high-dose AM increased peak heart rate (+17.8±2.3 bpm,
P
<0.01), lowered systolic (−24.6±0.9 mm Hg;
P
<0.01) and diastolic (−21.9±1.4 mm Hg;
P
<0.01) blood pressure, and increased cardiac output (+1.0±0.1 L/min in low dose, +2.9±0.2 L/min in high dose;
P
<0.01 for both). Despite a rise in plasma renin activity during high dose (
P
<0.05), aldosterone levels did not alter. Plasma norepinephrine levels increased 1295±222 pmol/L (
P
<0.001) and epinephrine increased 74±15 pmol/L (
P
<0.05) with high-dose AM compared with control. AM had no significant effect on urine volume and sodium excretion. In subjects with essential hypertension, the intravenous infusion of AM to achieve pathophysiological levels produced significant falls in arterial pressure, increased heart rate and cardiac output, and stimulated the sympathetic system and renin release without concurrent increase in aldosterone. Urinary parameters were unaltered. Although AM has potent hemodynamic and neurohumoral effects in subjects with essential hypertension, the threshold for urinary actions is set higher.
Angiotensin II–Induced Hypertension
Authors: Muthalif Mubarack M. , Karzoun Nour A. , Gaber Lillian , Khandekar Zinat , Benter Ibrahim F. , Saeed Abdelwahab E. , Parmentier Jean-Hugues , Estes Anne , Malik Kafait U.
Published: June 2012

Abstract
—We reported that norepinephrine and angiotensin II (Ang II) activate the Ras/mitogen-activated protein (MAP) kinase pathway primarily through the generation of cytochrome P450 (CYP450) metabolites. The purpose of the present study was to determine the contribution of Ras and CYP450 to Ang II–dependent hypertension in rats. Infusion of Ang II (350 ng/min for 6 days) elevated mean arterial blood pressure (MABP) (171±3 mm Hg for Ang II versus 94±5 for vehicle group,
P
<0.05). Ras is activated on farnesylation by farnesyl protein transferase (FPT). When Ang II was infused in combination with FPT inhibitor FPT III (232 ng/min) or BMS-191563 (578 ng/min), the development of hypertension was attenuated (171±3 mm Hg for Ang II plus vehicle versus 134±5 mm Hg for Ang II plus FPT III and 116±6 mm Hg for Ang II plus BMS-191563,
P
<0.05). Treatment with the MAP kinase kinase inhibitor PD-98059 (5 mg SC) reduced MABP. The CYP450 inhibitor aminobenzotriazole (50 mg/kg) also diminished the development of Ang II–induced hypertension to 113±8 mm Hg. The activities of Ras, MAP kinase, and CYP450 measured in the kidney were elevated in hypertensive animals. The infusion of FPT III, BMS-191563, or aminobenzotriazole reduced the elevation in Ras and MAP kinase activity. Morphological studies of the kidney showed that FPT III treatment ameliorated the arterial injury, vascular lesions, fibrinoid necrosis, focal hemorrhage, and hypertrophy of muscle walls observed in hypertensive animals. These data suggest that the activation of Ras and CYP450 contributes to the development of Ang II–dependent hypertension and associated vascular pathology.
Lacidipine and Blood Pressure Variability in Diabetic Hypertensive Patients
Authors: Frattola Alessandra , Parati Gianfranco , Castiglioni Paolo , Paleari Felice , Ulian Luisa , Rovaris Giovanni , Mauri Gabriele , Di Rienzo Marco , Mancia Giuseppe
Published: June 2012

Abstract
—The aim of our study was to assess the effects of lacidipine, a long-acting calcium antagonist, on 24-hour average blood pressure, blood pressure variability, and baroreflex sensitivity. In 10 mildly to moderately hypertensive patients with type II diabetes mellitus (aged 18 to 65 years), 24-hour ambulatory blood pressure was continuously monitored noninvasively (Portapres device) after a 3-week pretreatment with placebo and a subsequent 4-week once daily lacidipine (4 mg) or placebo treatment (double-blind crossover design). Systolic blood pressure, diastolic blood pressure, and heart rate means were computed each hour for 24 hours (day and night) at the end of each treatment period. Similar assessments were also made for blood pressure and heart rate variability (standard deviation and variation coefficient) and for 24-hour baroreflex sensitivity, which was quantified (1) in the time domain by the slope of the spontaneous sequences characterized by progressive increases or reductions of systolic blood pressure and RR interval and (2) in the frequency domain by the squared ratio of RR interval and systolic blood pressure spectral power ≈0.1 and 0.3 Hz over the 24 hours. Compared with placebo, lacidipine reduced the 24-hour, daytime, and nighttime systolic and diastolic blood pressure (
P
<0.05) with no significant change in heart rate. It also reduced 24-hour, daytime, and nighttime standard deviation (−19.6%, −14.4%, and −24.0%, respectively;
P
<0.05) and their variation coefficient. The 24-hour average slope of all sequences (7.7±1.7 ms/mm Hg) seen during placebo was significantly increased by lacidipine (8.7±1.8 ms/mm Hg,
P
<0.01), with a significant increase being obtained also for the 24-hour average α coefficient at 0.1 Hz (from 5.7±1.5 to 6.4±1.3 ms/mm Hg,
P
<0.01). Thus, in diabetic hypertensive patients, lacidipine reduced not only 24-hour blood pressure means but also blood pressure variability. This reduction was accompanied by an improvement of baroreflex sensitivity. Computer analysis of beat-to-beat 24-hour noninvasive blood pressure monitoring may offer valuable information about the effects of antihypertensive drugs on hemodynamic and autonomic parameters in daily life.
Hypothesis Regarding the Pathophysiological Role of Alternative Pathways of Angiotensin II Formation in Atherosclerosis
Authors: Arakawa Kikuo , Urata Hidenori
Published: June 2012

Abstract
—The renin-angiotensin system has been studied and recognized as one of the major blood pressure–regulating systems for the past century. In the last quarter century, however, many alternative pathways of angiotensin II formation have been found, and among them, chymase has been a focus of interest because of its specificity and potency in the human cardiovascular system. Chymase evidently is not involved in functional regulation of blood pressure at least in the short term, but evidence is accumulating that it may be involved in structural remodeling of the cardiovascular system. We found increased vascular chymase activity in atherosclerotic lesions of the human aorta as well as in cardiac remodeling after myocardial infarction. We found a significant positive correlation between serum total or LDL cholesterol levels and arterial chymase-dependent angiotensin II–forming activity in patients who were undergoing coronary artery bypass operation, suggesting that high serum cholesterol may trigger upregulation of vascular chymase and facilitate the development of atherosclerosis. This hypothesis was tested in Syrian hamsters fed a high cholesterol diet containing 0.5% cholesterol: A marked lipid deposition in the aortic cusp developed and the plasma cholesterol levels were positively correlated with aortic chymase activity. An orally active nonpeptide chymase inhibitor almost canceled this lipid deposition. These clinical and experimental data indicated an association between cholesterol and vascular chymase upregulation that may facilitate the development of atherosclerosis.
Renovascular Hypertension
Authors: Anderson W. P. , Kett M. M. , Stevenson K. M. , Edgley A. J. , Denton K. M. , Fitzgerald S. M.
Published: June 2012

Abstract
—Experimental narrowing of the main renal artery to produce hypertension increases the aorta-glomerular capillary pressure difference and vascular resistance. This article examines the hypothesis that hypertension also may be caused by structural changes that narrow intrarenal blood vessels, similarly increasing preglomerular vascular resistance and the aortic-glomerular capillary pressure gradient. There is evidence of both wall hypertrophy and lumen narrowing of the preglomerular arteries in spontaneously hypertensive rats, with increased preglomerular resistance and aortic-glomerular capillary pressure difference. We have also attempted to induce structural changes in renal-preglomerular vessels experimentally by infusing angiotensin II at low doses (0.5 to 4.5 ng/kg per minute) into the renal artery of Sprague-Dawley rats and greyhound dogs for up to 4 weeks. This angiotensin II infusion produced apparent dose-related effects on preglomerular vessel structure and hypertension. The possibility that hypertension may be induced by structural changes in preglomerular resistance vessel walls, by simulation of the hemodynamic effects of main renal artery stenosis, deserves further investigation.
Fetal and Childhood Growth and Hypertension in Adult Life
Authors: Eriksson Johan , Forsén Tom , Tuomilehto Jaakko , Osmond Clive , Barker David
Published: June 2012

Abstract
—The association between low birth weight and raised blood pressure has been extensively replicated. Little is known about the way childhood growth modifies the effects of low birth weight. We report on the fetal and childhood growth of 1958 men and women who received treatment for hypertension and belong to a cohort of 7086 people born in Helsinki, Finland, during 1924–1933. As expected, the men and women who developed hypertension had low birth weight (
P
=0.002). They were also shorter in body length at birth (
P
=0.02). After birth they experienced accelerated growth, so that by 7 years their heights and weights were approximately average. In a simultaneous regression, both birth length and tall height had statistically significant although opposing effects on hypertension (
P
=0.003 for birth length and 0.009 for height at 7 years). Accelerated postnatal growth was associated with better childhood living conditions. Children who later developed both hypertension and type 2 diabetes, rather than hypertension alone, had small placental size as well as small body size at birth, and their accelerated postnatal growth continued beyond 7 years. We suggest that hypertension may originate through retarded growth in utero followed by accelerated postnatal growth as a result of good living conditions. Retarded fetal growth leads to permanently reduced cell numbers in the kidney and other tissues, and subsequent accelerated growth may lead to excessive metabolic demand on this limited cell mass.
Phenotypic Evidence of Faulty Neuronal Norepinephrine Reuptake in Essential Hypertension
Authors: Rumantir Magdalena S. , Kaye David M. , Jennings Garry L. , Vaz Mario , Hastings Jacqueline A. , Esler Murray D.
Published: June 2012

Abstract
—Previous reports suggest that neuronal norepinephrine (NE) reuptake may be impaired in essential hypertension, perhaps because of dysfunction of the NE transporter, although the evidence is inconclusive. To further test this proposition, we applied phenotypically relevant radiotracer methodology, infusion of tritiated NE and quantification of NE metabolites, to 34 healthy lean subjects (body mass index <27.0 kg/m
2
), 19 overweight (body mass index >28.0 kg/m
2
) but otherwise healthy normotensive subjects, 13 untreated lean patients with essential hypertension, and 14 obesity-related hypertensives. Spillover of NE from the heart was increased in lean hypertensives only (mean±SD 33.4±20.6 versus 16.1±11.7 ng/min in lean normotensives,
P
<0.05), but this could have resulted from high cardiac sympathetic nerve firing rates, faulty NE reuptake, or both. The arterial plasma concentration of 3-methoxy-4-hydroxylphenylglycol, an extraneuronal metabolite of NE, was elevated in lean hypertensives only (3942±1068 versus 3055±888 pg/mL in healthy subjects,
P
<0.05). The fractional extraction of plasma tritiated NE in passage through the heart, determined on the basis of neuronal NE uptake, was reduced in lean essential hypertensives (0.65±0.19 versus 0.81±0.11 in healthy subjects,
P
<0.05). Cardiac release of the tritiated NE metabolite [
3
H]dihydroxylphenylglycol, produced intraneuronally by monoamine oxidase after uptake of [
3
H]NE by the transporter, was reduced in lean hypertensives only (992±1435 versus 4588±3189 dpm/min in healthy subjects,
P
<0.01) These findings suggest that neuronal reuptake of NE is impaired in essential hypertension. Through amplification of the neural signal, such a defect could constitute a neurogenic variant of essential hypertension. In obesity-related hypertension, there was no phenotypic evidence of NE transporter dysfunction.
NOS3 Glu298Asp Genotype and Blood Pressure Response to Endurance Training
Authors: Rankinen Tuomo , Rice Treva , Pérusse Louis , Chagnon Yvon C. , Gagnon Jacques , Leon Arthur S. , Skinner James S. , Wilmore Jack H. , Rao D. C. , Bouchard Claude
Published: June 2012

Abstract
—Endothelium-dependent vasodilation is a mechanism that may affect blood pressure response to endurance training. Because NO plays a central role in this process, the endothelial NO synthase gene is a good candidate for the regulation of exercise blood pressure. We investigated the associations between an endothelial NO synthase gene polymorphism (Glu298Asp) and endurance training–induced changes in resting and submaximal exercise blood pressure in 471 white subjects of the HERITAGE Family Study. Two submaximal exercise tests at 50 W were conducted both before and after a 20-week endurance training program. Steady-state exercise blood pressure was measured twice in each test with an automated unit. The Glu298Asp polymorphism was typed with a PCR-based method and digestion with
Ban
II. Both systolic and diastolic blood pressure at 50 W decreased in response to the training program, whereas resting blood pressure remained unchanged. The decrease in diastolic blood pressure at 50 W was greater (
P
=0.0005, adjusted for age, gender, baseline body mass index, and baseline diastolic blood pressure at 50 W) in the Glu/Glu homozygotes (4.4 [SEM 0.4] mm Hg, n=187) than in the heterozygotes (3.1 [0.4] mm Hg, n=213) and the Asp/Asp homozygotes (1.3 [0.7] mm Hg, n=71). The genotype accounted for 2.3% of the variance in diastolic blood pressure at 50 W training response. Both the Glu298 homozygotes and the heterozygotes had a greater (
P
=0.013) training-induced reduction in rate-pressure product at 50 W than the Asp298 homozygotes. These data suggest that DNA sequence variation in the endothelial NO synthase gene locus is associated with the endurance training–induced decreases in submaximal exercise diastolic blood pressure and rate-pressure product in sedentary normotensive white subjects.
Ambulatory Blood Pressure Monitoring and Organ Damage
Authors: Mancia Giuseppe , Parati Gianfranco
Published: June 2012

Several papers have suggested that 24-hour average blood pressure (BP) is superior to office BP in relation to hypertension target organ damage. This review article will specifically address the evidence provided in this regard by either cross-sectional or longitudinal studies. It will also critically discuss the available data supporting the concept that not only 24-hour average BP values, but also specific BP patterns occurring within the 24 hours may have clinical relevance. This is the case for daytime versus nighttime BP, the day/night BP difference, the morning BP rise, and overall BP variability.
Prognostic Significance of Blood Pressure and Heart Rate Variabilities
Authors: Kikuya Masahiro , Hozawa Atsushi , Ohokubo Takayoshi , Tsuji Ichiro , Michimata Mari , Matsubara Mitsunobu , Ota Masahiro , Nagai Kenichi , Araki Tsutomu , Satoh Hiroshi , Ito Sadayoshi , Hisamichi Shigeru , Imai Yutaka
Published: June 2012

Abstract
—To investigate the association between cardiovascular mortality and short-term variabilities in blood pressure and heart rate, we performed a long-term prospective study of ambulatory blood pressure monitoring in Ohasama, Japan, starting in 1987. We obtained ambulatory blood pressure and heart rate in 1542 subjects ≥40 years of age. Blood pressure and heart rate variabilities were estimated as a standard deviation measured every 30 minutes by ambulatory monitoring. There were 67 cardiovascular deaths during the follow-up period (mean=8.5 years). The Cox proportional hazards model, adjusted for possible confounding factors, demonstrated a significant increase in cardiovascular mortality, with an increase in daytime systolic ambulatory blood pressure variability. A similar trend was observed in daytime diastolic and nighttime ambulatory blood pressures. Cardiovascular mortality rate increased linearly, with a decrease in daytime heart rate variability. Subjects in whom the daytime systolic ambulatory blood pressure variability was larger than third quintile and the daytime heart rate variability was lower than the mean−SD were at extremely high risk of cardiovascular mortality. The blood pressure and heart rate variabilities obtained every 30 minutes by ambulatory blood pressure monitoring were independent predictors for cardiovascular mortality in the general population.
Cushing, Cortisol, and Cardiovascular Disease
Authors: Whitworth Judith A. , Mangos George J. , Kelly John J.
Published: June 2012

Abstract
—Cushing’s syndrome of glucocorticoid excess is named after the eminent Boston neurosurgeon Harvey W. Cushing (1869-1939). The recognition that glucocorticoid excess produces hypertension led to examination of the role of cortisol in essential hypertension, but it is only over the last decade that evidence has emerged to support the concept. Despite the widespread assumption that cortisol raises blood pressure as a consequence of renal sodium retention, there are few data consistent with the notion. Although it has a plethora of actions on brain, heart and blood vessels, kidney, and body fluid compartments, precisely how cortisol elevates blood pressure is unclear. Candidate mechanisms currently being examined include inhibition of the vasodilator nitric oxide system and increases in vasoconstrictor erythropoietin concentration.
Malignant Pheochromocytoma
Authors: Rao Fangwen , Keiser Harry R. , O’Connor Daniel T.
Published: June 2012

Abstract
—Chromaffin granule transmitters such as chromogranin A and catecholamines have been used in the diagnosis of pheochromocytoma, but the diagnostic and prognostic value of chromogranin A have not been explored in malignant pheochromocytoma. We evaluated these transmitters in patients with pheochromocytoma (n=27), both benign (n=13) and malignant (n=14). Patients with benign pheochromocytoma were studied before and after surgical excision (n=6), whereas patients with malignant pheochromocytoma were evaluated before and after combination chemotherapy with regular cycles of cyclophosphamide/dacarbazine/vincristine (nonrandomized trial in n=9). During treatment, patient responses to chemotherapy were divided according to anatomic and clinical criteria: responders (n=5) versus nonresponders (n=4). Plasma chromogranin A rose progressively (
P
<0.0001) from control subjects (48.0±3.0 ng/mL) to benign pheochromocytoma (188±40.5 ng/mL) to malignant pheochromocytoma (2932±960 ng/mL). Parallel changes were seen for plasma norepinephrine (
P
<0.0001), though plasma epinephrine was actually lower in malignant than benign pheochromocytoma (
P
=0.0182). In bivariate analyses, chromogranin A, norepinephrine, and epinephrine discriminated between pheochromocytoma and control subjects (all
P
<0.0001), whereas in a multivariate analyses, norepinephrine was the best discriminator (
P
=0.011). Chromogranin A was significantly different in benign versus malignant pheochromocytoma on both bivariate (
P
=0.0003) and multivariate (
P
=0.011) analyses. After excision of benign pheochromocytoma, chromogranin A (
P
=0.028), norepinephrine (
P
=0.047), and epinephrine (
P
=0.037) all fell to values near normal. During chemotherapy of malignant pheochromocytoma (n=9), plasma chromogranin A (
P
=0.047) and norepinephrine (
P
=0.02) fell but not epinephrine. In 5 responders to chemotherapy, there were significant declines in chromogranin A (
P
=0.03) and norepinephrine (
P
=0.03) but not epinephrine; in 4 nonresponders, none of the transmitters changed. Plasma chromogranin A varied longitudinally with tumor response and relapse. We conclude that plasma chromogranin A is an effective tool in the diagnosis of pheochromocytoma, and markedly elevated chromogranin A may point to malignant pheochromocytoma. During chemotherapy of malignant pheochromocytoma, chromogranin A can be used to gauge tumor response and relapse.
Baseline Characteristics of Participants in the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)
Authors: Grimm Richard H. , Margolis Karen L. , Papademetriou Vasilios , Cushman William C. , Ford Charles E. , Bettencourt Judy , Alderman Michael H. , Basile Jan N. , Black Henry R. , DeQuattro Vincent , Eckfeldt John , Hawkins C. Morton , Perry H. Mitchell , Proschan Michael
Published: June 2012

Abstract
—Diuretics and β-blockers have been shown to reduce the risk of cardiovascular morbidity and mortality in people with hypertension in long-term clinical trials. No study has compared newer more costly antihypertensive agents (calcium antagonists, ACE inhibitors, and α-adrenergic blockers) with diuretics for reducing the incidence of cardiovascular disease in an ethnically diverse group of middle-aged and elderly hypertensive patients. The study is a randomized, double-blind, active-controlled clinical trial designed to determine whether the incidence of the primary outcome, fatal coronary heart disease or nonfatal myocardial infarction, differs between treatment initiation with a diuretic versus each of 3 other antihypertensive drugs. Men and women aged ≥55 years with at least 1 other cardiovascular disease risk factor were randomly assigned to chlorthalidone (12.5 to 25 mg/d), amlodipine (2.5 to 10 mg/d), lisinopril (10 to 40 mg/d), or doxazosin (2 to 8 mg/d) for planned follow-up of 4 to 8 years. This report describes the baseline characteristics of the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) participants. A total of 42 448 participants were randomized from 625 sites in the United States, Canada, Puerto Rico, and the US Virgin Islands. The mean age was 67 years, with 35% aged ≥70 years. Among those randomized, 36% were black, 19% were Hispanic, and 47% were women. The sample includes a high proportion of people with diabetes (36%), patients with existing cardiovascular disease (47%), and smokers (22%). There were no important differences between the randomized treatment groups at baseline. ALLHAT will add greatly to our understanding of the management of hypertension by providing an answer to the following question: are newer antihypertensive agents similar, superior, or inferior to traditional treatment with diuretics?
Synergistic Antihypertensive Effects of Nifedipine on Endothelium
Authors: Brovkovych Viktor , Kalinowski Leszek , Muller-Peddinghaus Reiner , Malinski Tadeusz
Published: June 2012

Recent studies have suggested that part of the vasorelaxation caused by nifedipine, a 1,4-dihydropyridine Ca
2+
antagonist, depends on the endothelium. To study the effect of endothelium-dependent vasorelaxation, the release of NO and superoxide (O
2
−
) in the presence of nifedipine in isolated cultured rabbit endothelial cells was measured. Highly sensitive electrochemical microsensors were placed onto the cell membrane, and the kinetics of NO and O
2
−
were measured simultaneously with time resolutions of 0.1 and 0.05 ms, respectively. Nifedipine at its therapeutical concentrations stimulated NO release and scavenged O
2
−
in endothelial cells. The linear relationship between NO concentration and nifedipine concentration was observed in the range between 0.01 and 1 nmol/L. NO concentration reached a maximum of 200±10 nmol/L at 1.2 nmol/L of nifedipine. The NO concentration was ≈50% and 30% of the concentration measured in the presence of receptor-dependent (acetylcholine) and the receptor-independent (Ca
2+
ionophore A23187) NO synthase (eNOS) agonists, respectively. NO release stimulated by eNOS agonists was followed by the generation of the NO scavenger superoxide. The concentration of O
2
−
was significantly lower after stimulation with nifedipine (peak 5±0.5 nmol/L) than after stimulation with acetylcholine (15±1 nmol/L) and Ca
2+
ionophore (25±1 nmol/L). The average rate of NO release by nifedipine is relatively slow (17 nmol/L per second). This is in sharp contrast to the fast rate of NO release by acetylcholine and Ca
2+
ionophore (40 and 300 nmol/L per second, respectively). These experiments show that nifedipine, apart from its well-known Ca
2+
antagonistic properties in vascular smooth muscle cells, stimulates the release of significant concentration of NO in endothelium and also preserves NO concentration. Both these effects may be beneficial in the treatment of hypertension.