bluuebunny/crossref_metadata_2025 huggingface dataset:
Enalapril Induces Regression of Cardiac Hypertrophy and Normalization of pH
i
Regulatory Mechanisms
Authors: Ennis Irene L. , Alvarez Bernardo V. , de Hurtado María C. Camilión , Cingolani Horacio E.
Published: June 2012

Abstract
—Intracellular pH is under strict control in myocardium; H
+
are extruded from the cells by sodium-dependent mechanisms, mainly Na
+
/H
+
exchanger and Na
+
/HCO
3
−
symport, whereas Na
+
-independent Cl
−
/HCO
3
−
exchanger extrudes bases on intracellular alkalinization. Hypertrophic myocardium from spontaneously hypertensive rats (SHR) exhibits increased Na
+
/H
+
exchange activity that is accompanied by enhanced extrusion of bases through Na
+
-independent Cl
−
/HCO
3
−
exchange. The present experiments were designed to investigate the effect of enalapril-induced regression of cardiac hypertrophy on the activity of these exchangers. Male SHR and normotensive Wistar-Kyoto rats (WKY) received enalapril maleate (20 mg/kg per day) in the drinking water for 5 weeks. Gender- and age-matched SHR and WKY were used as untreated controls. Enalapril treatment significantly reduced systolic blood pressure in SHR and completely regressed cardiac hypertrophy. Na
+
/H
+
activity was estimated in terms of both steady pH
i
value in HEPES buffer and the rate of pH
i
recovery from CO
2
-induced acid load. Na
+
-independent Cl
−
/HCO
3
−
activity was assessed by measuring the rate of pH
i
recovery from intracellular alkalinization produced by trimethylamine exposure. Regression of cardiac hypertrophy was accompanied by normalization of Na
+
/H
+
and Na
+
-independent Cl
−
/HCO
3
−
exchange activities. Inhibition of protein kinase C (PKC) activity with chelerythrine (10 mmol/L) or calphostin C (50 nmol/L) returned both exchange activities to normal values. These results show that angiotensin-converting enzyme inhibition normalizes the enhanced activity of both exchangers while regressing cardiac hypertrophy. Because normalization of exchange activities could be also achieved by PKC inhibition, the data would suggest that PKC-dependent mechanisms play a significant role in the increased ion exchange activities of hypertrophic myocardium and in their normalization by angiotensin-converting enzyme inhibition.
Spontaneously Hypertensive Rats
Authors: Meneses Alfredo , Hong Enrique
Published: June 2012

Abstract
—Spontaneously hypertensive rats (SHR) of 3 to 12 months of age learned and retrieved less information than normotensive Wistar-Kyoto rats (WKY), although no difference was found with animals from 18 and 24 months of age. The combined influence of hypertension and aging had an additive detrimental effect on cognitive functions. Notwithstanding these deficiencies in learning and memory, SHR have seldom been used as a model in the screening of drugs with therapeutic potential for treatment of disorders of cognitive processes. Moreover, the calcium channel blocker nimodipine has beneficial effects on learning in both aged and hypertensive animals and humans. However, no attempt has been made to investigate whether nimodipine can reverse the additive deleterious effects of aging and hypertension in the same subject. We recently reported that deteriorated animals (middle-aged and/or hypertensive) chronically treated with nimodipine (via osmotic minipumps) exhibit higher learning scores. This information indicates that nimodipine can reverse the impairing effects of either aging or hypertension on learning; the presence of the two conditions, however, produces a severe impairment that can be partially reversed by this drug. Therefore, we propose that mature and middle-aged SHR represent a model for the screening of potentially useful drugs in the treatment of learning disorders, probably associated with hypertension and/or aging. Nevertheless, it must be remembered that the SHR is a genetic model and the appearance of neural disturbances could be a parallel genetic phenomenon and not necessarily or exclusively related to hypertension per se.
Interaction Between Body Size and Cardiac Workload
Authors: de Simone Giovanni , Devereux Richard B. , Kimball Thomas R. , Mureddu Gian Francesco , Roman Mary J. , Contaldo Franco , Daniels Stephen R.
Published: June 2012

Abstract
—The development of the left ventricle parallels body growth. During infancy, the relation between body size and left ventricular (LV) mass is very close. With advancing age, variability of LV mass in relation to body size markedly increases. To test the hypothesis that the age-related increase in variability of LV mass is due to the progressive impact of hemodynamic stimuli on LV growth, quantitative M-mode echocardiograms were obtained in 766 normal-weight, normotensive individuals over a range of ages from 1 day to 85 years (330 female subjects, 373 subjects younger than 18 years). LV mass was linearly related to height

2

(
r
2
=.69). Prediction of values of LV mass by body size was more accurate at birth and progressively less precise with increasing age. Stroke work (stroke volume times systolic pressure) was closely related to LV mass (
r
2
=.74). The explained variance of LV mass increased from 69% in the univariate regression with height

2

to 82% in a multivariate model including height
2.7
, stroke work, and gender. In children and adolescents (younger than 18 years), height

2

was the main determinant of LV mass, whereas during adulthood stroke work and gender were more important predictors of LV mass than height
2.7
. Thus (1) the influence of body growth on development of LV mass decreases after early infancy because of both the variability of hemodynamic load and the increasing effect of gender; (2) after adolescence, during adulthood, in normotensive, normal-weight individuals, the impact of hemodynamic load and male gender on LV mass is greater than the one of body size; and (3) an appreciable proportion of variability of LV mass remains unexplained with the studied models. This might be due to genotypic variations and/or measurement error.
Effects of a Novel Antihypertensive Drug, Cilnidipine, on Catecholamine Secretion From Differentiated PC12 Cells
Authors: Uneyama Hisayuki , Uchida Hirohisa , Yoshimoto Ryota , Ueno Shinya , Inoue Kazuhide , Akaike Norio
Published: June 2012

Abstract
—Effects of a novel dihydropyridine type of antihypertensive drug, cilnidipine, on the regulation of the catecholamine secretion closely linked to the intracellular Ca
2+
were examined using nerve growth factor (NGF)–differentiated rat pheochromocytoma PC12 cells. By measuring catecholamine secretion with high-performance liquid chromatography coupled with an electrochemical detector, we showed that high K
+
stimulation evoked dopamine release from PC12 cells both before and after NGF treatments. Cilnidipine depressed dopamine release both from NGF-treated and untreated PC12 cells in a concentration-dependent manner. In contrast, inhibition by nifedipine was markedly decreased in the differentiated PC12 cells. With intracellular Ca
2+
concentration ([Ca
2+
]
i
) measurements using fura 2, the elevation of high K
+
–evoked [Ca
2+
]
i
was separated into nifedipine-sensitive and -resistant components. The nifedipine-resistant [Ca
2+
]
i
increase was also blocked by cilnidipine, as well as ω-conotoxin-GVIA. By the use of the conventional whole-cell patch-clamp technique, the compositions of the high-voltage–activated Ca
2+
channel currents in the NGF-treated PC12 cells were divided into types: L-type, N-type, and residual current components. It was also estimated that cilnidipine at 1 and 3 μmol/L strongly blocked the N-type current without affecting the residual current. These results suggest that cilnidipine inhibits catecholamine secretion from differentiated PC12 cells by blocking Ca
2+
influx through the N-type Ca
2+
channel, in addition to its well-known action on the L-type Ca
2+
channel.
Enhanced Blood Pressure Sensitivity to Deoxycorticosterone in Mice With Disruption of Bradykinin B
2
Receptor Gene
Authors: Emanueli Costanza , Fink Edwin , Milia Anna Franca , Salis Maria Bonaria , Conti Milena , Demontis Maria Piera , Madeddu Paolo
Published: June 2012

Abstract
—The renal kallikrein-kinin system is activated under conditions of mineralocorticoid excess. To evaluate whether endogenous kinins exert a protective role against the development of mineralocorticoid-induced hypertension, we studied the cardiovascular effects induced by long-term administration of deoxycorticosterone (DOC; 0.3 μmol/g body wt SC once per week for 6 weeks) or vehicle in transgenic mice (Bk2r
−/−
) lacking the bradykinin B
2
receptor gene and in wild-type controls (Bk2r
+/+
). Under basal conditions, Bk2r
−/−
mice showed higher systolic blood pressure (tail-cuff plethysmography) than wild-type Bk2r
+/+
and heterozygous Bk2r
+/−
mice (121±2 versus 114±2 and 115±2 mm Hg, respectively;
P
<0.05 for both comparisons). Heart rate was higher in Bk2r
−/−
and Bk2r
+/−
than in Bk2r
+/+
(459±12 and 418±7 versus 390±7 bpm;
P
<0.05 for both comparisons). Systolic blood pressure was increased by DOC in transgenic as well as in wild-type mice, whereas no change was induced by the vehicle. The pressor response to DOC was more rapid and pronounced in Bk2r
−/−
than in Bk2r
+/+
and Bk2r
+/−
(30±5 versus 15±4 and 6±3 mm Hg, respectively, at 3 weeks;
P
<0.01 for both comparisons). The difference in systolic blood pressure was consistent with that detected by direct intra-arterial measurements of mean blood pressure. Neither DOC nor its vehicle altered heart rate or gain in body weight over time. Under basal conditions, urinary sodium excretion did not differ between strains. During DOC administration, cumulative urinary sodium excretion was lower in Bk2r
−/−
than in Bk2r
+/+
(2.59±0.15 versus 3.31±0.22 mmol, respectively, during the first week;
P
<0.05). Urinary kinin excretion was increased by DOC in both Bk2r
−/−
(from 0.65±0.17 to 4.27±0.80 pmol/24 h;
P
<0.01) and Bk2r
+/+
(from 0.55±0.09 to 6.27±1.48 pmol/24 h;
P
<0.05). The increase in urinary kinin excretion was similar between strains. These results show that integrity of the bradykinin B
2
receptor is essential for regulation of blood pressure and heart rate under basal conditions. In addition, they indicate that activation of the kallikrein-kinin system represents a compensatory response against the development of hypertension induced by mineralocorticoid excess.
Recent Advances on Large Arteries in Hypertension
Authors: Safar Michel E. , London Gerard M. , Asmar Roland , Frohlich Edward D.
Published: June 2012

Abstract
—The most classic hemodynamic concept explaining the increased mean arterial pressure in hypertension reflects an increased total peripheral resistance dynamically and an increased wall-to-lumen ratio to suppress smaller arteries. However, a more current consideration takes into account not only that steady component but also the pulsatile component of blood pressure, a point that importantly modifies the traditional hemodynamic definition. Whereas mean arterial pressure is almost constant along the arterial tree, the pulse pressure increases markedly from the more central to the peripheral arteries, indicating that in vivo each artery should be characterized according to its own blood pressure curve. This important concept implies major modifications in the methods used to investigate the relationships between mechanical factors and large artery structure and function. It therefore seems reasonable that in hypertension the large arteries should no longer be considered as passive conduits but rather in terms of their active behavioral response to the mechanical forces to which they are subjected. New investigational aspects in hypertension therefore now involve not only genetic, cellular, and molecular mechanisms but also transductional hemodynamic mechanisms reflecting changing patterns in the extracellular matrix that influence structural remodeling of the vessels.
Angiotensin-Converting Enzyme Inhibition, But Not Calcium Antagonism, Improves a Response of the Renal Vasculature to
l
-Arginine in Patients With Essential Hypertension
Authors: Higashi Yukihito , Oshima Tetsuya , Sasaki Shota , Nakano Yukiko , Kambe Masayuki , Matsuura Hideo , Kajiyama Goro
Published: June 2012

Abstract
—Endothelial function has been shown to be impaired in patients with essential hypertension. The purpose of the present study was to determine whether antihypertensive drug therapy improves impaired endothelium-dependent renal vasorelaxation in essential hypertensive patients without atherosclerosis. We evaluated the effects of intravenous infusion of
l
-arginine (500 mg/kg given over 30 minutes) on systemic and renal hemodynamics in 27 patients with mild to moderate essential hypertension who were randomly assigned to treatment with either the angiotensin-converting enzyme inhibitor imidapril or the calcium antagonist amlodipine for 12 weeks in a double-blind fashion. After the 12 weeks, the decrease in blood pressure was similar in the imidapril (n=14) and amlodipine (n=13) groups. The increase in renal plasma flow was also similar in both groups.
l
-Arginine–induced renovascular relaxation was increased by imidapril (renal plasma flow, 9.6±5.1% to 14.4±7.4%; renal vascular resistance, −10.4±8.1% to −16.7±9.2%,
P
<0.05, respectively) but not by amlodipine. Urinary excretion of nitrite/nitrate in response to
l
-arginine was significantly increased by imidapril (90±29% to 134±63%,
P
<0.05) but remained unchanged by amlodipine. These findings suggest that angiotensin-converting enzyme inhibition improves the impaired endothelium-dependent renovascular relaxation in patients with essential hypertension due to the increase in nitric oxide production and that the reduction in blood pressure with a calcium antagonist does not play a major role in the potentiation of
l
-arginine/nitric oxide–mediated effects.
Effects of Gonadal Steroids and Their Antagonists on DNA Synthesis in Human Vascular Cells
Authors: Somjen Dalia , Kohen Fortune , Jaffe Anat , Amir-Zaltsman Yehudit , Knoll Esther , Stern Naftali
Published: June 2012

Abstract
—The cardiovascular effect of estrogen is currently under intense investigation, but the role of androgens in vascular biology has attracted little attention. Because endothelial repair and vascular smooth muscle cell (VSMC) proliferation affect atherogenesis, we analyzed the effects of 17β-estradiol (E
2
), dihydrotestosterone (DHT), and sex hormone antagonists on DNA synthesis in human umbilical VSMCs and in E304 cells (a human umbilical endothelial cell line). In VSMCs, both E
2
and DHT had a biphasic effect on [
3
H]thymidine incorporation into DNA: low concentrations (0.3 nmol/L for E
2
, 3 nmol/L for DHT) stimulated [
3
H]thymidine incorporation (+35% and +41%, respectively), whereas high concentrations (30 nmol/L for E
2
, 300 nmol/L for DHT) inhibited [
3
H]thymidine incorporation (−40%). In contrast, E
2
(0.3 to 300 nmol/L) and DHT (3 to 3000 nmol/L) dose-dependently enhanced [
3
H]thymidine incorporation in E304 cells (peak, +85% for both). In VSMCs, high concentrations of E
2
and DHT inhibited platelet-derived growth factor (PDGF)–or insulin-like growth factor (IGF-1)–induced DNA synthesis (−50% to 80%), whereas PDGF- or IGF-1–dependent DNA synthesis in E304 cells was further increased by E
2
. The antiestrogens tamoxifen and raloxifene mimicked the effects of E
2
on DNA synthesis in both VSMCs and E304 cells. However, when coincubated with a stimulatory concentration of E
2
(0.3 nmol/L), tamoxifen and raloxifene blocked E
2
-induced [
3
H]thymidine incorporation in E304 cells but not in VSMCs. Finally, the androgen antagonist flutamide inhibited the biphasic effects of DHT on VSMCs and blocked the increase in DNA elicited by DHT in E304 cells. The results suggest complex, dose-dependent, and cell-specific interactions of estrogens, androgens, and their respective antagonists in the control of cellular proliferation in the vascular wall. Gonadal steroid–dependent inhibition of VSMC proliferation and stimulation of endothelial replication may contribute to vascular protection and remodeling responses to vascular injury.
Ambulatory Blood Pressure and Urinary Albumin Excretion in Clinically Healthy Subjects
Authors: Clausen Peter , Jensen Jan S. , Borch-Johnsen Knut , Jensen Gorm , Feldt-Rasmussen Bo
Published: June 2012

Abstract
—A slightly elevated urinary albumin excretion rate (UAER) is a predictor of atherosclerotic cardiovascular disease. The mechanism is unknown, but moderate office blood pressure elevation has been demonstrated as part of a clustering of known atherosclerotic risk factors in subjects with elevated UAER. Because 24-hour ambulatory blood pressure is a superior predictor of hypertensive target organ involvement, we aimed to investigate blood pressure profile in clinically healthy subjects with elevated UAER. Ambulatory blood pressure monitoring was performed with a portable recorder in 27 subjects with an elevated UAER (>6.6 μg/min, overnight urine collection) and 46 normoalbuminuric control subjects. Mean±SD systolic and diastolic ambulatory blood pressures (24-hour) were significantly higher in subjects with elevated UAER than in normoalbuminuric controls (134±12 versus 128±11 mm Hg and 78±7 versus 75±6 mm Hg,
P
<0.05), as were systolic and diastolic blood pressure loads [median (range): 42% (6 to 94%) versus 23% (1 to 89%) and 20% (0 to 68%) versus 6% (0 to 62%),
P
<0.05]. The circadian variation of blood pressure was normal in subjects with elevated UAER. However, the increased urinary loss of albumin could not be solely related to the higher blood pressure. In conclusion, apparently healthy subjects with elevated UAER had slightly but significantly higher 24-hour systolic and diastolic blood pressure levels in addition to increased blood pressure loads but normal circadian variation. The demonstrated differences in blood pressure may offer a partial explanation for the association between elevated urinary albumin excretion and atherosclerotic cardiovascular risk.
Bradykinin-Induced Reductions in Collagen Gene Expression Involve Prostacyclin
Authors: Gallagher Ann Marie , Yu Hisahiro , Printz Morton P.
Published: June 2012

Abstract
—Cardiac fibrosis after myocardial infarction and in chronic hypertension involves an increase in the synthesis and deposition of collagen within the myocardium. Angiotensin-converting enzyme (ACE) inhibitors limit hypertrophy and fibrosis; their mechanism of action remains controversial, although kinins have been implicated to play a role. Because both bradykinin and prostaglandins (PG) have been shown to reduce collagen gene expression in cardiac fibroblasts, the goal of this study was to determine whether the bradykinin effect was mediated through enhanced prostaglandin formation by cardiac fibroblasts. Bradykinin increased [
3
H]arachidonic acid metabolite release 2.3-fold over control and stimulated a dose-dependent increase in 6-keto PGF
1α
(the stable metabolite of PGI
2
) release from these cells, in which 1 nmol/L bradykinin produced a 4-fold increase in 6-keto PGF
1α
release. Beraprost (a PGI
2
analogue) reduced steady-state proα1(I) and proα1(III) collagen mRNA levels by 35.6±6.6% and 34.2±10.0%, respectively. Bradykinin-induced reductions in collagen type I and III gene expression were reversed by pretreatment with indomethacin. Our results indicate that one mechanism by which bradykinin modulates collagen biosynthesis via the rabbit cardiac fibroblast involves formation of arachidonic acid metabolites, particularly PGI
2
. The results of the present study argue that stabilization of endogenous kinins (as by ACE inhibitors) would enhance prostacyclin production and result in the attenuation of collagen gene expression, with potential implications for collagen synthesis and deposition within the myocardium.
Effects of Losartan and Enalapril on Small Artery Structure in Hypertensive Rats
Authors: Rizzoni Damiano , Porteri Enzo , Piccoli Alfonso , Castellano Maurizio , Bettoni Giorgio , Muiesan Maria Lorenza , Pasini Giancarlo , Guelfi Daniele , Mulvany Michael J. , Rosei Enrico Agabiti
Published: June 2012

Abstract
—We evaluated the effects on cardiovascular structure of the angiotensin-converting enzyme (ACE) inhibitor enalapril and of the angiotensin II receptor blocker losartan, administered either at hypotensive or nonhypotensive dosage in spontaneously hypertensive rats (SHR). SHR were treated from ages 4 to 12 weeks with low-dose (1 mg · kg
−1
· d
−1
) enalapril, low-dose (0.5 mg · kg
−1
· d
−1
) losartan, high-dose (25 mg · kg
−1
· d
−1
) enalapril, or high-dose (15 mg · kg
−1
· d
−1
) losartan. Untreated WKY and SHR were also studied. Rats were killed at 13 weeks of age, and the heart was weighed. Mesenteric small arteries were dissected and mounted on a micromyograph for determination of media thickness and lumen diameter. In fixed arteries, cell volume, number of cells per segment length, and number of cell layers were measured using the unbiased “disector” method. Systolic blood pressure was significantly reduced by the high doses of both drugs, but the hypotensive effect was greater with enalapril than with losartan (
P
<0.05). In the high-dose enalapril and losartan groups, there were similar reductions in relative left ventricular mass, media/lumen ratio, and number of cell layers of resistance arteries; however, there were no differences in the cell volume or number of cells per segment length of resistance arteries. Low-dose enalapril did not affect systolic blood pressure or any of the structural parameters. The results show that the hypotensive effects of both losartan and enalapril were associated with outward remodeling of resistance arteries at the cellular level. The effect of losartan on resistance artery structure was equal to that of enalapril, despite the smaller hypotensive effect.
Insulin-Mediated Growth in Aortic Smooth Muscle and the Vascular Renin-Angiotensin System
Authors: Kamide Kei , Hori Mark T. , Zhu Jian-Hua , Barrett Jack D. , Eggena Peter , Tuck Michael L.
Published: June 2012

Abstract
—Insulin has been shown to directly affect blood vessel tone and to promote vascular hypertrophy, but the mechanism of these actions remains uncertain. Because angiotensin I (Ang I)–converting enzyme inhibitors have been shown to improve insulin action and to impede the progression of vascular hypertrophy in hypertensive animal models, it is possible that the vascular properties of insulin may be mediated through the tissue renin-angiotensin system (RAS). To evaluate this relationship, we first investigated the effect of insulin on components of the RAS using cultured rat vascular smooth muscle cells (VSMCs). Insulin treatment (1000 μU/mL) markedly increased angiotensinogen mRNA expression and angiotensinogen production. We next investigated the role of the RAS in insulin-mediated cell proliferation, using [
3
H]thymidine uptake. Studies were done both with insulin alone and in the presence of captopril (1×10
−7
to 10
−5
mol/L) and losartan (1×10
−9
to 10
−7
mol/L). [
3
H]Thymidine uptake was increased significantly by 1000 μU/mL insulin, and this stimulation was reduced by 1×10
−6
mol/L captopril (−38.8%,
P
<0.05) and by 1×10
−8
mol/L losartan (−37.5%,
P
<0.05). Further studies showed that the degree of insulin-mediated [
3
H]thymidine uptake in VSMCs could be duplicated by 4×10
−10
mol/L Ang II. Losartan reduced the effects of both Ang II and insulin on [
3
H]thymidine uptake by about 40% to 45% of baseline (
P
<0.05). Captopril reduced insulin-mediated [
3
H]thymidine uptake but did not affect Ang II–mediated [
3
H]thymidine uptake. In summary, insulin induced significant stimulation of angiotensinogen expression and production and stimulated growth similar to that seen with Ang II in cultured rat VSMCs. Inhibition of Ang II production or its binding to the Ang II type 1 (AT
1
) receptor inhibited insulin-mediated growth in a fashion similar to that seen with inhibition of Ang II–mediated growth. Thus, insulin can modulate the vascular RAS, and the effect of insulin on vascular growth may be via direct effects on angiotensinogen expression and translation operative through both the AT
1
receptor and the conversion of Ang I to Ang II.
Association Between a Polymorphism in the G Protein β3 Subunit Gene and Lower Renin and Elevated Diastolic Blood Pressure Levels
Authors: Schunkert Heribert , Hense Hans-Werner , Döring Angela , Riegger Günter A. J. , Siffert Winfried
Published: June 2012

Abstract
—G
i
proteins mediate the intracellular effects of many vasoactive and proliferative stimuli. Recently such signaling was found to be enhanced in cultured cells of some hypertensive subjects. A polymorphism at position 825 (C→T) of the G protein β3 subunit gene (GNB3) was strictly related to this phenotype. The aim of the present investigation was to test the association between this polymorphism and blood pressure and plasma renin levels in humans. A population-based sample (n=608) was analyzed by questionnaire and characterized for blood pressure; plasma renin, prorenin, and aldosterone levels; and G
β3
C825T allele status. In individuals without antihypertensive medication (n=474; age range, 52 to 67 years), the polymorphism was mildly associated with diastolic blood pressure (CC: 88.6±0.3 mm Hg, n=218; versus CT: 90.1±0.7 mm Hg, n=209; versus TT: 91.8±1.7 mm Hg, n=47;
P
=0.02 for trend) but not with systolic blood pressure. Furthermore, the 825T allele was also significantly associated with lower renin and prorenin levels, whereas the aldosterone to renin ratio was elevated in these subjects. Significant associations between the 825T allele and diastolic blood pressure, plasma renin, and prorenin levels (inverse), and the aldosterone to renin ratio persisted after adjustment for age, gender, body mass index, and systolic blood pressure. Finally, when the entire sample was considered and an adjustment was made for covariates, the presence of arterial hypertension and the use of antihypertensive medication were both 1.8-fold higher in the TT than in the CC genotype group (
P
<0.05 and
P
=0.06, respectively). This observation, if replicated in further studies, suggests a molecular mechanism that unifies a higher diastolic blood pressure, a lower renin level, and an elevated aldosterone to renin ratio, ie, a combination of features frequently found in patients with arterial hypertension.
Relation Between Number of Cardiovascular Risk Factors/Events and Noninvasive Doppler Ultrasound Assessments of Aortic Compliance
Authors: Lehmann Eldon D. , Hopkins Kathleen D. , Rawesh Ataullah , Joseph Ramina C. , Kongola Kadiadia , Coppack Simon W. , Gosling Raymond G.
Published: June 2012

Abstract
—The aim of this study was to establish the relation between noninvasive Doppler ultrasound assessments of aortic compliance, based on “foot-to-foot” aortic pulse wave velocity measurements, and presumed atherosclerotic load in patients with vascular disease and/or diabetes mellitus. One hundred ten patients with vascular disease and/or diabetes mellitus (arteriopaths) underwent measurement of in vivo aortic compliance using Doppler ultrasound. Demographic data on these subjects were recorded along with details of cardiovascular risk factors and events. Aortic compliance values were compared with data from 51 age-matched healthy, asymptomatic subjects putatively free of vascular disease (controls). Data are expressed as mean±SD. Arteriopaths were aged 64.1±8.4 years and had total cholesterol levels of 5.9±1.1 mmol/L and aortic compliance of 0.78±0.42%/10 mm Hg [1.33 kPa]. Most arteriopaths had 2 or more cardiovascular risk factors and events: diabetes (n=41), hypertension (n=45), smoking (n=86), cerebrovascular/transient ischemic event (n=13), myocardial infarction (n=44), angina (n=51), and/or peripheral vascular disease (n=33). Controls were aged 64.3±12.1 years with total cholesterol of 6.1±1.1 mmol/L and aortic compliance of 1.14±0.46%/10 mm Hg [1.33 kPa] (
P
<0.002 versus arteriopaths). Subset analysis revealed that patients with the greatest number of cardiovascular risk factors and events (n=5) had the stiffest aortas (aortic compliance, 0.58±0.15%/10 mm Hg [1.33 kPa]) compared with those patients with the median and mean (n=2) number of risk factors and events (aortic compliance, 0.80±0.50%/10 mm Hg [1.33 kPa];
P
<0.02). The data suggest that a significant inverse relation exists between presumed atherosclerotic load (as assessed by the number of cardiovascular risk factors and events) and aortic compliance determined noninvasively based on aortic pulse wave velocity measurements. If these findings are confirmed by prospective, longitudinal follow-up studies, such measurements may prove useful as a noninvasive marker of vascular risk.
Role of Calcium-Sensitive Tyrosine Kinase Pyk2/CAKβ/RAFTK in Angiotensin II–Induced Ras/ERK Signaling
Authors: Murasawa Satoshi , Mori Yasukiyo , Nozawa Yoshihisa , Masaki Hiroya , Maruyama Katsuya , Tsutsumi Yoshiaki , Moriguchi Yasutaka , Shibasaki Yasunobu , Tanaka Yoko , Iwasaka Toshiji , Inada Mitsuo , Matsubara Hiroaki
Published: June 2012

Abstract
—In cardiac fibroblasts, angiotensin II (Ang II) induced a rapid increase in extracellular signal–regulated kinase (ERK) activity in a pertussis toxin–insensitive manner. This ERK activation was abolished by the G
q
-associated phospholipase C inhibitor U73122 but was insensitive to protein kinase C (PKC) inhibitors or PKC downregulation by phorbol ester. Intracellular Ca
2+
chelation by BAPTA-AM or TMB-8 abolished Ang II–induced ERK activation, whereas treatment with EGTA or nifedipine did not affect it. Ca
2+
ionophore A23187 also induced a rapid increase in ERK activity to an extent similar to that of Ang II stimulation. Calmodulin inhibitors (W7 and calmidazolium) and tyrosine kinase inhibitors (genistein and ST638) completely blocked ERK activation by Ang II and A23187. Both Ang II and A23187 caused a rapid increase in the binding of GTP to p21
Ras
, which was nearly abolished by genistein and calmidazolium. Transfection with the dominant negative mutant of Ras and the Ras inhibitor manumycin completely inhibited Ang II–induced ERK activation. It was also found for the first time that cardiac fibroblasts abundantly expressed Ca
2+
-sensitive tyrosine kinase Pyk2/CAKβ/RAFTK and that Ang II markedly induced its activation in a Ca
2+
/calmodulin-sensitive manner. Overexpression of the dominant negative mutant of Pyk2 significantly attenuated Ang II– or A23187-induced ERK activities (36% and 38% inhibition compared with that in mock-transfected cells, respectively) and ERK tyrosine phosphorylation levels, as well as an increase in the binding of GTP to p21
Ras
. These findings demonstrate that in cardiac fibroblasts, Ang II–induced Ras/ERK activation is dominantly regulated by G
q
-coupled Ca
2+
/calmodulin signaling and that Pyk2 plays an important role in the signal transmission for efficient activation of the Ang II–induced Ras/ERK pathway.
Intralipid Enhances α
1
-Adrenergic Receptor–Mediated Pressor Sensitivity
Authors: Haastrup Adetola T. , Stepniakowski Konrad T. , Goodfriend Theodore L. , Egan Brent M.
Published: June 2012

Abstract
—The dyslipidemia in obese hypertensive persons may contribute to their increased vascular α-adrenergic receptor reactivity and tone. To further examine this notion, we conducted 2 studies of pressor sensitivity to phenylephrine, an α
1
-adrenergic receptor agonist, in lean normotensive subjects. In the first study (n=6), pressor responses to phenylephrine were obtained before and during a saline and heparin infusion. On another day, pressor reactivity to phenylephrine was measured before and during infusion of 20% Intralipid at 0.5 mL · m
−2
· min
−1
with heparin at 1000 U/h to increase lipoprotein lipase activity and raise nonesterified fatty acids (NEFAs). In the second study (n=8), baseline reactivity to phenylephrine was obtained on 2 separate days and repeated after raising NEFAs and triglycerides either with 0.8 mL · m
−2
· min
−1
of 20% Intralipid alone or together with heparin. The infusion of saline and heparin did not significantly change plasma NEFAs from baseline (516±90 versus 512±108 μmol/L, respectively;
P
=NS) or the dose of phenylephrine required to raise mean blood pressure by 20 mm Hg ([PD
20PE
]; 1.00±0.14 versus 0.95±0.10 μg · kg
−1
· min
−1
, respectively,
P
=NS). Intralipid at 0.5 mL · m
−2
· min
−1
with heparin raised plasma NEFAs to 793±30 μmol/L per liter (
P
<0.05 versus baseline) and reduced PD
20PE
from 1.01±0.10 to 0.80±0.09 μg · kg
−1
· min
−1
(
P
<0.05). Compared with baseline, Intralipid alone increased plasma NEFAs to 946±80 μmol/L (
P
<0.05), and NEFAs increased further with the addition of heparin to 2990±254 μmol/L (
P
<0.01). Despite an apparently greater increase of plasma NEFAs with Intralipid and heparin, Intralipid alone and together with heparin similarly reduced PD
20PE
. Across all study conditions, changes in levels of triglycerides and NEFAs correlated with changes in mean arterial pressure responses to phenylephrine, especially at the 0.4-μg · kg
−1
· min
−1
infusion rate of phenylephrine (
r
=0.64,
P
<0.01 and
r
=0.54,
P
<0.01, respectively). These data suggest that raising levels of plasma NEFAs and/or triglycerides enhances α
1
-adrenoceptor–mediated pressor sensitivity. The findings suggest that lipid abnormalities in obese hypertensives, which include elevated NEFAs and triglycerides, contribute to greater vascular α
1
-adrenergic reactivity.
Effects of Dietary Fish and Weight Reduction on Ambulatory Blood Pressure in Overweight Hypertensives
Authors: Bao Danny Q. , Mori Trevor A. , Burke Valerie , Puddey Ian B. , Beilin Lawrence J.
Published: June 2012

Abstract
—Obesity is a major factor contributing to hypertension and increased risk of cardiovascular disease. Regular consumption of dietary fish and ω3 fatty acids of marine origin can lower blood pressure (BP) levels and reduce cardiovascular risk. This study examined the potential effects of combining dietary fish rich in ω3 fatty acids with a weight loss regimen in overweight hypertensive subjects, with ambulatory BP levels as the primary end point. Using a factorial design, 69 overweight medication-treated hypertensives were randomized to a daily fish meal (3.65 g ω3 fatty acids), weight reduction, the 2 regimens combined, or a control regimen for 16 weeks. Sixty-three subjects with a mean±SEM body mass index of 31.6±0.5 kg/m
2
completed the study. Weight fell by 5.6±0.8 kg with energy restriction. Dietary fish and weight loss had significant independent and additive effects on 24-hour ambulatory BP. Effects were greatest on awake systolic and diastolic BP (
P
<0.01); relative to control, awake pressures fell 6.0/3.0 mm Hg with dietary fish alone, 5.5/2.2 mm Hg with weight reduction alone, and 13.0/9.3 mm Hg with fish and weight loss combined. These results also remained significant after further adjustment for changes in urinary sodium, potassium, or the sodium/potassium ratio, as well as dietary macronutrients. Dietary fish also significantly reduced 24-hour (−3.1±1.4 bpm,
P
=0.036) and awake (−4.2±1.6 bpm,
P
=0.013) ambulatory heart rates. Weight reduction had a significant effect on sleeping heart rate only (−3.2±1.7 bpm,
P
=0.037). Combining a daily fish meal with a weight-reducing regimen led to additive effects on ambulatory BP and decreased heart rate. The effects were large, suggesting that cardiovascular risk and antihypertensive drug requirements are likely to be reduced substantially by combining dietary fish meals rich in ω3 fatty acids with weight-loss regimens in overweight medication-treated hypertensives. The reduction in heart rate seen with dietary fish suggests a cardiac/autonomic component, as well as vascular effects, of increased consumption of ω3 fatty acid from fish.
Role of Nitric Oxide in Cyclosporine A–Induced Hypertension
Authors: Oriji Gibson K. , Keiser Harry R.
Published: June 2012

Abstract
—Cyclosporine A (CsA) is an immunosuppressive agent that also causes hypertension. The effect of CsA on vascular responses was determined in Sprague-Dawley rats and isolated rat aortic rings. Male rats weighing 250 to 300 g were given either CsA (25 mg · kg
−1
· d
−1
) in olive oil or vehicle by intraperitoneal injection for 7 days. CsA administration produced a 42% increase (
P
<0.001) in mean arterial pressure (MAP) that reached a plateau after 3 days. Conversely, the levels of both nitrate/nitrite, metabolites of nitric oxide (NO), and cGMP, which mediates NO action, decreased by 50% (
P
<0.001) and 35% (
P
<0.001), respectively, in the urine. Thoracic aortic rings from rats treated with CsA and precontracted with endothelin (10
−9
mol/L) showed a 35% increase (
P
<0.001) in tension, whereas endothelium-dependent relaxation induced by acetylcholine (ACh, 10
−9
mol/L) was inhibited 65% (
P
<0.001) compared with that in untreated rats. This response was similar to that of endothelium-denuded aortic rings from untreated rats in which ACh-induced relaxation was completely abolished (
P
<0.001), but relaxation induced by
S
-nitroso-
N
-acetylpenicillamine (SNAP, 10
−8
mol/L) was unaffected (
P
<0.001). ACh-induced formation of both nitrate/nitrite and cGMP by both denuded and CsA-treated aortic rings was inhibited 95% (
P
<0.001) and 65% (
P
<0.001), respectively, compared with intact aortic rings. The effects of CsA were reversed both in vivo and in vitro by pretreatment with
l
-arginine (10 mg · kg
−1
· d
−1
IP), the precursor of NO. There were no changes in MAP and tension in rats treated with
l
-arginine alone. In summary, CsA inhibits endothelial NO activity, with resulting increases in MAP and tension, and this inhibition can be overcome by parenteral administration of
l
-arginine.
Role of nNOS in Blood Pressure Regulation in eNOS Null Mutant Mice
Authors: Kurihara Nobutaka , Alfie Marcos E. , Sigmon David H. , Rhaleb Nour-Eddine , Shesely Edward G. , Carretero Oscar A.
Published: June 2012

Abstract
—The role of neural nitric oxide synthase (nNOS) in regulating blood pressure (BP) remains uncertain. Recently it was reported that in mice lacking functional endothelial NOS (eNOS) genes (−/−), acute administration of a nonselective NOS inhibitor,
N
w
-nitro-
l
-arginine, decreased mean BP, suggesting that NO released by non-eNOS isoforms increases BP. Because the inducible NOS isoform is not constitutively expressed and when induced causes hypotension, we hypothesize that it is NO produced by nNOS that increases BP in the absence of eNOS activity. To test this hypothesis, we studied the acute effect of selective and nonselective nNOS inhibitors on BP and cerebellar NOS activity in eNOS (−/−), wild-type (+/+), and heterozygous (+/−) mice as well as in +/+ mice with renovascular hypertension. Because it is not known whether the decrease in BP caused by acute NOS inhibition in −/− mice can occur chronically, we also studied the effect of chronic NOS inhibition on both BP and cerebellar NOS activity. eNOS (−/−) mice had higher BP than +/+ or +/−mice, and acute administration of the selective nNOS inhibitor 7-nitroindazole (7-NI) decreased their mean BP from 137±13 to 124±12 mm Hg (
P
<0.01). In +/+, +/−, or renovascular hypertensive +/+ mice, 7-NI caused a small but insignificant rise from 105±5 to 110±6 mm Hg, from 115±9 to 119±13 mm Hg, and from 146±6 to 150±6 mm Hg, respectively. Fifteen minutes after administration of 7-NI, cerebellar NOS activity decreased by 70%; however, this inhibitory effect was brief, since 2 hours after 7-NI administration NOS returned toward control values. Chronic oral or intraperitoneal administration of 7-NI did not inhibit cerebellar NOS activity, whereas the nonselective NOS inhibitor
N
G
-nitro-
l
-arginine methyl ester (L-NAME) decreased this activity by 50%. Therefore, we studied the effect of chronic L-NAME administration (4 weeks) on BP. In −/− mice, chronic L-NAME administration decreased BP from 135±4 to 120±3 mm Hg (
P
<0.05), whereas in +/+ and +/−mice, as expected, it increased BP from 109±2 to 125±3 mm Hg (
P
<0.001) and from 107±6 to 119±5 mm Hg (
P
<0.02), respectively. After L-NAME administration was stopped, BP returned to baseline. These results suggest that in eNOS −/− mice, NO derived from nNOS increases BP both acutely and chronically.
Parameters of Lymphocyte Na
+
-Ca
2+
Regulation and Blood Pressure
Authors: Horiguchi Makoto , Kimura Masayuki , Skurnick Joan , Aviv Abraham
Published: June 2012

Abstract
—Alterations in cellular Ca
2+
and Na
+
regulation play a role in the pathogenesis of essential hypertension. Using peripheral lymphocytes from 68 normal persons, we observed the following relationships for major cellular Ca
2+
regulatory parameters. Among men and women, Na
+
-Ca
2+
exchanger activity was positively correlated with the resting cytosolic free Ca
2+
([Ca
2+
]
c
) (
r
=0.43,
P
=0.0003), and the resting [Ca
2+
]
c
was positively correlated with cytosolic Na
+
([Na
+
]
c
) (
r
=0.50,
P
=0.0001). For men only, store-operated Ca
2+
entry was positively correlated with Na
+
-Ca
2+
exchanger activity (
r
=0.63,
P
=0.0001). In addition, systolic and diastolic blood pressures were positively correlated with [Na
+
]
c
in men (
r
=0.53,
P
=0.001, and
r
=0.41,
P
=0.017, respectively) but not in women (
r
=0.30,
P
=0.088, and
r
=0.24,
P
=0.17, respectively). Some of the relationships between cellular and blood pressure parameters were confounded by serum triglycerides. These observations indicate a gender effect on cellular Ca
2+
-Na
+
regulation and its relationship with blood pressure.
Arginine Vasopressin–Mediated Stimulation of Nitric Oxide Within the Rat Renal Medulla
Authors: Park Frank , Zou Ai-Ping , Cowley Allen W.
Published: June 2012

Abstract
—The present study was designed to determine whether arginine vasopressin (AVP) can stimulate nitric oxide (NO) production within the renal medulla and thereby modulate renal medullary blood flow. An in vivo microdialysis/NO trapping technique was used to determine changes in medullary interstitial [NO]. AVP (2 ng/kg per minute) was delivered into the renal medullary interstitium and resulted in a significant increase in renal medullary [NO] of 35%, which was blocked by pretreatment with nitro-
l
-arginine methyl ester (L-NAME) (1.3 μg/kg per minute) administered into the renal medullary interstitium. The vasopressin V
2
receptor agonist 1-desamino-8-
d
-arginine vasopressin (dDAVP) resulted in a significant increase of 32% in renal medullary interstitial [NO]. No change in renal medullary interstitial [NO] was observed after selective vasopressin V
1
receptor stimulation. Laser-Doppler flowmetry with implanted optical fibers was performed to measure cortical and medullary blood flow changes within the kidney. Renal interstitial infusion of dDAVP in rats pretreated with a vasopressin V
1
receptor antagonist resulted in a 15% increase (
P
<0.05) in medullary blood flow, which was completely blocked by pretreatment with L-NAME (1.3 μg/kg per minute). This study demonstrates that AVP increases renal medullary interstitial [NO] through vasopressin V
2
receptor stimulation, which in turn elevates blood flow to the renal medulla.
Reactive Oxygen Species Are Critical in the Oleic Acid–Mediated Mitogenic Signaling Pathway in Vascular Smooth Muscle Cells
Authors: Lu Gang , Greene Eddie L. , Nagai Toshi , Egan Brent M.
Published: June 2012

Abstract
—Obese hypertensive patients with cardiovascular risk factor clustering have increased plasma nonesterified fatty acid levels and are at high risk for atherosclerotic events. Our previous studies demonstrated that oleic acid induces a mitogenic response in rat aortic smooth muscle cells (RASMCs) through protein kinase C (PKC)– and extracellular signal–regulated kinase (ERK)–dependent pathways. In the present study we investigated the possibility that the generation of reactive oxygen species (ROS) constitutes a critical component of the oleic acid–induced mitogenic signaling pathway in RASMCs. We studied the effect(s) of oleic acid on the generation of ROS using the oxidant-sensitive fluoroprobe 2′,7′-dichlorofluorescin diacetate. Relative fluorescence intensity and fluorescent images were obtained with laser confocal scanning microscopy from 1 to 5 minutes, since preliminary studies demonstrated that the peak fluorescence intensity occurred within 5 minutes. Oleic acid (100 μmol/L) induced a time-dependent increase of cell fluorescence that was >8-fold of that seen in control cells at 5 minutes. This was blocked by catalase, which suggests that H
2
O
2
was the principal ROS. The oleic acid–induced increases in H
2
O
2
were blocked when PKC was inhibited with the use of bisindolylmaleimide and when PKC activity was downregulated by exposing RASMCs to phorbol 12–myristate 13–acetate for 24 hours. Stearic and elaidic acids, which are weak PKC activators, did not significantly increase H
2
O
2
production. The increase of H
2
O
2
in response to oleic acid was inhibited by the antioxidant
N
-acetylcysteine.
N
-Acetylcysteine also completely blocked ERK activation and the increase of thymidine incorporation in response to oleic acid. The data suggest that generation of H
2
O
2
in RASMCs exposed to oleic acid is PKC dependent. Moreover, H
2
O
2
production emerges as a critical intermediary event in the oleic acid–mediated mitogenic signaling pathway between the activation of PKC and ERK. These observations raise the possibility that the elevated plasma nonesterified fatty acids, including oleic acid, in obese hypertensive patients contribute to vascular growth and remodeling by a PKC-dependent mechanism to generate ROS that subsequently activate ERK.
I
1
-Imidazoline Agonist Moxonidine Decreases Sympathetic Nerve Activity and Blood Pressure in Hypertensives
Authors: Wenzel René Roland , Spieker Lukas , Qui Su , Shaw Sidney , Lüscher Thomas Felix , Noll Georg
Published: June 2012

Abstract
—Moxonidine is an I
1
-imidazoline receptor agonist that reduces blood pressure in hypertensives. Experimental data suggest that moxonidine inhibits central sympathetic activity. However, whether such a mechanism is involved in vivo in humans is still unclear. We investigated the effects of 0.4 mg moxonidine orally on muscle sympathetic nerve activity and heart rate in an open study in 8 healthy volunteers. Furthermore, we studied the effects of 0.4 mg moxonidine on muscle sympathetic nerve activity, heart rate, blood pressure, 24-hour blood pressure profile, and hormone plasma levels in 25 untreated hypertensives in a double-blind, placebo-controlled study. Moxonidine decreased muscle sympathetic nerve activity in both healthy volunteers (
P
<0.05 versus baseline) and hypertensives (
P
<0.02 versus placebo). Plasma norepinephrine also decreased (
P
<0.01), whereas plasma epinephrine and renin levels did not change (
P
=NS). Furthermore, moxonidine decreased systolic (
P
<0.0001) and diastolic (
P
<0.001) blood pressure. Heart rate decreased after moxonidine in healthy subjects (
P
<0.05); in hypertensives, heart rate decreased during the night hours (
P
<0.05) but not during daytime (
P
=NS). Plasma levels of LDL, HDL, and total cholesterol were not influenced by the drug (
P
=NS). Moxonidine decreases systolic and diastolic blood pressure by inhibiting central nervous sympathetic activity. This makes this new drug suitable for the treatment of human hypertension and possibly for other cardiovascular diseases with increased sympathetic nerve activity, ie, ischemic heart disease and heart failure.