bluuebunny/crossref_metadata_2025 huggingface dataset:
Sympathoinhibitory Function of the α
2A
-Adrenergic Receptor Subtype
Authors: Makaritsis Konstantinos P. , Johns Conrado , Gavras Irene , Altman John D. , Handy Diane E. , Bresnahan Margaret R. , Gavras Haralambos
Published: June 2012

Abstract
—Presynaptic α
2
-adrenergic receptors (α
2
-AR) are distributed throughout the central nervous system and are highly concentrated in the brain stem, where they contribute to neural baroreflex control of blood pressure (BP). To explore the role of the α
2A
-AR subtype in this function, we compared BP and plasma norepinephrine and epinephrine levels in genetically engineered mice with deleted α
2A
-AR gene to their wild-type controls. At baseline, the α
2A
-AR gene knockouts (n=11) versus controls (n=10) had higher systolic BP (123±2.5 versus 115±2.5 mm Hg,
P
<0.05), heart rate (730±15 versus 600±18 b/min,
P
<0.001), and norepinephrine (1.005±0.078 versus 0.587±0.095 ng/mL,
P
<0.01), respectively. When submitted to subtotal nephrectomy and given 1% saline as drinking water, both α
2A
-AR gene knockouts (n=14) and controls (n=14) became hypertensive, but the former required 15.6±2.5 days versus 29.3±1.4 days for the controls (
P
<0.001). End-point systolic BP was similar for both at 155±2.1 versus 152±5.2 mm Hg, but norepinephrine and epinephrine levels were twice as high in the knockouts at 1.386±0.283 and 0.577±0.143 versus 0.712±0.110 and 0.255±0.032 ng/mL, respectively,
P
<0.05 for both. We conclude that the α
2A
-AR subtype exerts a sympathoinhibitory effect, and its loss leads to a hypertensive, hyperadrenergic state.
Left Ventricular Mass, Stroke Volume, and Ouabain-Like Factor in Essential Hypertension
Authors: Manunta Paolo , Stella Paola , Rivera Rodolfo , Ciurlino Daniele , Cusi Daniele , Ferrandi Mara , Hamlyn John M. , Bianchi Giuseppe
Published: June 2012

Abstract
—Many patients with essential hypertension (EH) exhibit increased left ventricular mass. Similarly, elevated circulating levels of an endogenous ouabainlike factor (OLF) have been described in some but not all patients with EH. Moreover, ouabain has a hypertrophic influence on isolated cardiac myocytes. Accordingly, we investigated relationships among plasma OLF, left ventricular mass, and cardiac function in patients with EH. Plasma OLF was determined in 110 normotensive subjects and 128 patients with EH. Echocardiographic parameters and humoral determinants were measured in EH. Plasma OLF levels were increased (
P
<0.0001) in patients with EH (377±19 pmol/L) versus normotensive (253±53 pmol/L) subjects. The distribution of plasma OLF was unimodal in normotensives, whereas it was bimodal in EH. Twenty-four–hour diastolic ambulatory blood pressure was slighter higher in EH with high OLF compared with EH with normal OLF (93.2±1.14 versus 89.4±1.33 mm Hg,
P
=0.03). Left ventricular mass index and stroke volume in EH with high OLF were greater than in EH with normal OLF (101.9±3.3 versus 86.1±2.5 g/m
2
,
P
=0.0003, and 57.10±1.48 versus 52.30±1.14 mL/m
2
,
P
=0.02, respectively), although heart rate was slower (74.2±1.3 versus 80.5±1.3 bpm,
P
=0.005). Multiple regression analysis that tested the influence of body mass index, age, gender, 24-hour blood pressure, and OLF on left ventricular mass revealed independent contributions of systolic (13.2%) and diastolic (12.4%) blood pressure and plasma OLF (11.6%) to left ventricular mass. We conclude that ≈50% of patients with uncomplicated EH have elevated-high circulating OLF levels, higher diastolic blood pressure, greater left ventricular mass and stroke volume, and reduced heart rate. We propose that the OLF affects cardiovascular function and structure and should be considered as a factor that contributes to the risk of morbid events.
Detection and Control of High Blood Pressure in the Community
Authors: Meissner Irene , Whisnant Jack P. , Sheps Sheldon G. , Schwartz Gary L. , O’Fallon W. Michael , Covalt Jody L. , Sicks JoRean D. , Bailey Kent R. , Wiebers David O.
Published: June 2012

Abstract
—At the community level, the effect of national programs in increasing hypertension awareness, prevention, treatment, and control is unclear. This study evaluated the degree of detection and control of high blood pressure in a random population-based sample of Olmsted County, Minnesota, residents ≥45 years old, of whom 636 subjects among 1245 eligible residents agreed to participate. Home interview and home and office measurements of blood pressure were used to estimate awareness, treatment, and control rates for hypertension in the community. Mean blood pressures (±SD) were 138/80±20/12 mm Hg for men and 137/76±23/11 mm Hg for women. The overall prevalence of hypertension was 53%. The percentage of subjects with treated and controlled hypertension was 16.6%. Thirty-nine percent of subjects were unaware of their hypertension. Despite clinical trial evidence of reduced morbidity and mortality with antihypertensive therapy, recently reported national data suggest a leveling-off trend for treatment and control of hypertension. This population-based study supports these observations and suggests that at a community level, hypertension awareness and blood pressure control rates are suboptimal, presumably because of decreased attention to the detection and control of hypertension.
Serum Calcium and Cardiovascular Risk Factors and Diseases
Authors: Jorde Rolf , Sundsfjord Johan , Fitzgerald Patrick , Bønaa Kaare H.
Published: June 2012

Abstract
—Total serum calcium levels were measured in 12 865 men and 14 293 women, between the ages of 25 and 97 years, in the Tromsø Study during 1994 and 1995. With the use of a sex-specific multiple linear regression model with age, calcium, body mass index, cholesterol, HDL cholesterol, triglycerides, systolic and diastolic blood pressure, and pulse as possible covariates, serum calcium was significantly (
P
<0.001) and positively associated with systolic and diastolic blood pressure, serum cholesterol, and HDL cholesterol in both sexes. A similar but weaker association was observed between serum calcium and triglycerides in men (
P
<0.01). In all age groups, serum calcium levels were higher in men with a history of myocardial infarction than in those without, and the difference was significant (
P
<0.0001) in a linear regression analysis adjusted for age. When all the other variables were also included in a logistic regression model, serum calcium was a highly significant (
P
<0.0001) predictor of myocardial infarction in men, with an odds ratio of 1.2 per 0.1 mmol/L increase in serum calcium. In women, a nonsignificant trend was again seen. Because the free or ionized form of calcium is the physiologically important form and serum calcium was not corrected for serum albumin in our study, the results must be interpreted with caution. However, it appears likely that serum calcium is a predictor of cardiovascular disease in men.
Alternative Angiotensin II Formation in Rat Arteries Occurs Only at Very High Concentrations of Angiotensin I
Authors: Inoue Kiyo , Nishimura Hikaru , Kubota Jiro , Kawamura Keishiro
Published: June 2012

Abstract
—Contrary to previous reports, recent enzymatic assays showed the predominance of chymase-like activity in rat arteries. We determined the existence and significance of such alternative pathways in rat carotid arteries by measuring contraction of arterial rings in organ baths and blood pressure in conscious rats. Hamster aorta served as a positive control for chymase. Temocapril (30 μmol/L) inhibited the contractions to angiotensin (Ang) I (10
−9
to 10
−5
mol/L) except at high concentrations of Ang I (>10
−7
mol/L). Addition of chymostatin (100 μmol/L) to temocapril exerted a synergistic inhibitory effect. Hamster aorta gave similar results, except that temocapril was 30-fold less effective than in rat arteries. [Pro
11
,
d
-Ala
12
]Ang I (10
−8
to 10
−5
mol/L), a chymase-specific substrate, provoked similar responses in rat and hamster arteries; chymostatin, but not temocapril, attenuated the responses. CV 11974 (30 μmol/L), an Ang II type 1 receptor antagonist, abolished the responses to both peptides. In conscious rats, Ang I (0.03 to 30 μg/kg) and [Pro
11
,
d
-Ala
12
]Ang I (7 to 700 μg/kg) produced similar pressor responses. Not only CV 11974 (1 mg/kg) but also temocapril (2 mg/kg) abolished Ang I–induced responses in vivo. CV 11974, but not temocapril, inhibited responses to [Pro
11
,
d
-Ala
12
]Ang I. Our results showed the presence of the alternative pathway in rat arteries, but it did not play a major role. Arteries with the opposing characteristics of chymase responded equally to [Pro
11
,
d
-Ala
12
]Ang I. These findings suggest that biochemical and [Pro
11
,
d
-Ala
12
]Ang I–derived results may not reflect the functional significance of chymase.
Nitric Oxide Synthase Isotype Expression in Salt-Sensitive and Salt-Resistant Dahl Rats
Authors: Ni Zhenmin , Oveisi Fariba , Vaziri Nosratola D.
Published: June 2012

Abstract
—Previous studies have suggested that salt-sensitive hypertension in humans and experimental animals may in part be due to dysregulation of the
l
-arginine/nitric oxide system. This study was conducted to determine the endothelial, inducible, and neuronal nitric oxide synthase expressions in the kidney, heart, aorta, and brain of salt-sensitive and salt-resistant Dahl rats. We studied salt-sensitive and salt-resistant Dahl rats maintained on high- (8%) and regular- (0.2%) salt diets for 3 weeks. Blood pressure was modestly elevated in both Dahl salt-sensitive and salt-resistant rats consuming regular diet and severely increased in sensitive but not resistant rats consuming the high-salt diet. The Dahl salt-sensitive animals showed a significant reduction in kidney, heart, and aorta inducible nitric oxide synthase protein abundance on the regular diet, with further reductions on the high-salt diet. In addition, the high-salt diet markedly downregulated endothelial nitric oxide synthase expression in the kidney and aorta but not in the heart of the Dahl salt-sensitive animals. The rise in blood pressure in the Dahl salt-sensitive rats on the high-salt diet was accompanied by a significant elevation of brain neuronal nitric oxide synthase protein. In contrast, salt-resistant animals showed no change in heart, kidney, and aorta endothelial or brain neuronal nitric oxide synthase and considerably less intense changes in inducible isotype than that seen in the salt-sensitive group in response to the high-salt diet. In conclusion, the study revealed a marked downregulation of inducible nitric oxide synthase in the Dahl salt-sensitive rats on the regular diet, with further reductions on the high-salt diet. Furthermore, Dahl salt-sensitive rats consuming the high-salt diet showed significant reductions of kidney and aorta endothelial nitric oxide synthase and an upregulation of brain neuronal nitric oxide synthase expression.
The Role of α-Adducin Polymorphism in Blood Pressure and Sodium Handling Regulation May Not Be Excluded by a Negative Association Study
Authors: Glorioso Nicola , Manunta Paolo , Filigheddu Fabiana , Troffa Chiara , Stella Paola , Barlassina Cristina , Lombardi Cinzia , Soro Aldo , Dettori Francesco , Parpaglia Paolo Pinna , Alibrandi Maria Teresa Sciarrone , Cusi Daniele , Bianchi Giuseppe
Published: June 2012

Abstract
—The basic requirement for declaring an association study positive is that the “hypertension-favoring” allele is more frequent in hypertensive cases than in normotensive controls. However, both positive and negative associations with hypertension have been found for the same polymorphism when studied in different populations. In the present study, we addressed the question of the possible cause(s) of this discrepancy among populations by using the α-adducin polymorphism as a paradigm. Four hundred ninety hypertensives and 176 normotensives enrolled in Sassari, Italy, and 468 hypertensives and 181 normotensives enrolled in Milano, Italy, were genotyped for the α-adducin Gly460Trp polymorphism. The blood pressure response to 2 months of hydrochlorothiazide therapy could be evaluated in 143 (85 in Sassari and 58 in Milano) hypertensives with and without the 460Trp α-adducin allele. The α-adducin 460Trp allele was not significantly more frequent in hypertensives in the Sassari population but was more frequent in hypertensives than in normotensives in Milano (
P
=0.019). Basal plasma renin activity was lower and blood pressure fall after diuretic therapy more pronounced (
P
<0.01) in hypertensives carrying at least one 460Trp allele than in Gly460Gly homozygotes, irrespective of their membership in the Sassari or Milano cohort. The effect of α-adducin genotype in predicting basal plasma renin activity and blood pressure decrease with diuretic treatment is similar in Sassari and Milano, despite the lack of association of the α-adducin genotype with hypertension in Sassari.
Plasma Homocysteine, Aortic Stiffness, and Renal Function in Hypertensive Patients
Authors: Bortolotto Luiz A. , Safar Michel E. , Billaud Eliane , Lacroix Christian , Asmar Roland , London Gérard M. , Blacher Jacques
Published: June 2012

Abstract
—Hyperhomocysteinemia has been associated with both vascular structure alterations and vascular clinical end points. To assess the relation between plasma homocysteine, structure and function of large arteries, and the presence of clinical vascular disease, we investigated a population of 236 hypertensive patients. We estimated arterial stiffness by measuring the carotid-femoral pulse wave velocity. Total plasma homocysteine was determined by fluorometric high-performance liquid chromatography. The presence of cardiovascular disease was defined on the basis of clinical events, including coronary heart disease, cerebrovascular disease, and peripheral vascular disease. In this population, pulse wave velocity was positively correlated with homocysteine, even after adjustments for age, mean blood pressure, extent of atherosclerosis, and creatinine clearance
(P
=0.016). Analysis of variance showed statistically significant differences between the mean values of homocysteine, creatinine clearance, and pulse wave velocity according to the extent of atherosclerosis, with an increase in these 3 parameters concomitant with an increase in the number of vascular sites involved with atherosclerosis. In conclusion, in hypertensive patients the levels of homocysteine are strongly and independently correlated to arterial stiffness measured by aortic pulse wave velocity. Plasma homocysteine, creatinine clearance, and aortic pulse wave velocity are higher in patients presenting with clinical vascular disease. These results suggest that the evaluation of aortic distensibility and homocysteine levels can help in cardiovascular risk assessment in hypertensive populations.
Effect of Cyclooxygenase-2 Inhibition on Renal Function After Renal Ablation
Authors: Sanchez Pedro Lopez , Salgado Luis Miguel , Ferreri Nicholas R. , Escalante Bruno
Published: June 2012

Abstract
—Kidney failure is the common end of hypertension and renal diseases. Several authors have suggested that vasodilatory prostaglandins participate in the hemodynamic mechanism responsible for the development of kidney failure. However, the mechanism by which prostaglandins are increased in renal disease is not clear. Recently, 2 isoforms of the enzyme responsible for prostaglandin synthesis, cyclooxygenase, have been described as cyclooxygenase-1 (COX-1), a constitutive isoform, and cyclooxygenase-2 (COX-2), an inducible isoform. In the present study, we investigated whether COX-2–dependent prostaglandins participate in the evolution of renal functional changes after renal ablation. We inhibited prostaglandin synthesis by COX-1 and COX-2 with indomethacin (3 mg/kg) and prostaglandin synthesis by COX-2 with NS-398 (3 mg/kg) and tested the effect of these inhibitors on the renal functional changes elicited by renal ablation. Renal ablation produced an increase in urinary volume, protein, and prostaglandin E
2
, whereas urinary sodium and potassium were not affected and urinary osmolarity decreased; treatment with indomethacin or NS-398 partially prevented the renal functional changes elicited by renal ablation. Immunoblots for COX showed an increase in the expression of COX-2 protein 2 days after renal ablation. Furthermore, COX-2 mRNA expression was increased 1 day after renal ablation. These data suggest that COX-2–dependent prostaglandins participate in the renal mechanisms associated with the development of renal functional changes after renal ablation.
Role of Endothelin-1 in Hypertension
Authors: Schiffrin Ernesto L.
Published: June 2012

Abstract
—Endothelin-1 (ET-1) is overexpressed in the vascular wall in certain models of experimental hypertension: deoxycorticosterone acetate salt–treated rats, deoxycorticosterone acetate salt–treated spontaneously hypertensive rats (SHR), stroke-prone SHR, Dahl salt–sensitive rats, angiotensin II–infused rats, and 1-kidney 1 clip Goldblatt rats; it is not overexpressed in SHR, 2-kidney 1-clip hypertensive rats, or L-NAME–treated rats. In hypertensive rats without generalized vascular overexpression, however, expression of ET-1 was often enhanced in intramyocardial coronary arteries, suggesting a role of endothelin in myocardial ischemia in hypertension. In rats overexpressing ET-1, ET
A/B
and ET
A
-selective receptor antagonists lowered blood pressure and reduced vascular growth, particularly in small arteries, beyond what could be attributed to blood pressure lowering, suggesting a direct effect of ET-1 on growth. Hypertensive rats treated with endothelin antagonists are protected from stroke and renal injury. The ET
A/B
antagonist bosentan induced blood-pressure reductions in mildly hypertensive patients similar to those achieved with an angiotensin-converting enzyme inhibitor. Moderately to severely hypertensive patients presented with enhanced expression of prepro-ET-1 mRNA in the endothelium of subcutaneous resistance arteries, suggesting that these stages of hypertension may respond particularly well to endothelin antagonism. Hypertensive patients with coronary artery disease have increased arterial expression of ET-1, and increased plasma levels of immunoreactive endothelin have been described in black patients. ET-1 plays an important role in atherosclerosis, for which hypertension is an important risk factor. Thus, ET-1 may be involved in experimental and human hypertension. Endothelin antagonists may prove effective as disease-modifying agents if they are shown clinically, as they are experimentally, to offer target organ protection and reduce long-term complications of hypertension. This remains to be demonstrated in humans.
Blood Pressure and Small Arteries in DOCA-Salt–Treated Genetically AVP-Deficient Rats
Authors: Intengan Hope D. , Park Jeong Bae , Schiffrin Ernesto L.
Published: June 2012

Abstract
—Hypertension is associated with structural and mechanical abnormalities of resistance arteries. We have recently reported that vasopressin may be involved in the blood pressure elevation and remodeling of resistance arteries in deoxycorticosterone acetate (DOCA)-salt hypertension, perhaps by modulating vascular endothelin-1 expression. We tested this hypothesis further by examining DOCA-salt hypertension in homozygous vasopressin-deficient Brattleboro (BB) rats in comparison with Long-Evans (LE; control) rats. Mesenteric resistance arteries (lumen <300 μm) were studied on pressurized myographs. After 5 weeks, systolic blood pressure was greater in LE DOCA-salt–treated rats (189±5 mm Hg) compared with uniephrectomized (UNx) LE control rats (117±4 mm Hg;
P
<0.01). The increase in blood pressure induced by DOCA-salt treatment was attenuated in vasopressin-deficient rats, such that BB DOCA-salt–treated rats exhibited only a slight elevation of blood pressure (134±6 mm Hg) compared with BB-UNx rats (111±4 mm Hg;
P
<0.05). Resistance arteries in LE DOCA-salt–treated rats had a smaller lumen diameter and a larger media width, media cross-sectional area, and media-lumen ratio compared with LE-UNx rats. Isobaric stiffness was unaltered in resistance arteries from LE DOCA-salt–treated rats, despite stiffening of the arterial wall components as indicated by a significant increase in the slope of the media stress–incremental elastic modulus relationship. DOCA-salt treatment in the absence of endogenous vasopressin, ie, in homozygous
di
/
di
BB rats, failed to alter vascular structure or wall component stiffness and resulted in a lesser degree of blood pressure elevation. Reverse transcription–polymerase chain reaction analysis revealed that DOCA-salt treatment enhanced endothelin gene expression in LE rats but failed to do so in BB rats. These data indicate that vasopressin plays a critical role in modulating vascular structure and mechanics, as well as blood pressure, in DOCA-salt–induced hypertension. Moreover, these effects of vasopressin are in part mediated by enhancement of endothelin expression.
Ca
2+
-Insensitive Vascular Protein Kinase C During Pregnancy and NOS Inhibition
Authors: Kanashiro Celia A. , Alexander Barbara T. , Granger Joey P. , Khalil Raouf A.
Published: June 2012

Abstract
—Pregnancy-induced hypertension is associated with increased vascular resistance; however, the cellular mechanisms involved are unclear. We have previously found that the relation between Ca
2+
entry and the developed force in vascular smooth muscle is altered during normal pregnancy and in a rat model of pregnancy-induced hypertension produced by long-term treatment with the nitric oxide synthase inhibitor
N
G
-nitro-
l
-arginine methyl ester (L-NAME). The purpose of this study was to investigate whether the pregnancy-associated changes in the vascular Ca
2+
entry-force relation reflect changes in the amount and/or activity of Ca
2+
-insensitive protein kinase C (PKC) isoforms. Active stress and the amount and activity of PKC were measured in deendothelialized aortic strips from nonpregnant and pregnant rats untreated or treated with L-NAME and incubated in Ca
2+
-free (2 mmol/L EGTA) Krebs solution. In nonpregnant rats, the PKC activator phorbol 12,13-dibutyrate (PDBu, 10
−6
mol/L) and the α-adrenergic agonist phenylephrine (Phe, 10
−5
mol/L) caused significant, maintained increases in active stress and PKC activity that were inhibited by the PKC inhibitors staurosporine and calphostin C. Western blots in aortic strips of nonpregnant rats revealed the Ca
2+
-insensitive δ-PKC and ζ-PKC isoforms. Both PDBu and Phe caused translocation of δ-PKC from the cytosolic to the particulate fraction. Compared with nonpregnant rats, the amount of δ-PKC and ζ-PKC and the PDBu-stimulated and Phe-stimulated stress, PKC activity and translocation of δ-PKC were significantly reduced in late pregnant rats but significantly enhanced in pregnant rats treated with L-NAME. The PDBu-induced and Phe-induced responses in nonpregnant rats treated with L-NAME were not significantly different from nonpregnant rats, whereas the responses in pregnant rats treated with L-NAME+
l
-arginine were not significantly different from pregnant rats. These results provide evidence that a signaling pathway in vascular smooth muscle possibly involving the Ca
2+
-insensitive δ-PKC and ζ-PKC isoforms is reduced in late pregnancy and enhanced during long-term inhibition of nitric oxide synthesis. The changes in the amount and activity of vascular PKC isoforms may, in part, explain the changes in vascular resistance during normal pregnancy and pregnancy-induced hypertension.
AT
1
Receptor Antagonism Reduces Endothelial Dysfunction and Intimal Thickening in Atherosclerotic Rabbits
Authors: de las Heras Natalia , Aragoncillo Paloma , Maeso Rosaura , Vazquez-Pérez Sandra , Navarro-Cid Josefa , DeGasparo Marc , Mann Jessica , Ruilope Luis M. , Cachofeiro Victoria , Lahera Vicente
Published: June 2012

Abstract
—The effects of angiotensin (AT)
1
receptor antagonists on functional and morphological alterations associated with atherosclerosis are not well known. The current study was performed to examine the long-term effects of valsartan (3 or 10 mg/kg per day for 10 weeks) on endothelial function and structural changes in aorta from rabbits fed with either a control diet or a cholesterol-enriched diet. Rabbits fed with the cholesterol-rich diet showed higher (
P
<0.05) plasma levels of cholesterol than did controls. Treatment with valsartan (3 or 10 mg/kg per day) did not alter plasma cholesterol levels or systolic arterial pressure in any group. Contractions induced by angiotensin II were comparable in both control and hypercholesterolemic rabbits and were markedly reduced by treatment with valsartan. Relaxations induced by acetylcholine were lower in hypercholesterolemic rabbits than in controls. Treatment with valsartan (3 or 10 mg/kg per day) enhanced (
P
<0.05) this response in hypercholesterolemic rabbits but not in controls. Lumen and media cross-sectional areas were comparable in control and hypercholesterolemic rabbits. Vessel area was higher (
P
<0.05) in hypercholesterolemic rabbits than in controls. Intimal lesion was 29.5±6% in cholesterol-fed rabbits and nonexistent in control rabbits. Treatments with 3 and 10 mg/kg per day valsartan reduced (
P
<0.05) intimal lesion to 2.4±0.7% and 2.7±0.9%, respectively, and increased lumen area in hypercholesterolemic rabbits. No changes in either vessel or media cross-sectional areas were observed in these animals. In summary, angiotensin II, through AT
1
receptors, appears to play a key role in the development of the vascular functional and structural changes associated with hypercholesterolemia. AT
1
receptor antagonists, besides their antihypertensive effects, could be an important therapeutic tool to reduce the development of atherosclerosis.
Statins and Blockers of the Renin-Angiotensin System
Authors: Faggiotto Agostino , Paoletti Rodolfo
Published: June 2012

Abstract
—In addition to their primary mode of action, statins and blockers of the renin-angiotensin system possess common additional properties that are under active investigation. The inhibition of cellular proliferation, the restoration of endothelial activity, the inhibition of platelet reactivity, and an antioxidant potential are only a few examples of shared effects that target the arterial wall. These and other properties may eventually become exploited for the improved treatment of cardiovascular diseases and of other diseases apparently unrelated to the cardiovascular field, including inflammation and cancer. This review analyzes the current knowledge on the pleiotropic properties of these classes of drugs. Direct comparison indicates that study of the associations among these drugs may eventually disclose additive or synergistic effects that, perhaps even at lower dosages, may provide improved vascular protection and a strong alliance against several atherogenic mechanisms.
Ambulatory Blood Pressure and M;etabolic Abnormalities in Hypertensive Subjects With Inappropriately High Left Ventricular Mass
Authors: Palmieri Vittorio , de Simone Giovanni , Roman Mary J. , Schwartz Joseph E. , Pickering Thomas G. , Devereux Richard B.
Published: June 2012

Abstract
—Appropriateness of left ventricular (LV) mass to cardiac workload can be evaluated by the ratio of observed LV mass to the value predicted for an individual’s gender, height
2.7
, and stroke work at rest (%PLVM). It is unclear which pathophysiological factors are associated with inappropriately high LV mass in hypertensive subjects. Adequate LV mass was defined by the 90% confidence interval (73% to 128%) of the distribution of %PLVM in 393 normal-weight normotensive subjects. In 185 hypertensive subjects (aged 56±11 years; 60% male, 29% black), according to %PLVM, 164 (88%) had adequate LV mass, 16 (9%) had inappropriately high LV mass (%PLVM >128%), and 5 (3%) had %PLVM <73% (low LV mass). Age, gender, smoking habit, proportion of never-treated subjects, total cholesterol, triglycerides, and creatinine levels did not differ significantly between subjects with adequate and inappropriately high LV mass. Body mass index, fasting glucose, and proportion of black subjects were higher (all
P
<0.05), while HDL cholesterol was lower (
P
<0.05) in subjects with inappropriately high LV mass. Blood pressure at the echocardiogram was comparable between subjects with adequate and inappropriately high LV mass, but the latter group had higher ambulatory blood pressure (
P
<0.01). Subjects with inappropriately high LV mass also had higher aortic root dimension and LV relative wall thickness and relatively lower LV systolic performance than those with adequate LV mass (all
P
<0.001). Larger aortic root diameter and lower systolic function were also found in hypertensive subjects with inappropriate LV hypertrophy compared with those with adequate LV hypertrophy. In an exploratory case-control study that compared subjects with low %PLVM with age-matched counterparts with adequate LV mass, low %PLVM was associated with lower body mass index, more favorable metabolic profile, and higher LV myocardial contractility. Higher body mass index, larger aortic root, and black race were independent correlates of increased %PLVM. Thus, in arterial hypertension, levels of LV mass inappropriately high for gender, cardiac workload, and height
2.7
are associated with higher body mass index, higher ambulatory blood pressure, larger aortic root diameters, and relatively low myocardial contractility.
Respiratory Systolic Pressure Variability During Atrial Fibrillation and Sinus Rhythm
Authors: Pitzalis Maria Vittoria , Massari Francesco , Forleo Cinzia , Fioretti Agnese , Colombo Roberto , Balducci Cataldo , Mastropasqua Filippo , Rizzon Paolo
Published: June 2012

Abstract
—Previous studies have found that respiratory variations of ventricular response in atrial fibrillation are infrequent and inconsistent. This asynchrony between heart rate and respiration may characterize the physiological mechanisms coupling heart rate and systolic blood pressure oscillations in the respiratory band. The aim of this study was to evaluate whether synchronous variations in systolic blood pressure and respiration depend on a simultaneous change in heart rate. Univariate and bivariate spectral analyses were made of the R-R interval, systolic blood pressure, and respiratory signals during controlled respiration (16 breaths/min) in 24 patients with atrial fibrillation before and after efficacious electrical cardioversion and in 24 age- and sex-matched control subjects. During atrial fibrillation, the spectral coherence between respiration and heart rate was low (0.18±0.03), but there was a high level of coherence between respiration and systolic blood pressure (0.67±0.05). After cardioversion, the coherence between respiration and heart rate increased to 0.86±0.04, whereas the geometric mean values of the concomitant respiratory systolic blood pressure oscillations decreased by 72% (from 21.1 to 5.9 mm Hg
2
,
P
<0.001), which was similar to that observed in the control group (5.7 mm Hg
2
). These results confirm the inconsistent effect of respiration on heart rate response during atrial fibrillation and demonstrate that respiratory sinus arrhythmia is not a prerequisite for systolic blood pressure oscillations but may play an antioscillatory role in respiratory systolic blood pressure variability, which is probably mediated by arterial baroreflex mechanisms.
Matrix-Dependent Gene Expression of Egr-1 and PDGF A Regulate Angiotensin II–Induced Proliferation in Human Vascular Smooth Muscle Cells
Authors: Ling Shanhong , Dai Aozhi , Ma Yunn-Hwa , Wilson Emily , Chatterjee Kanu , Ives Harlan E. , Sudhir Krishnankutty
Published: June 2012

Abstract
—We have previously shown, in a neonatal rat cell line, that angiotensin II (Ang II)–induced proliferation in vascular smooth muscle cells is extracellular matrix (ECM) dependent. We hypothesized that such an effect might be mediated via differences in Ang II–induced increases in the transcriptional factor early growth response-1 (Egr-1) gene and, consequently, in platelet-derived growth factor (PDGF). Cultured human newborn aortic smooth muscle cells were studied on 4 different surfaces: (1) plastic, (2) laminin, (3) collagen, and (4) fibronectin. Ang II–induced increases in DNA synthesis were significantly greater on collagen (2.0±0.3-fold) and fibronectin (1.9±0.3-fold) than on laminin (1.0±0.2-fold) or plastic (1.4±0.2-fold). As with DNA synthesis, at 48 and 72 hours, Ang II–induced increases in cell numbers occurred only in cells grown on collagen and fibronectin culture plates and were blocked by an antagonist to the angiotensin type 1 (losartan, 10 μmol/L) but not the angiotensin type 2 (PD 123319, 10 μmol/L) receptor. Anti-PDGF AA antibody (6 μg/mL) blocked the increase in DNA synthesis by 60% to 64% in cells on collagen or fibronectin cultures but not on plastic cultures. When PDGF-AA (10 ng/mL) and Ang II were added together, DNA synthesis increased 2-fold and did not differ on the various ECM proteins. Increases in PDGF A-chain mRNA were observed only in cells grown on collagen (3.21±0.65-fold) and fibronectin (2.86±0.49-fold) plates 2 to 8 hours after the addition of Ang II and were blocked by losartan but not PD 123319. Expression of Egr-1, an early growth response gene, increased at 15 minutes, peaked at 30 minutes, and returned to normal after 2 hours with Ang II treatment. Ang II–induced increases in Egr-1 mRNA were greater on collagen (4.82±0.66-fold at maximum) and fibronectin (4.01±0.56-fold) than on laminin (2.74±0.45-fold) or plastic (2.53±0.40-fold) and were blocked by losartan but not PD 123319. Thus, in human vascular smooth muscle cells in culture, Ang II–induced proliferation is mediated via the angiotensin type 1 receptor, dependent on ECM proteins, and regulated by differential gene expression of Egr-1 and PDGF-1.
J-Shaped Relation Between Blood Pressure and Stroke in Treated Hypertensives
Authors: Vokó Zoltán , Bots Michiel L. , Hofman Albert , Koudstaal Peter J. , Witteman Jacqueline C. M. , Breteler Monique M. B.
Published: June 2012

Abstract
—The objective of this study was to investigate the relationship between hypertension and risk of stroke in the elderly. The study was performed within the framework of the Rotterdam Study, a prospective population-based cohort study. The risk of first-ever stroke was associated with hypertension (relative risk, 1.6; 95% CI, 1.2 to 2.0) and with isolated systolic hypertension (relative risk, 1.7; 95% CI, 1.1 to 2.6). We found a continuous increase in stroke incidence with increasing blood pressure in nontreated subjects. In treated subjects, we found a J-shaped relation between blood pressure and the risk of stroke. In the lowest category of diastolic blood pressure, the increase of stroke risk was statistically significant compared with the reference category. Hypertension and isolated systolic hypertension are strong risk factors for stroke in the elderly. The increased stroke risk in the lowest stratum of blood pressure in treated hypertensive patients may indicate that the therapeutic goal of “the lower the better” is not the optimal strategy in the elderly.
Doxorubicin Selectively Inhibits Brain Versus Atrial Natriuretic Peptide Gene Expression in Cultured Neonatal Rat Myocytes
Authors: Chen Songcang , Garami Miklos , Gardner David G.
Published: June 2012

Abstract
—Doxorubicin is an antineoplastic agent with significant cardiotoxicity. We examined the effects of this agent on the expression of the natriuretic peptide (NP) genes in cultured neonatal rat atrial myocytes. Doxorubicin suppressed NP secretion, steady-state NP mRNA levels, and NP gene promoter activity. In each instance, brain NP (BNP) proved to be more sensitive than atrial NP (ANP) to the inhibitory effects of the drug. ICRF-187 and probucol reversed the inhibition by doxorubicin of ANP mRNA accumulation and ANP gene promoter activity while exerting no effect on BNP mRNA levels or promoter activity. This represents the first identification of the NP genes as targets of doxorubicin toxicity in the myocardial cell. This inhibition operates predominantly at a transcriptional locus and has more potent effects on BNP versus ANP secretion/gene expression. Measurement of BNP secretion/gene expression may provide a sensitive marker of early doxorubicin cardiotoxicity.
cGMP-Mediated Negative-Feedback Regulation of Endothelial Nitric Oxide Synthase Expression by Nitric Oxide
Authors: Vaziri Nosratola D. , Wang Xiu Q.
Published: June 2012

Abstract
—Earlier studies have demonstrated that nitric oxide (NO) exerts a fast-acting inhibitory influence on endothelial NO synthase (eNOS) enzymatic activity in isolated vascular tissue preparations. The present study was designed to examine the possible effect of NO on eNOS protein expression in cultured endothelial cells and intact animals. Human coronary endothelial cells were incubated with
S
-nitroso-
N
-acetyl-penicillamine (SNAP, an NO donor), oxyhemoglobin (HGB, an NO trapping agent), SNAP plus HGB, or inactive vehicle (control). In other experiments, cells were treated with 3-isobutyl-1-methylxanthine (a phosphodiesterase inhibitor), 1
H
-[1,2,4]oxadiazolo-[4,3–2]quinoxalin-1-one (ODQ, a guanylate cyclase inhibitor), SNAP plus ODQ, 8-bromo-cGMP (8-Br-cGMP, a cell-permeable cGMP compound), 8-Br-cGMP plus HGB, or inactive vehicle in order to discern the effect of cGMP. The incubations were conducted for 24 hours, and total nitrate plus nitrite production and eNOS protein abundance (Western analysis) were measured. To determine the effect of NO on eNOS expression in vivo, rats were treated with either the NO donor isosorbide dinitrate or placebo by gastric gavage for 48 hours, and aortic eNOS protein expression was examined. The NO donor SNAP markedly depressed, whereas the NO scavenger HGB significantly raised, eNOS protein expression. The downregulatory action of SNAP was completely abrogated by HGB. Phosphodiesterase inhibitor and 8-Br-cGMP downregulated, whereas the guanylate cyclase inhibitor ODQ upregulated eNOS protein expression. The downregulatory action of SNAP was completely overcome by the guanylate cyclase inhibitor ODQ, and the upregulatory action of the NO scavenger HGB was abrogated by 8-Br-cGMP. Administration of NO donor resulted in a marked downregulation of aortic eNOS protein expression in intact animals, thus confirming the in vitro findings. NO serves as a negative-feedback regulator of eNOS expression via a cGMP-mediated process.
Intralymphocyte Free Magnesium in Patients With Primary Aldosteronism
Authors: Delva Pietro , Pastori Caterina , Degan Maurizio , Montesi Germana , Brazzarola Paolo , Lechi Alessandro
Published: June 2012

Abstract
—It is known that hyperaldosteronism has been associated with magnesium deficiency, yet there are no data on the intracellular concentration of ionized magnesium ([Mg
2+
i
]) in subjects with primary aldosteronism (PA). We measured intralymphocyte free magnesium ([Mg
2+
i
]) and intralymphocyte free calcium ([Ca
2+
i
]) in 16 patients with PA and 26 normotensive control subjects (NCs). [Mg
2+
i
] and [Ca
2+
i
] were also measured in blood lymphocytes incubated in vitro with aldosterone, according to a fluorimetric method. In subjects with PA, [Mg
2+
i
] was significantly lower than that in NCs (mean±SD; PA 203±56 μmol/L, NCs 291±43 μmol/L, 95% confidence interval 57 to 119,
P
=0.001). In the patients, [Ca
2+
i
] did not prove to be statistically different from that of NCs (mean±SD; PA 47.2±10.6 nmol/L, NCs 53.2±11 nmol/L). The lymphocytes exposed to the action of aldosterone showed a significant reduction in [Mg
2+
i
] (n=15, NCs 271±28 μmol/L, aldosterone treatment 188±39 μmol/L,
P
=0.001, 95% confidence interval 57 to 108). The dose-effect curve of aldosterone on [Mg
2+
i
] showed an EC
50
value of ≈0.5 to 1 nmol/L aldosterone. The reduction in [Mg
2+
i
] mediated by aldosterone is antagonized by the receptor inhibitor of aldosterone; it is inhibited by inhibitors of protein synthesis and is not measurable when the lymphocytes are incubated in an Na
+
-free medium. The data are consistent with the hypothesis that aldosterone affects the cellular homeostasis of magnesium, probably through modification of the activity of the Na
+
-Mg
2+
antiporter.
Restraint Stress
Authors: McDougall Stuart J. , Paull Jeremy R. A. , Widdop Robert E. , Lawrence Andrew J.
Published: June 2012

Abstract
—With the use of a restraint stress paradigm, both normotensive Wistar-Kyoto (WKY ) rats and spontaneously hypertensive rats (SHR) underwent acute (1-hour restraint in a Perspex tube), chronic (1-hour restraint for 10 consecutive days), or no-restraint (control) stress. Rats experiencing chronic restraint were previously implanted with telemetric probes to measure heart rate and blood pressure. Basal (prestress session) cardiovascular variables did not change during the course of the study (SHR: mean arterial pressure 129±1 mm Hg, heart rate 288±4 bpm; WKY rats: mean arterial pressure 103±1 mm Hg, heart rate 285±3 bpm). Restraint caused tachycardia and pressor responses in the WKY rats and SHR, but these effects were greater in the hypertensive strain. The duration of restraint-induced tachycardia did not change in the WKY rats between acute and chronic stress; however, a graded reduction in the duration of restraint-induced tachycardia occurred in the SHR, decreasing to WKY rat levels by day 7 of the 10-day regimen. These data indicate that although the WKY rats can effectively “cope” within a single period of restraint, the coping mechanism is apparently impaired in the SHR compared with the WKY rats. A reduced capacity to cope with processive stressors may thus have an affect on cardiovascular regulation and represent an additional risk factor in hypertension.
Angiotensin III Depressor Action in the Conscious Rabbit Is Blocked by Losartan but not PD 123319
Authors: Rowe Brian P. , Dixon Byron
Published: June 2012

Abstract
—Vasodilator and vasodepressor properties of angiotensins have been reported, and mediation by prostaglandins or nitric oxide has been proposed. Other studies indicate that angiotensin AT
2
receptors might mediate a depressor action, and the present study was designed to delineate and explore this possibility in a conscious rabbit model. Large intravenous boluses of angiotensin III (15 nmol/kg) produced a predictable pressor peak (82±4 mm Hg) followed by a depressor phase (20±3 mm Hg), whereas equipressor doses of angiotensin II were less effective at producing depressor responses. Angiotensin-(1–7) did not exert a depressor action, and the reduced potency of angiotensin IV (relative to angiotensin III) was similar for both the pressor and depressor phases (≈100-fold). It is clear that specific angiotensin IV or angiotensin-(1–7) receptors do not mediate depressor effects in this model. The AT
1
antagonist losartan (1 mg/kg) blocked both the pressor and depressor components of the angiotensin III response, whereas the AT
2
antagonist PD 123319 (35 mg/kg) had no effect on either element of the response. The data obtained with the angiotensin receptor subtype–selective compounds, losartan and PD 123319, suggest that the depressor action is an AT
1
-mediated effect and give no indication that AT
2
receptors could be involved. Paradoxically, the greater potency of angiotensin III as a vasodepressor belies the conclusion that the response is AT
1
-mediated, because AT
1
receptors have a greater affinity for angiotensin II versus angiotensin III.
NF-κB Inhibition Ameliorates Angiotensin II–Induced Inflammatory Damage in Rats
Authors: Muller Dominik N. , Dechend Ralf , Mervaala Eero M. A. , Park Joon-Keun , Schmidt Folke , Fiebeler Anette , Theuer Jürgen , Breu Volker , Ganten Detlev , Haller Hermann , Luft Friedrich C.
Published: June 2012

Abstract
—We recently reported that the activation of nuclear factor-κB (NF-κB) promotes inflammation in rats harboring both human renin and angiotensinogen genes (double-transgenic rats [dTGR]). We tested the hypothesis that the antioxidant pyrrolidine dithiocarbamate (PDTC) inhibits NF-κB and ameliorates renal and cardiac end-organ damage. dTGR feature hypertension, severe renal and cardiac damage, and a 40% mortality rate at 7 weeks. Electrophoretic mobility shift assay showed increased NF-κB DNA binding activity in hearts and kidneys of dTGR. Chronic PDTC (200 mg/kg SC) treatment decreased blood pressure (162±8 versus 190±7 mm Hg;
P
=0.02) in dTGR compared with dTGR controls. The cardiac hypertrophy index was also significantly reduced (4.90±0.1 versus 5.77±0.1 mg/g;
P
<0.001). PDTC reduced 24-hour albuminuria by >95% (2.5±0.8 versus 57.1±8.7 mg/d;
P
<0.001) and prevented death. Vascular injury was ameliorated in small renal and cardiac vessels. Electrophoretic mobility shift assay showed that PDTC inhibited NF-κB binding activity in heart and kidney, whereas AP-1 activity in the kidney was not decreased. dTGR exhibited increased left ventricular c-
fos
and c-
jun
mRNA expression. PDTC treatment reduced c-
fos
but not c-
jun
mRNA. Immunohistochemistry showed increased p65 NF-κB subunit expression in the endothelium and smooth muscle cells of damaged small vessels, as well as infiltrating cells in glomeruli, tubules, and collecting ducts of dTGR. PDTC markedly reduced the immunoreactivity of p65. PDTC also prevented the NF-κB–dependent transactivation of the intercellular adhesion molecule ICAM-1 and inducible nitric oxide synthase. Monocyte infiltration was markedly increased in dTGR kidneys and hearts. Chronic treatment reduced monocyte/macrophage infiltration by 72% and 64%, respectively. Thus, these results demonstrate that PDTC inhibits NF-κB activity, ameliorates inflammation, and protects against angiotensin II-induced end-organ damage.
Cyclic AMP Inhibited Proliferation of Human Aortic Vascular Smooth Muscle Cells, Accompanied by Induction of p53 and p21
Authors: Hayashi Shin-ichiro , Morishita Ryuichi , Matsushita Hidetsugu , Nakagami Hironori , Taniyama Yoshiaki , Nakamura Toshinori , Aoki Motokuni , Yamamoto Kei , Higaki Jitsuo , Ogihara Toshio
Published: June 2012

Abstract
—Although cAMP is an important second messenger that plays a pivotal role in the regulation of platelet aggregation and dilatation of blood vessels, little is known about the action of cAMP on the growth of vascular smooth muscle cells (VSMCs). Thus, we initially studied the effects of cAMP accumulation by using various cAMP stimulants, including a phosphodiesterase type 3 inhibitor (cilostazol) on human aortic VSMC growth. Accumulation of cAMP inhibited the platelet-derived growth factor (PDGF)-stimulated VSMC growth in a dose-dependent manner (
P
<0.01), whereas PDGF significantly stimulated the growth of human VSMCs. Thus, we focused on the role of cell cycle regulatory genes, especially on a negative regulator, an anti-oncogene, p53. The protein of p53 was potentiated by cilostazol as well as forskolin and 8-bromo-cAMP, whereas PDGF decreased p53 expression. Upregulation of p53 protein by cAMP was further confirmed by the observation that the decrease in p21, a p53-inducible protein, by PDGF was significantly attenuated by cilostazol in a dose-dependent manner (
P
<0.01). These results revealed that accumulation of cAMP inhibited VSMC proliferation, which was at least in part due to an increase in p53-p21 expression. Because p53 and p21 have been reported to induce apoptosis, we examined apoptotic cells for cAMP accumulation. Incubation of VSMCs with cilostazol resulted in a significant increase in apoptotic cells in a dose-dependent manner compared with vehicle treatment as assessed by nuclear chromatic morphology (
P
<0.01); forskolin also stimulated apoptotic cells. Consistent with nuclear staining, DNA fragmentation in VSMCs treated with forskolin as well as 8-bromo-cAMP and cilostazol was significantly increased compared with DNA fragmentation in VSMCs treated with vehicle, whereas PDGF significantly decreased the rate of DNA fragmentation (
P
<0.01). Overall, these results demonstrated that cAMP inhibited the proliferation of human aortic VSMCs, accompanied by p53-p21–mediated apoptosis. Analogues of cAMP that have direct inhibitory effects on VSMC proliferation can be considered as potential antiproliferative drugs against VSMC growth.