bluuebunny/crossref_metadata_2025 huggingface dataset:
Angiotensin II Type AT
2
Receptor mRNA Expression and Renal Vasodilatation Are Increased in Renal Failure
Authors: Bautista Rocío , Sánchez Alicia , Hernández José , Oyekan Adebayo , Escalante Bruno
Published: September 2007

Abstract
—

— Kidney failure is associated with changes in renal vascular responses to angiotensin (Ang) II. We characterized expression of Ang II receptors and the renal vasoconstrictor and vasodilator responses to Ang II in kidneys from sham-operated and kidney failure rats. In the isolated perfused kidney of sham-operated rats, Ang II (1, 2, 4, and 8 ng) increased perfusion pressure by 27±6, 41±10, 54±11, and 74±12 mm Hg, respectively. These responses were amplified by 62±10% (
P
<0.05) in kidney failure rats. Losartan (1 μmol/L), an angiotensin type 1 (AT
1
) receptor blocker, abolished renal vasoconstriction induced by Ang II, unmasking a renal vasodilatation that was greater in kidney failure rats. CGP-42112 (1 μmol/L) or PD 123,319 (1 μmol/L), angiotensin type 2 (AT
2
) receptor ligands, blunted Ang II-induced renal vasodilatation. In the renal tissue of kidney failure rats, there was a marked increase in expression of AT
1
and AT
2
mRNA receptor. Ang II-induced vasodilatation was blunted by eicosatetraynoic acid (1 μmol/L), the all-purpose inhibitor of arachidonic acid metabolism; clotrimazole (1 μmol/L), an inhibitor of epoxygenase-dependent arachidonic acid metabolism; or
N
ω-nitro-
l
-arginine methyl ester (L-NAME; 1 μmol/L), an inhibitor of NO synthesis. On stimulation with Ang II, 20-HETE was the predominant product released into the renal effluent of sham-operated rats, whereas epoxy-eicosatrienoic acids were the predominant products released into the effluent of kidney failure rats. These data suggest that during development of kidney failure, there is induction of the AT
2
receptors, which may account for increased Ang II-dependent vasodilatation through the predominant release of epoxyeicosatrienoic acids .
Dietary Protein and Soluble Fiber Reduce Ambulatory Blood Pressure in Treated Hypertensives
Authors: Burke Valerie , Hodgson Jonathan M. , Beilin Lawrie J. , Giangiulioi Nella , Rogers Penny , Puddey Ian B.
Published: September 2007

In population studies, higher blood pressure has been associated with lower intake of protein and, possibly, lower fiber consumption. In the present randomized controlled trial, we sought to determine whether dietary protein and fiber had additive effects on blood pressure reduction in hypertensives. Treated hypertensive patients changed for 4 weeks (familiarization) to a diet low in protein (12.5% energy) and fiber (15 g/d). Patients (n=41) were then randomized to 1 of 4 groups in an 8-week factorial study of parallel design in which they continued the low-protein, low-fiber diet alone or had supplements of soy protein to increase protein intake to 25% energy, of psyllium to provide an additional 12 g soluble fiber/d, or of both protein and fiber. The 24-hour ambulatory blood pressure was compared from the end of familiarization to the end of intervention. In the 36 subjects who provided complete data, protein and fiber had significant additive effects to lower 24-hour and awake systolic blood pressure. Relative to control subjects, the net reduction in 24-hour systolic blood pressure was 5.9 mm Hg with fiber and with protein. Findings were independent of age, gender, and change in weight, alcohol intake, or urinary sodium and potassium. Relative to reduced fiber and protein intake, dietary protein and soluble fiber supplements lower blood pressure additively in hypertensives. These findings have important implications for the prevention and management of hypertension, particularly in populations in which high blood pressure is prevalent in association with diets low in protein, fiber, or both.
Chronic Exposure to Vasopressin Upregulates ENaC and Sodium Transport in the Rat Renal Collecting Duct and Lung
Authors: Nicco Carole , Wittner Monika , DiStefano Antonio , Jounier Sylvie , Bankir Lise , Bouby Nadine
Published: September 2007

Vasopressin is known to acutely stimulate sodium transport in the renal collecting duct. We investigated the long-term regulation by vasopressin of the epithelial sodium channel (ENaC) in the rat kidney. Five-day infusion of dDAVP (a V
2
receptor agonist) to Brattleboro rats lacking vasopressin induced a marked increase in β- and γ-subunit ENaC mRNA levels in the renal cortex (β, 85%; γ, 100%), with no change in α-ENaC mRNA. Expression of β- and γ-ENaC mRNAs was also enhanced in lung (β, 49%; γ, 33%) but not in distal colon (an organ devoid of V
2
receptors). Similar results were obtained in Sprague Dawley rats after either partial water restriction or dDAVP infusion for 5 days. Transepithelial voltage and transepithelial sodium and water net fluxes were measured in isolated perfused cortical collecting ducts of Brattleboro rats. Acute addition of 2×10
−10
mol/L dDAVP to the bath increased sodium and water fluxes in the same proportion, and to a far greater extent in dDAVP-infused than in control Brattleboro rats (change in Na
+
net flux, 337±30 versus 49±11 pmol · min
−1
· mm
−1
, respectively;
P
<0.001). These effects were abolished by amiloride. Extrarenal water losses, partly originating from the lung, were reduced by high plasma vasopressin level. This study shows that vasopressin increases sodium transport in the renal collecting duct and probably in the lung, through a differential transcriptional regulation of ENaC subunits. This effect is followed by isoosmotic water reabsorption and likely contributes to the process of water conservation. It could lead to less efficient sodium excretion, however, and thus participate in some forms of salt-sensitive hypertension.
An Endothelium-Derived Hyperpolarizing Factor–Like Factor Moderates Myogenic Constriction of Mesenteric Resistance Arteries in the Absence of Endothelial Nitric Oxide Synthase–Derived Nitric Oxide
Authors: Scotland Ramona S. , Chauhan Sharmila , Vallance Patrick J.T. , Ahluwalia Amrita
Published: September 2007

Myogenic tone is an important determinant of vascular tone and blood flow in small resistance arteries of certain vascular beds. The role of the endothelium in myogenic responses is unclear. We hypothesized that endothelium-derived NO release modulates myogenic constriction in small resistance arteries and that mesenteric small arteries from mice with targeted disruption of the gene for endothelial NO synthase (eNOS) (knockout mice) demonstrate greater myogenic tone than do wild-type mice. Third-order mesenteric arteries (≈200 μm) were isolated and mounted in a pressure myograph. Internal diameter was recorded over a pressure range of 10 to 80 mm Hg. Removal of the endothelium significantly (
P
<0.05) enhanced the magnitude of myogenic constriction in wild-type mice. Similarly, pretreatment of arteries with
N
G
-nitro-
l
-arginine methyl ester (L-NAME; 300 μmol/L) produced a comparable significant (
P
<0.05) increase in myogenic tone, whereas indomethacin (5 μmol/L) had no effect. eNOS knockout arteries also exhibited myogenic constriction. Neither L-NAME nor indomethacin had any effect on myogenic tone in the arteries of eNOS knockout mice. However, blockade of potential endothelium-derived hyperpolarizing factor–like mechanisms via inhibition of K
+
flux using either apamin (100 nmol/L) with charybdotoxin (100 nmol/L), Ba
2+
(30 μmol/L) with ouabain (1 mmol/L), or 18α-glycyrrhetinic acid (100 μmol/L) significantly (
P
<0.01) enhanced myogenic constriction. This study demonstrates that basal endothelium-derived NO modulates myogenic tone in mesenteric small arteries of wild-type mice. However, eNOS knockout arteries display normal myogenic responsiveness despite the absence of basal NO activity. The data suggest that this compensatory effect is due to the activity of an endothelium-derived hyperpolarizing factor to normalize vascular tone.
Pulse Pressure, Arterial Stiffness, and Drug Treatment of Hypertension
Authors: Van Bortel Luc M.A.B. , Struijker-Boudier Harry A.J. , Safar Michel E.
Published: September 2007

Epidemiological studies in the past decade have stressed the importance of pulse pressure as an independent risk factor for cardiovascular morbidity and mortality. We briefly review the epidemiological evidence and discuss in more detail the pathophysiological basis for this observation and the therapeutic consequences. We focus on the vascular determinants of increased pulse pressure. Both longitudinal and cross-sectional components of the vascular system contribute to the shape of the arterial pressure wave and, thereby, to pulse pressure. The primary longitudinal component is the architecture of the arterial tree, which determines the major reflection sites for the pressure wave. The cross-sectional architecture of the vascular system consists of a geometric (diameter) and a structural (composition vessel wall) component. Both diameter and composition of the vessel wall vary greatly when going from central to more peripheral arteries. We review the implications for the functional properties of various arterial segments. Finally, we discuss the therapeutic consequences of targeting pulse pressure rather than mean blood pressure with various drug classes. Among the antihypertensive agents, nitrates, NO donors, and drugs that interfere with the renin-angiotensin-aldosterone system may offer useful tools to lower pulse pressure, in addition to mean blood pressure. Future developments may include non-antihypertensive agents that target collagen or other components of the arterial wall matrix. However, large-scale clinical trials will have to confirm the therapeutic value of these agents in the treatment of increased pulse pressure and arterial stiffness.
Improvement in Blood Pressure, Arterial Stiffness and Wave Reflections With a Very-Low-Dose Perindopril/Indapamide Combination in Hypertensive Patient
Authors: Asmar Roland G. , London Gérard M. , O’Rourke Michael E. , Safar Michel E. ,   for the REASON Project coordinators and investigators
Published: September 2007

International guidelines recommend that antihypertensive drug therapy should normalize not only diastolic (DBP) but also systolic blood pressure (SBP). Therapeutic trials based on cardiovascular mortality have recently shown that SBP reduction requires normalization of both large artery stiffness and wave reflections. The aim of the present study was to compare the antihypertensive effects of the very-low-dose combination indapamide (0.625 mg) and perindopril (2 mg) (Per/Ind) with the β-blocking agent atenolol (50 mg) to determine whether Per/Ind decreases SBP and pulse pressure (PP) more than does atenolol and, if so, whether this decrease is predominantly due to reduction of aortic pulse wave velocity (PWV) (automatic measurements) and reduction of wave reflections (pulse wave analysis, applanation tonometry). In a double-blind randomized study, 471 patients with essential hypertension were followed for 12 months. For the same DBP reduction, Per/Ind decreased brachial SBP (−6.02 mm Hg; 95% confidence interval, −8.90 to −3.14) and PP (−5.57; 95% confidence interval, −7.70 to −3.44) significantly more than did atenolol. This difference was significantly more pronounced for the carotid artery than for the brachial artery. Whereas the 2 antihypertensive agents decreased PWV to a similar degree, only Per/Ind significantly attenuated carotid wave reflections, resulting in a selective decrease in SBP and PP. The very-low-dose combination Per/Ind normalizes SBP, PP, and arterial function to a significantly larger extent than does atenolol, a hemodynamic profile that is known to improve survival in hypertensive populations with high cardiovascular risk.
Prospective Evaluation of a Method for Estimating Ascending Aortic Pressure From the Radial Artery Pressure Waveform
Authors: Pauca Alfredo L. , O’Rourke Michael F. , Kon Neal D.
Published: September 2007

Pressure wave reflection in the upper limb causes amplification of the arterial pulse so that radial systolic and pulse pressures are greater than in the ascending aorta. Wave transmission properties in the upper limbs (in contrast to the descending aorta and lower limbs) change little with age, disease, and drug therapy in adult humans. Such consistency has led to use of a generalized transfer function to synthesize the ascending aortic pressure pulse from the radial pulse. Validity of this approach was tested for estimation of aortic systolic, diastolic, pulse, and mean pressures from the radial pressure waveform. Ascending aortic and radial pressure waveforms were recorded simultaneously at cardiac surgery, before initiation of cardiopulmonary bypass, with matched, fluid-filled manometer systems in 62 patients under control conditions and during nitroglycerin infusion. Aortic pressure pulse waves, generated from the radial pulse, showed agreement with the measured aortic pulse waves with respect to systolic, diastolic, pulse, and mean pressures, with mean differences <1 mm Hg. Control differences in Bland-Altman plots for mean±SD in mm Hg were systolic, 0.0±4.4; diastolic, 0.6±1.7; pulse, −0.7±4.2; and mean pressure, −0.5±2.0. For nitroglycerin infusion, differences respectively were systolic, −0.2±4.3; diastolic, 0.6±1.7; pulse, −0.8±4.1; and mean pressure, −0.4±1.8. Differences were within specified limits of the Association for the Advancement of Medical Instrumentation SP10 criteria. In contrast, differences between recorded radial and aortic systolic and pulse pressures were well outside the criteria (respectively, 15.7±8.4 and 16.3±8.5 for control and 14.5±7.3 and 15.1±7.3 mm Hg for nitroglycerin). Use of a generalized transfer function to synthesize radial artery pressure waveforms can provide substantially equivalent values of aortic systolic, pulse, mean, and diastolic pressures.
Conventional Antihypertensive Drug Therapy Does Not Prevent the Increase of Pulse Pressure With Age
Authors: Mourad Jean-Jacques , Blacher Jacques , Blin Patrick , Warzocha Ursula ,   on behalf of the investigators of the PHASTE study
Published: September 2007

Increased pulse pressure (PP), an independent predictor of cardiovascular risk, may be quantified on the basis of the prevalence of isolated systolic hypertension (ISH) in the population at large. The purpose of this study was to estimate the prevalence of ISH and its relation to age and drug therapy in a large group of outpatient hypertensive subjects in France. Between March and December 1999, 2975 French general practitioners included 17 716 consecutive patients with uncontrolled hypertension (systolic blood pressure [SBP] >140 mm Hg and/or diastolic blood pressure [DBP] >90 mm Hg), either treated or not treated. They were asked to complete a questionnaire concerning associated cardiovascular risk factors and ongoing antihypertensive therapy. Subjects were classified according to 5 age ranges (from 18 to 103 years). In each age range, SBP, DBP, mean blood pressure, and PP were significantly lower (
P
<0.001) in treated subjects than in untreated subjects, with the exception of PP in subjects >75 years. The latter finding resulted from a significant increase of SBP and PP with age, together with a significant lowering of DBP with age, irrespective of drug treatment. Subsequently, the prevalence of ISH increased with age from 20.4% to 35.2% in men and women. In any given age range, drug therapy for hypertension is associated with marginally lower values of PP. In the studied populations, the increase of PP with age is independent of gender and of the presence of antihypertensive drug treatment, leading to an increased prevalence of ISH and a subsequent increase of cardiovascular risk with age.
Cyclic Strain Increases Protease-Activated Receptor-1 Expression in Vascular Smooth Muscle Cells
Authors: Nguyen Kytai T. , Frye Stacie R. , Eskin Suzanne G. , Patterson Cam , Runge Marschall S. , McIntire Larry V.
Published: September 2007

Cyclic strain regulates many vascular smooth muscle cell (VSMC) functions through changing gene expression. This study investigated the effects of cyclic strain on protease-activated receptor-1 (PAR-1) expression in VSMCs and the possible signaling pathways involved, on the basis of the hypothesis that cyclic strain would enhance PAR-1 expression, reflecting increased thrombin activity. Uniaxial cyclic strain (1 Hz, 20%) of cells cultured on elastic membranes induced a 2-fold increase in both PAR-1 mRNA and protein levels. Functional activity of PAR-1, as assessed by cell proliferation in response to thrombin, was also increased by cyclic strain. In addition, treatment of cells with antioxidants or an NADPH oxidase inhibitor blocked strain-induced PAR-1 expression. Preincubation of cells with protein kinase inhibitors (staurosporine or Ro 31-8220) enhanced strain-increased PAR-1 expression, whereas inhibitors of NO synthase, tyrosine kinase, and mitogen-activated protein kinases had no effect. Cyclic strain in the presence of basic fibroblast growth factor induced PAR-1 mRNA levels beyond the effect of cyclic strain alone, whereas no additive effect was observed between cyclic strain and platelet-derived growth factor-AB. Our findings that cyclic strain upregulates PAR-1 mRNA expression but that shear stress downregulates this gene in VSMCs provide an opportunity to elucidate signaling differences by which VSMCs respond to different mechanical forces.
Selective Angiotensin II Receptor Antagonism Reduces Insulin Resistance in Obese Zucker Rats
Authors: Henriksen Erik J. , Jacob Stephan , Kinnick Tyson R. , Teachey Mary K. , Krekler Michael
Published: September 2007

Effects of oral administration of the angiotensin II receptor antagonist (selective AT1-subtype) irbesartan on glucose tolerance and insulin action on skeletal-muscle glucose transport were assessed in the insulin-resistant obese Zucker rat. In the acute study, obese rats received either vehicle (water) or irbesartan 1 hour before the experiment. Although irbesartan had no effect on glucose transport (2-deoxyglucose uptake) in the epitrochlearis muscle, which consists mainly of type IIb fibers, acute angiotensin II receptor antagonism led to a dose-dependent increase in insulin action in the predominantly type I soleus muscle. Irbesartan at 25 and 50 mg/kg induced significant increases (41% and 50%, respectively;P<0.05) in insulin-mediated glucose transport. Moreover, these acute irbesartan-induced improvements in soleus-muscle glucose transport were associated with enhancements in whole-body insulin sensitivity (r=−0.732;P<0.05), as assessed during an oral glucose tolerance test. After chronic administration of irbesartan (21 days at 50 mg · kg−1· d−1), glucose tolerance was enhanced further, and insulin-mediated glucose transport was significantly elevated in both epitrochlearis (32%) and soleus (73%) muscle. Chronic angiotensin II receptor antagonism was associated with significant increases in glucose transporter-4 (GLUT-4) protein expression in soleus (22%) and plantaris (20%) muscle and myocardium (15%). Chronic irbesartan-induced increases in whole-body insulin sensitivity were associated with increased insulin-mediated glucose transport in both epitrochlearis (r=−0.677;P<0.05) and soleus (r=−0.892;P<0.05) muscle. In summary, angiotensin II receptor (AT1-subtype) antagonism, either acutely or chronically, improves glucose tolerance, at least in part because of an enhancement in skeletal-muscle glucose transport, and the effect of chronic angiotensin II receptor antagonism on type I skeletal-muscle glucose uptake is associated with an increase in GLUT-4 protein expression.
Acute Gender-Specific Hemodynamic and Inotropic Effects of 17β-Estradiol on Rats
Authors: Beyer Martin E. , Yu Georg , Hanke Hartmut , Hoffmeister Hans Martin
Published: September 2007

Estrogen has cardioprotective effects. In addition to beneficial effects on lipid metabolism, estrogen affects the vascular tone and may reduce endothelial dysfunction. In the present study, we examined acute gender-specific hemodynamic and inotropic effects of 17β-estradiol (17β-E) versus the control situation in open-chest rats. In addition to measurements in the intact circulation, myocardial function was examined on the basis of isovolumic registration independent of peripheral vascular effects. Regarding the dose-dependent and gender-specific effects of 17β-E, in female rats, 17β-E (50, 100, or 200 ng/kg) increased cardiac output (CO) (26%, 43%, and 59% versus control animals) as a result of reduction in total peripheral resistance (TPR) (−13%, −18%, and −24%) without any effect on myocardial contractility (isovolumic left ventricular systolic pressure, −1%, 0%, and −6%). These vascular effects are less pronounced in male rats (for 200 ng/kg 17β-E: CO, 34%; TPR, −14%). We investigated gender-specific effects of 200 ng/kg 17β-E after pretreatment with the estrogen receptor (ER) antagonist ICI 182,780. ER blockade reduced the effects of estrogen in female rats (CO, 29%; TPR, −17%) and male rats (CO, 19%; TPR, −11%). Regarding the effects of 200 ng/kg 17β-E after pretreatment with

N
G

-nitro-
l
-arginine methyl ester, NO synthesis inhibition completely prevented the acute vascular effects of estrogen in female rats (CO, −4%; TPR, 1%). In addition, immunohistochemical staining revealed no gender-specific differences of the vascular ER distribution. 17β-E caused an acute dose-dependent and gender-specific reduction in the afterload. ERs are involved in both genders in this vasodilative effect that is mediated by NO. This NO-mediated effect may explain in part the cardioprotective effect of estrogen.
Blockade of Angiotensin Receptor Subtypes in Arcuate Uterine Artery of Pregnant and Postpartum Rats
Authors: St-Louis Jean , Sicotte Benoit , Bédard Sophie , Brochu Michèle
Published: September 2007

During pregnancy, uterine circulation undergoes hypertrophy and hyperplasia. We investigated the effects of angiotensin (Ang) II receptor subtype (AT
1
/AT
2
) blockade on increased responses to the peptide during reversible remodeling of the uterine vasculature in pregnant and postpartum rats. Uterine arcuate arteries were set up in wire myographs for microvessel and submitted to a tension equivalent to 50 mm Hg transmural pressure. Cumulative concentration-response curves to Ang II were measured in the absence and presence of losartan on the same vascular segment. A similar protocol was repeated in the presence of PD 123,319, an AT
2
receptor blocker, again in the absence and presence of losartan. Responses to Ang II on the arcuate artery increased markedly during pregnancy and returned to the prepregnant level within 12 days postpartum. Losartan (10
−7
mol/L) produced a parallel right shift of the concentration-response curve to Ang II in all groups of tissues, but potency of the AT
1
receptor blocker was reduced at the end of pregnancy and in the early postpartum period. PD 123,319 (10
−7
mol/L) significantly increased maximum response to Ang II in arterial segments of the nonpregnant, term-pregnant, and 5 days postpartum rats. AT
1
receptor expression was decreased in arcuate arteries of term-pregnant rats. These results show that contractile responses to Ang II on the uterine arcuate artery of the rat are mediated by the AT
1
receptor and that blockade of AT
2
receptors potentiated responses to the peptide. They also indicate that, in uterine vessels, AT
2
receptor stimulation interferes with Ang II responses, but this effect is decreased in uterine arcuate arteries in the peripartum period.
Endothelin-1 Gene Variant Associates With Blood Pressure in Obese Japanese Subjects
Authors: Asai Takashi , Ohkubo Takayoshi , Katsuya Tomohiro , Higaki Jitsuo , Fu Yuxiao , Fukuda Masayuki , Hozawa Atsushi , Matsubara Mitsunobu , Kitaoka Hirofumi , Tsuji Ichiro , Araki Tsutomu , Satoh Hiroshi , Hisamichi Shigeru , Imai Yutaka , Ogihara Toshio
Published: September 2007

Abstract
—1

A recent report based on the results of 2 epidemiological studies, the Etude Cas-Temoin de l’Infarctus Myocarde (ECTIM) and the Glasgow Heart Scan Study, revealed that a G/T polymorphism with an amino acid substitution (Lys→Asn) at codon 198 in exon 5 of the endothelin-1 gene (
ET-1
) is associated with blood pressure in overweight people. They suggested that G/T polymorphism of
ET-1
strongly interacted with body mass index (BMI) in the determination of BP levels. To examine interaction among G/T polymorphism of
ET-1
, BMI, and BP, we performed an association study in a general Japanese population. Subjects (n=1250) were recruited from Ohasama, a cohort in a rural community of northern Japan. DNA was extracted from buffy coat of participants, and G/T polymorphism of
ET-1
was determined by the TaqMan probe polymerase chain reaction method, a powerful tool for semiautomatic genotype determination of a large number of samples. Frequency of T (Asn 198) allele in Japanese (27%) was slightly but significantly higher than in whites (24%). Baseline characteristics (age, BMI, systolic and diastolic BP, and antihypertensive treatment) of all subjects were not significantly different according to the genotype of G/T polymorphism. However, in obese subjects (≥25 kg/m
2
) diastolic BPs were significantly associated with G/T polymorphism of
ET-1
. After adjustment for confounding factors, significant association remained; for overweight subjects, diastolic BP level in those with T allele (GT + TT) was 1.8 mm Hg (
P
=0.04) higher than in those with GG genotype. That similar results were obtained from subjects of different races suggests that the Lys198Asn polymorphism of
ET-1
is involved in determination of BP levels in obese subjects.
Cardiovascular Effects of an Earthquake
Authors: Parati Gianfranco , Antonicelli Roberto , Guazzarotti Francesco , Paciaroni Enrico , Mancia Giuseppe
Published: September 2007

The increased cardiovascular mortality during an earthquake has been related, among other factors, to a sympathetically mediated increase in heart rate and blood pressure. However, this is supported only by indirect evidence collected after an earthquake, whereas for obvious technical difficulties, no data are available on the acute blood pressure and heart rate effects during an earthquake. In a patient undergoing 24-hour ambulatory blood pressure monitoring (Spacelabs 90207), we had the opportunity to directly record the acute blood pressure and heart rate changes induced by an earthquake (magnitude 4.7 according to the Richter scale) that struck central Italy in March 1998. Systolic blood pressure rose to 150 mm Hg, diastolic blood pressure rose to 122 mm Hg, and heart rate rose to 150 bpm at the time of the strongest tremor. Prequake blood pressure levels were restored only 1 hour later, but blood pressure remained characterized by a pronounced variability throughout the following 6 hours. Thus, a sympathetically mediated combined increase in blood pressure and heart rate may represent an important pathophysiological mechanism responsible for the increased frequency of cardiovascular events during an earthquake. The associated increase in blood pressure variability might further contribute to the increase in cardiovascular risk typical of this condition. Our case report further supports the usefulness of ambulatory blood pressure monitoring to assess the blood pressure and heart rate effects of sudden daily life events, the actual cardiovascular impact of which can hardly be quantified through traditional measurements.
Flow Pulsatility Is a Critical Determinant of Oxidative Stress in Endothelial Cells
Authors: Silacci Paolo , Desgeorges Alain , Mazzolai Lucia , Chambaz Céline , Hayoz Daniel
Published: September 2007

Atherosclerotic plaques are found in regions exposed to disturbed flow, suggesting the active participation of the hemodynamic environment in atherogenesis. Indeed, unidirectional and oscillatory flow patterns (ie, bidirectional) have been shown to induce contrasting effects on endothelial function. The purpose of the present study was to evaluate the effect of these 2 flow patterns characterizing plaque-free and plaque-prone regions, respectively, on the oxidative stress of endothelial cells. NADH-dependent oxidase activity was shown to be equally induced (2- to 3-fold) in endothelial cells exposed to pulsatile unidirectional or oscillatory flow patterns. Under these flow conditions, an increase in endothelial cell oxidative state compared with static cultures was observed. Pulsatility of flow, but not cyclic stretch, was a critical determinant of flow-induced superoxide anion production. P22phox mRNA level increased in cells exposed to both unidirectional and oscillatory shear stress, suggesting that
p22phox
gene expression upregulation contributes to flow-induced increase in superoxide anion production in endothelial cells. In conclusion, we demonstrate a flow-induced increase in oxidative stress in endothelial cells. This chronic increase is dependent on the pulsatile nature of flow and is mediated in part by upregulation of an NADH-dependent oxidase expression.
Does Leptin Stimulate Nitric Oxide to Oppose the Effects of Sympathetic Activation?
Authors: Mitchell Jennifer L. , Morgan Donald A. , Correia Marcelo L.G. , Mark Allyn L. , Sivitz William I. , Haynes William G.
Published: September 2007

Leptin decreases appetite and increases sympathetic nerve activity and arterial pressure. Recent reports suggest that leptin may also have peripheral vasodilator actions that would tend to reduce arterial pressure. We tested the hypothesis that the direct vascular actions of leptin oppose sympathetically mediated vasoconstriction. We evaluated the effects of intravenous leptin (1 mg/kg over 3 hours) on arterial pressure and mesenteric, hindlimb, and renal blood flows in conscious rats. We then tested whether blockade of nitric oxide or the sympathetic nervous system would unmask a pressor or depressor effect of leptin, consistent with direct vascular actions. Acute intravenous administration of leptin alone did not change arterial pressure or regional blood flows. This was despite a significant increase in lumbar sympathetic nerve activity. Administration of the nitric oxide synthase inhibitor
N
G
-nitro-
l
-arginine methyl ester significantly increased arterial pressure and caused vasoconstriction. However, leptin did not have any significant effect on hemodynamics in the presence of
N
G
-nitro-
l
-arginine methyl ester despite continued sympathoactivation. α-Adrenoceptor blockade with prazosin alone or combined with yohimbine significantly decreased arterial pressure and caused vasodilation. Again, leptin did not have any effect on arterial pressure or regional blood flow in the presence of sympathetic blockade. These data demonstrate that leptin does not have vasodilator actions in vivo at concentrations that are sufficient to increase sympathetic nerve activity. The absence of a pressor effect of leptin-induced sympathetic activation may merely reflect the brief duration of leptin administration. These data support the concept that the chronic hemodynamic actions of leptin are likely to be related to sympathetic activation.
Compressibility of the Carotid Artery in Patients With Pseudoxanthoma Elasticum
Authors: Boutouyrie Pierre , Germain Dominique P. , Tropeano Anne-Isabelle , Laloux Brigitte , Carenzi Franck , Zidi Mustapha , Jeunemaitre Xavier , Laurent Stéphane
Published: September 2007

The arterial wall has generally been considered as noncompressible in in vitro studies. However, compressibility of the arterial wall (CAW) has never been studied in vivo in humans. Large interstitial proteoglycans play a major role in sustaining the compression generated by pulsatile forces. The aims of the present study were to develop an experimental methodology for the assessment of CAW in vivo in humans and to study CAW in patients with pseudoxanthoma elasticum (PXE), a genetic disease characterized by proteoglycan accumulation and fragmented, swollen, and calcified elastic fibers in connective tissues. We studied 19 female patients with PXE and 15 normal female control subjects matched for age and blood pressure. A high-resolution echo-tracking system was used for the continuous determination of internal diameter and wall thickness at the site of the common carotid artery. Matrices of the radiofrequency signal were analyzed with a dedicated software to measure carotid wall cross-sectional area every 4 milliseconds during 4 to 6 cardiac cycles. CAW was calculated as the stroke change in cross-sectional area. CAW was 44% higher in patients with PXE than in control subjects (6.8±2.6% versus 4.7±2.7%, respectively;
P
<0.05). In control subjects, CAW decreased with age in a linear manner (
r
=−0.75,
P
<0.01). In PXE patients, the relationship with age was not homogeneous: CAW tended to increase with age before 40 years (
P
=0.07) and significantly decreased with age in older patients (
P
<0.01). Carotid geometry and elastic properties did not differ between PXE patients and control subjects. In conclusion, CAW was measurable in vivo and noninvasively in humans. The higher CAW of PXE patients compared with that of control subjects suggests that proteoglycans are important determinants of compressibility.
Radial Artery Flow-Mediated Dilatation in Heart Failure Patients
Authors: Giannattasio Cristina , Achilli Felice , Grappiolo Alessandra , Failla Monica , Meles Ester , Gentile Gaetano , Calchera Ivan , Capra Anna , Baglivo Jolanda , Vincenzi Antonella , Sala Luigi , Mancia Giuseppe
Published: September 2007

Congestive heart failure (CHF) is associated with an impaired flow-mediated vasodilation that reflects an impaired endothelial function. Limited information is available, however, on whether and to what extent this impairment is improved by pharmacological or nonpharmacological treatment. We measured radial artery diameter and blood flow by an echo-tracking Doppler device both at baseline and after 4 minutes of hand ischemia, which increases diameter through NO secretion mediated by an increase in flow and shear stress. Data were collected from 44 CHF patients (New York Heart Association class I to III) under standard treatment (diuretic, digitalis, and enalapril, 20 mg/d), in whom CHF severity was assessed by a cardiopulmonary stress test, and from 16 age- and sex-matched controls. CHF patients were then randomized to maintain for (A) 2 months of standard treatment (n=11), (B) treatment with double the ACE inhibitor dose (n=11), (C) standard treatment with an angiotensin II antagonist (losartan, 50 mg/d; n=11), or (D) standard treatment with bicycle training for 30 minutes, 3 times a week (n=11). At baseline, radial artery diameter and flow were similar in CHF patients and controls; CHF patients had a modest although significant impairment in flow increase (−36%) and a striking impairment (−78%) in diameter increase following the 4 minutes of ischemia. After 2 months, baseline diameter and flow remained unaltered in the 4 groups. After the 4 minutes of ischemia, radial artery flow and diameter increased as before in the group under standard treatment (A), whereas in the other 3 groups, the increase was significantly (
P
<0.05) and, for diameter, markedly (B, 83%; C, 92%; and D, 95%) greater. The vasodilatation induced by trinitroglycerin was similar in CHF and control subjects and not affected by treatments. In CHF, radial artery shows a marked reduction in flow-mediated vasodilation, reflecting impairment of endothelial function. This impairment can be markedly improved by treatments that effectively block the renin-angiotensin system either at ACE or at ACE plus angiotensin receptor level. This is the case also with nonpharmacological treatment of CHF.
Cyclic Stretch Enhances the Expression and Activity of Coronary Endothelium-Derived Hyperpolarizing Factor Synthase
Authors: Fisslthaler Beate , Popp Rüdiger , Michaelis U. Ruth , Kiss Ladislau , Fleming Ingrid , Busse Rudi
Published: September 2007

Endothelium-derived hyperpolarizing factor (EDHF) mediates NO/prostacyclin-independent relaxation in the coronary circulation. Because hemodynamic stimuli modulate endothelial gene expression and because coronary arteries are subjected to pronounced variations in vessel distension, we determined the effects of cyclic stretch on the expression and activity of the coronary EDHF synthase/cytochrome P450 (CYP) 2C8/9. In cultured porcine coronary and human umbilical vein endothelial cells, acute application of cyclic stretch (6%, 1 Hz, 10 minutes) elicited the generation of 8,9-epoxyeicosatrienoic acid (EET), 11,12-EET, and 14,15-EET. Prolonged stretch (4 to 36 hours) increased the expression of CYP 2C mRNA and protein 5- to 10-fold and was accompanied by a 4- to 8-fold increase in EET generation. A corresponding increase in CYP 2C mRNA and protein was also observed in pressurized segments of porcine coronary artery perfused under pulsatile conditions (8%, 1 Hz) for 6 hours. Although in cultured endothelial cells, cyclic stretch elicited the rapid activation of tyrosine kinases as well as Akt and the p38 mitogen-activated protein kinase, the mechanism by which cyclic stretch induces the expression of CYP 2C could not be elucidated, because inhibitors of these pathways induced CYP 2C expression in cells maintained under static conditions. These results have identified coronary EDHF synthase/CYP 2C as a novel mechanosensitive gene product in native and cultured endothelial cells. Because this enzyme generates both EETs and superoxide anions, this finding has wide-reaching implications for vascular homeostasis in conditions of manifest endothelial dysfunction.
Brachial Artery Elastic Mechanics in Patients With Heart Failure
Authors: Kaiser Daniel R. , Mullen Kathleen , Bank Alan J.
Published: September 2007

Studies of arterial elasticity in patients with heart failure (HF) have produced varying results. In addition, the direct effects of smooth muscle relaxation on arterial wall mechanics in these patients have not been well characterized. Nineteen patients with New York Heart Association class II to IV HF and 17 age- and size-matched normal subjects were studied by using a recently validated technique for measuring brachial arterial wall mechanics over a wide pressure range. The left brachial artery was imaged through a water-filled blood pressure cuff by use of an ultrasound wall-tracking system at baseline and after 0.4 mg sublingual nitroglycerin (NTG). Simultaneous radial artery pressure waveforms were recorded by tonometry. Transmural pressure (TP) was reduced by increasing water pressure in the cuff. Baseline area, compliance, and pulse wave velocity versus TP curves were similar in the normal subjects and the patients with HF. The incremental elastic modulus versus TP curve tended to be lower in the patients with HF. The wall-to-lumen ratio was increased in HF (
P
=0.05). NTG significantly shifted the area versus TP (
P
<0.001) and compliance versus TP (
P
<0.05) curves upward and the pulse wave velocity versus TP (
P
<0.05) curve downward in both groups. NTG also significantly (
P
<0.001) shifted the stress versus strain curve to the right in both groups but did not alter the incremental elastic modulus versus TP curve. We conclude that the brachial arterial wall-to-lumen ratio is increased in HF. This finding occurs together with a trend toward reduced arterial stiffness such that overall mechanical behavior of the brachial artery is preserved. Smooth muscle relaxation with NTG produces similar improvements in brachial arterial wall mechanics in normal subjects and in patients with HF.
Angiotensin II Induces Phenotype-Dependent Apoptosis in Vascular Smooth Muscle Cells
Authors: Bascands Jean-Loup , Girolami Jean-Pierre , Troly Muriel , Escargueil-Blanc Isabelle , Nazzal Dani , Salvayre Robert , Blaes Nelly
Published: September 2007

Angiotensin II regulates vascular structure through growth and apoptosis, with implications in pathophysiology. Subtypes of vascular smooth muscle cells with specific morphology, growth, or apoptotic features have been isolated. Here, we investigated the effects of angiotensin II on apoptosis of 2 morphologically different rat aortic smooth muscle cell phenotypes. Spindle and epithelioid cell lines cultured under low serum conditions were stimulated by angiotensin II. Responsiveness was evaluated by calcium signaling. In both phenotypes, an angiotensin II type 1 receptor–mediated transient intracellular calcium peak arose from intracellular pools. However, a sustained nifedipine-sensitive calcium entry occurred specifically in epithelioid cells. Angiotensin II did not impair spindle cell survival, whereas a delayed reduction in cell number occurred in epithelioid cells. Cell death through apoptosis was characterized by cellular and nuclear morphology. Consistently, DNA fragmentation, evaluated by biochemical quantification, nuclei staining, and ladders, and caspase 3-like activity were promoted by angiotensin II in epithelioid cells. Kinetics of annexin V binding showed that apoptosis was a delayed process. Angiotensin II–induced apoptosis of epithelioid cells was prevented by angiotensin II type 1 but not type 2 receptor antagonists and was inhibited by a calcium chelator or calcium antagonist. Conversely, epithelioid cell apoptosis could be induced by a calcium ionophore. Thus, the death signaling promoted by angiotensin II in epithelioid cells involves type 1 receptor–mediated calcium entry. These data suggest that angiotensin II can promote angiotensin II type 1 receptor–mediated apoptosis in vascular smooth muscle cells, depending on their phenotype. This process may play a role in vascular remodeling in cardiovascular diseases.
Angiotensin AT
1
Receptor Stimulates Heat Shock Protein 27 Phosphorylation In Vitro and In Vivo
Authors: Meier Matthias , King George L. , Clermont Allen , Perez Alexandra , Hayashi Michio , Feener Edward P.
Published: September 2007

The angiotensin type 1 receptor (AT
1
) exerts a variety of its signaling and cellular actions through its effects on protein phosphorylation. Phosphoproteomic analysis of angiotensin (Ang) II–stimulated aortic smooth muscle cells revealed that heat shock protein 27 (HSP27) represents a major protein phosphorylation target of the AT
1
signaling pathway. Stimulation of cells with Ang II resulted in 1.7-fold (
P
<0.05) and 5.5-fold (
P
<0.001) increases in HSP27 phosphoisoforms at pI 5.7 and pI 5.4, respectively. This was accompanied by a 54% (
P
<0.01) decrease in the nonphosphorylated HSP27 isoform, located at pI 6.4. Treatment of samples with alkaline phosphatase reversed this redistribution of HSP27 phosphoisoforms. Ang II–stimulated HSP27 phosphorylation was completely blocked by pretreatment of cells with the AT
1
antagonist CV11974. Phosphoamino acid analysis demonstrated that Ang II–induced phosphorylation of both HSP27 phosphoisoforms occurred exclusively on serine. Protein kinase C inhibition completely blocked phorbol ester–induced HSP27 phosphorylation but did not impair Ang II–stimulated phosphorylation of HSP27, suggesting that AT
1
increased HSP27 phosphorylation by a protein kinase C–independent pathway. Intrajugular infusion of Ang II in rats increased HSP27 in aorta by 1.7-fold (
P
<0.02), and this response was inhibited by CV11974. These results suggest that Ang II–induced HSP27 phosphorylation is a physiologically relevant AT
1
signaling event. Because serine phosphorylation of HSP27 blocks its ability to cap F-actin, Ang II/AT
1
–induced HSP27 phosphorylation may play a key role in actin filament remodeling required for smooth muscle cell migration and contraction.
Pressure Amplification Explains Why Pulse Pressure Is Unrelated to Risk in Young Subjects
Authors: Wilkinson Ian B. , Franklin Stanley S. , Hall Ian R. , Tyrrell Sian , Cockcroft John R.
Published: September 2007

Pulse pressure rather than diastolic pressure is the best predictor of coronary heart disease risk in older subjects, but the converse is true in younger subjects. We hypothesized that this disparity results from an age-related difference in pressure amplification from the aorta to brachial artery. Data from 212 subjects age <50 years and 230 subjects age ≥50 years were abstracted from a community database. All subjects were free from cardiovascular disease, diabetes, and medication. Peripheral blood pressure was assessed by sphygmomanometry. Radial artery waveforms recorded noninvasively by applanation tonometry were used to derive central blood pressure. Pressure amplification (peripheral/central pulse pressure ratio) was linearly related to age (
r
=0.7;
P
<0.001). There was an inverse, linear relationship between amplification and diastolic pressure in the younger group (
r
=0.3;
P
<0.001) but not in older subjects (
r
=0.1;
P
=0.2). There was no relationship in either group when the amplification ratio was calculated with nonaugmented central pressure. Amplification is reduced in older subjects because of enhanced wave reflection. In younger, but not older, subjects, amplification declines as diastolic pressure rises. Therefore, peripheral pulse pressure underestimates the effect that diastolic pressure has on central pulse pressure in younger subjects. This may explain why diastolic pressure is a better predictor of risk in this age group and suggests that assessment of central pressure may improve risk stratification further.
Local Hemodynamic Changes in Hypertension
Authors: Frohlich Edward D.
Published: September 2007

As a result of antihypertensive therapy, there has been a remarkable decrease in morbidity and mortality from such cardiovascular endpoints as stroke, coronary heart disease, and major hypertensive emergencies. In contrast, there has been no relenting in the increasing prevalence of cardiac failure and end-stage renal disease (ESRD) associated with hypertensive cardiovascular disease. Recent experience in our laboratories that involved the natural development of the cardiac and renal hemodynamic alterations in spontaneously hypertensive rats demonstrated that the natural history and pathophysiological lesions associated with cardiac failure and ESRD may be vastly different from the heretofore more pressure-dependent brain and other cardiac endpoints reported in earlier years. These initial antihypertensive agents (eg, diuretics, β-adrenergic receptor inhibitors) had minimal anti-ischemic and antifibrotic effects on heart and kidney and did not exert the cardiac and nephroprotective hemodynamic effects of the newer classes of agents. The cardiac and renal endpoints resulting in organ failure today are more related to ischemia, intraorgan fibrosis, and aging. Our experimental studies summarized herein strongly suggest that the newer classes of antihypertensive drugs (ie, ACE inhibitors, angiotensin II type 1 receptor antagonists, certain calcium antagonists, and perhaps
l
-arginine) may reverse these pathophysiological lesions through improving blood flow and flow reserve, their antifibrotic and other actions. To this end, we look forward to the results of ongoing, well-controlled, and prospectively conducted multicenter clinical studies designed to demonstrate prevention of cardiac and renal failure.