bluuebunny/crossref_metadata_2025 huggingface dataset:
Role Of Calcitonin Gene-Related Peptide and Substance P in Dahl-Salt Hypertension
Authors: Katki Khurshed A. , Supowit Scott C. , DiPette Donald J.
Published: September 2007

Abstract
—

— Calcitonin gene-related peptide (CGRP) and substance P are known to play a counterregulatory role in acquired models of salt-dependent hypertension. In contrast, neuronal production of these peptides is decreased in the spontaneously hypertensive rat, which may contribute to the elevated blood pressure. To determine the role played by CGRP and substance P in Dahl-salt hypertension, 4- to 6-week-old male salt-resistant (DR) and salt-sensitive (DS) rats were divided into 4 groups (n=5/group) and pair-fed low-salt (0.2% NaCl) (DR/LS and DS/LS) and high-salt (8% NaCl) diets (DR/HS and DS/HS) for 3 weeks. After 3 weeks, all the rats had venous (for drug administration) and arterial (for blood pressure monitoring) catheters surgically implanted and were studied in the conscious and unrestrained state. Mean arterial pressure was significantly higher in the DS/HS rats animals (185.8±1.6 mm Hg,
P
<0.001). Intravenous administration of CGRP and SP receptor antagonists was without effect in any of the groups studied. CGRP and SP mRNA content from dorsal root ganglia were not significantly different between the groups. Whereas immunoreactive CGRP was decreased in the DS groups (DS/HS, 9.4±0.4 pg/μg protein; DS/LS, 11.1±0.8 pg/μg protein;
P
<0.01) compared with the DR groups (DR/HS, 13.9±0.6 pg/μg protein; DR/LS, 14.6±0.6 pg/μg protein), neuronal SP production was similar between all the groups. Thus, CGRP and substance P do not play a counterregulatory role in Dahl-salt hypertension. The decrease in neuronal CGRP expression in DS rats appears to be genetically determined as in SHR, however, and may contribute to the increase in blood pressure following salt-loading.
Ca
2+
Influx is Increased in 2-Kidney, 1-Clip Hypertensive Rat Aorta
Authors: Callera Glaucia Elena , Varanda Wamberto Antonio , Bendhack Lusiane Maria
Published: September 2007

Abstract
—

— Arteries from hypertensive rats show a greater contraction in response to Ca
2+
channel activator and an increased sensitivity to Ca
2+
entry blockers compared with those of normotensive rats. These facts suggest an altered Ca
2+
influx through membrane channels. In this study, this hypothesis was tested by direct activation of voltage-gated Ca
2+
channels using Bay K 8644, a dihydropyridine sensitive large conductance (L-type) Ca
2+
channel opener in aortas from 2-kidney, 1-clip (2K1C) hypertensive rats. Because the membrane potential of smooth muscle cells is an important regulator of the conformational state of L-type Ca
2+
channels and, consequently, dihydropyridine affinity, the effect of 10 mmol/L KCl on the responses to Bay K 8644 was also studied. Maximal contraction (ME) and sensitivity to Bay K 8644 were greater in 2K1C rats than in 2K normotensive rats (ME, 1.77±0.15 versus 1.25±0.19 g; negative log molar value [pD
2
], 8.27±0.07 versus 7.92±0.08). When the KCl concentration was increased from 4.7 to 10 mmol/L in the bathing medium, no differences were observed in the contractile effect of Bay K 8644 between 2K1C and 2K (ME, 1.28±0.13 versus 1.14±0.21 g; pD
2
, 8.56±0.08 versus 8.38±0.07). The cell resting membrane potential of 2K1C aorta vascular smooth muscle cells were less negative than in 2K (−35.19±4.91 versus −48.32±1.88 mV). Basal intracellular Ca
2+
concentration ([Ca
2+
]
i
) was greater in cultured vascular smooth muscle cells from 2K1C than from 2K (293.4±25.83 versus 205.40±12.83 nmol/L). In 2K1C, Bay K 8644 induced a larger increase in [Ca
2+
]
i
than in 2K (190.60±45.65 versus 92.57±14.67 nmol/L), and in 10 mmol/L KCl, this difference was abolished (134.90±45.12 versus 125.20±32.17 nmol/L). The main conclusion of the present work is that the increased contractile response to Bay K 8644 in 2K1C aortas is due to an increased Ca
2+
influx through voltage-gated Ca
2+
channels.
Two Linked Blood Pressure Quantitative Trait Loci on Chromosome 10 Defined by Dahl Rat Congenic Strains
Authors: Garrett Michael R. , Zhang Xiaotong , Dukhanina Oksana I. , Deng Alan Y. , Rapp John P.
Published: September 2007

A quantitative trait locus (QTL) for blood pressure was previously detected on rat chromosome 10 (RNO10) by linkage analysis and confirmed by the construction of congenic strains that encompass large regions of RNO10. In the present study, the rat RNO10 blood pressure QTL was dissected by the further construction of congenic substrains. The original congenic region was shown to contain 2 blood pressure QTLs (QTL 1 and QTL 2) ≈24 cM apart. These were localized to a <2.6-cM region between markers D10Rat27 and D10Rat24 for QTL 1 and to a <3.2-cM region between D10Rat12 and D10Mco70 for QTL 2. Comparative mapping suggests that the rat RNO10 QTL 2 could be localized very close to a blood pressure QTL described by sib-pair analysis on human chromosome 17, but this is not definitively established because of multiple and complex chromosomal rearrangements between rodents and humans.
Inverse Association Between Free Insulin-Like Growth Factor-1 and Isovolumic Relaxation in Arterial Systemic Hypertension
Authors: Galderisi Maurizio , Vitale Giovanni , Lupoli Giovanni , Barbieri Michelangela , Varricchio Gina , Carella Carlo , de Divitiis Oreste , Paolisso Giuseppe
Published: September 2007

Several trials have suggested that insulin-like growth factor-1 (IGF-1) may have a pathophysiological role in the development of arterial essential hypertension. To verify the possible association of IGF-1 with left ventricular morphological and functional echocardiographic parameters in hypertension, we studied 40 male patients with newly diagnosed hypertension and 15 normotensive control subjects. Doppler echocardiography was performed and circulating free IGF-1 levels were determined in all subjects. Circulating free IGF-1 levels were higher in hypertensives than in control subjects (
P
<0.01). A significant inverse correlation was observed between free IGF-1 and isovolumic relaxation time in the overall population (
r
=−0.37,
P
<0.01) and in hypertensives (
r
=−0.57,
P
<0.0001), whereas this relation disappears in normotensives. These results were confirmed by multivariate analysis. The present study confirms that arterial essential hypertension represents a clinical condition associated with an increased synthesis of IGF-1. The observation of an inverse, independent association between free IGF-1 and isovolumic relaxation time suggests 2 alternative hypotheses: a possible beneficial effect of IGF-1 to diastolic relaxation or a resistance to IGF-1 in hypertension.
Involvement of Brain Mineralocorticoid Receptor in Salt-Enhanced Hypertension in Spontaneously Hypertensive Rats
Authors: Rahmouni Kamal , Barthelmebs Mariette , Grima Michèle , Imbs Jean-Louis , De Jong Wybren
Published: September 2007

We recently showed that brain mineralocorticoid receptors (MRs) are involved in blood pressure and kidney function control in normotensive Wistar rats. We now assessed the involvement of brain MRs in spontaneously hypertensive rats (SHR), in which the presence of adrenocorticoids has been shown to be required for the development of hypertension. The effect of a single intracerebroventricular (ICV) injection of an MR antagonist (RU28318) on systolic blood pressure (SBP) and renal function was examined in conscious adult SHR and Wistar-Kyoto rats (WKY) maintained on a standard-sodium diet (0.4% Na
+
). In WKY, a long-lasting decrease in SBP was caused by the ICV injection of 10 ng RU28318 as previously reported in Wistar rats, associated with increased urinary excretion of water and electrolytes. In SHR maintained on the standard diet, the ICV injection of RU28318 (10 or 100 ng) had no effect on cardiovascular and renal functions. However, the ICV injection of 10 ng RU28318 in SHR after 3 weeks of high sodium intake (8% Na
+
) caused a long-lasting decrease in SBP. The effect was present at 8 hours (ΔSBP 34±2 mm Hg), persisted at 24 hours (ΔSBP 29±1 mm Hg), and disappeared at 48 hours after the injection. The hypotension was not associated with changes in heart rate, urinary excretion of water and electrolytes, and plasma renin activity, whereas renal denervation did not affect the decrease in SBP. A more pronounced decrease in SBP (49±3 mm Hg at 8 hours) was observed with 100 ng RU28318. This dose of the antagonist was without effect after subcutaneous administration. Thus, brain MRs appear to participate in the maintenance of hypertension in conscious adult SHR sensitized by sodium loading.
Neither the New Zealand Genetically Hypertensive Strain nor Dahl Salt-Sensitive Strain Has an A1079T Transversion in the α1 Isoform of the Na
+
,K
+
-ATPase Gene
Authors: Barnard Ross , Kelly Greg , Manzetti Sergio Otterlei , Harris Eugenie L.
Published: September 2007

A putative 1079A→T mutation in the α1 isoform of the Na
+
, K
+
-ATPase (
Atp1a1
) gene of the Dahl salt-sensitive rat inbred by John Rapp (SS/Jr) strain was projected to cause a conformation change in the membrane hydrophobic region of the protein product, possibly resulting in hypertension. The existence of the mutation was challenged, but the challenge was apparently rebutted. The New Zealand genetically hypertensive (GH) rat is known to have a blood pressure quantitative trait locus on chromosome 2 containing the gene for the ATPase. Thus, we sought to determine whether the GH rat carried the 1079A→T transversion. We chose a method, first nucleotide change analysis, that can detect point mutations in a mixed population of polymerase chain reaction (PCR) products, even in the presence of PCR bias, and confirmed our analysis by restriction enzyme digestion of PCR products. To ensure the validity of our analyses, we used site-directed mutagenesis to create positive controls containing the mutation. Surprisingly, we found that neither the GH nor the SS/Jr strain had the A1079T transversion. Indeed, the transversion was not found in any strain tested. As an incidental observation, we have sequenced the intron preceding the exon containing the putative A1079T transversion. Within this intron, a single-base C/T polymorphism was observed at base 132. Our results definitively eliminate the putative A1079T transversion in
Atp1a1
as a causative factor underlying hypertension in the GH, spontaneously hypertensive, and SS/Jr rat strains and indicate that alternative candidate genes in the region defined by the chromosome 2 hypertension quantitative trait locus should be examined.
Impairment of Renal Vasodilation With
l
-Arginine Is Related to More Severe Disease in Untreated Hypertensive Patients
Authors: Bello Elena , Caramelo Carlos , Martell Nieves , Alcázar José María , González Javier , López María Dolores , Ruilope Luis Miguel , González Francisco Román , Rovira Adela María , Gazapo Rosa , Soldevilla María José , Casado Santos
Published: September 2007

Data remain insufficient to place the decreased response to
l
-arginine in hypertensive patients within a consistent pathophysiological sequence. The aim of the present study in patients with essential hypertension was to assess the relationships between the response to
l
-arginine and a set of relevant clinical and laboratory parameters. In this prospective, interventional study, we administered
l
-arginine to untreated hypertensive individuals and healthy control subjects and measured the clearance of inulin and of
para
-aminohippurate and a set of biochemical and clinical variables.
l
-Arginine infusion revealed major differences between control subjects and 1 subgroup (group B) of hypertensive individuals. Group B hypertensives (n=18) had no increase in inulin clearance and no decrease in renal vascular resistance with
l
-arginine; however, in another subset of hypertensive patients (group A, n=27), the insulin clearance increased and renal vascular resistance decreased similar to the control group (group C, n=11). The ambulatory blood pressure monitoring in group B showed both an increased mean diastolic pressure and a “nondipper” pattern in the nocturnal regulation of arterial pressure. These findings in group B were accompanied by significant alterations in optic fundus and left ventricle hypertrophy and increased microalbuminuria (all,
P
<0.05). Furthermore, group B individuals had significantly lower values of HDL cholesterol and a higher baseline atherogenic index, plasma insulin level, and glucose/insulin index. We disclose a previously undescribed relationship between end organ repercussion and decreased renal hemodynamic response to
l
-arginine. Our results may help to understand the mechanisms that lead to target organ damage in hypertension.
Lipids Stimulate the Production of 6-keto-prostaglandin F
1α
in Human Dorsal Hand Veins
Authors: Haastrup Adetola , Gadegbeku Crystal A. , Zhang Da , Mukhin Yurii V. , Greene Eddie L. , Jaffa Ayad A. , Egan Brent M.
Published: September 2007

Obese hypertensives have increased nonesterified fatty acids (NEFAs) and α-adrenergic vascular reactivity. Raising NEFAs locally with intralipid and heparin augments dorsal hand venoconstrictor responses to phenylephrine, an α
1
-adrenoceptor agonist. The enhanced venoconstrictor responses were reversed by indomethacin. The findings suggest that raising NEFAs leads to the generation of cyclooxygenase (COX) product(s) that enhance vascular reactivity. To test this notion, 6-keto-PGF
1α
and TxB
2
, the stable metabolites of prostaglandin H
2
(PGH
2
); prostacyclin (PGI
2
); and thromboxane (TxA
2
), were measured ≈1.5 to 2 cm downstream of a dorsal hand vein infusion of intralipid and heparin (n=10) or saline and heparin (n=5) for 2 hours each. During the third hour, intralipid and heparin (experimental) and saline and heparin (control) were continued, and either saline (control) or indomethacin (intervention) were infused. Intralipid and heparin raised local 6-keto PGF
1α
concentrations by 350% to 500% (
P
<0.005), but saline and heparin did not (
P
=NS). TxB
2
levels did not change significantly with any infusion. Infusion of indomethacin during the third hour of intralipid and heparin lowered plasma 6-keto-PGF
1α
(
P
<0.05), whereas infusion of saline with intralipid and heparin did not (
P
=NS). Oleic and linoleic acids at 100 μmol/L, increased 6-keto-PGF
1α
in vascular smooth muscle cells (VSMCs) through a protein kinase C and extracellular, signal-regulated kinase independent pathway. However, oleic and linoleic acids increased intracellular Ca
2+
in VSMCs. The data indicate that NEFAs induce the production of COX products, perhaps via Ca
2+
-dependent activation of phospholipase A
2
. The COX product(s) may contribute to increased vascular α-adrenergic reactivity among insulin-resistant individuals when NEFAs are elevated.
Genome Scan for Blood Pressure in Dutch Dyslipidemic Families Reveals Linkage to a Locus on Chromosome 4p
Authors: Allayee Hooman , de Bruin Tjerk W.A. , Michelle Dominguez K. , Cheng Li S.-C. , Ipp Eli , Cantor Rita M. , Krass Kelly L. , Keulen Eric T.P. , Aouizerat Bradley E. , Lusis Aldons J. , Rotter Jerome I.
Published: September 2007

Genes contributing to common forms of hypertension are largely unknown. A number of studies in humans and in animal models have revealed associations between insulin resistance, dyslipidemia, and elevated hypertension. To identify genes contributing to blood pressure (BP) variation associated with insulin-resistant dyslipidemia, we conducted a genome-wide scan for BP in a set of 18 Dutch families exhibiting the common lipid disorder familial combined hyperlipidemia. Our results reveal a locus on chromosome 4 that exhibits a significant lod score of 3.9 with systolic BP. In addition, this locus also appears to influence plasma free fatty acid levels (lod=2.4). After adjustment for age and gender, the lod score for systolic BP increased to 4.6, whereas the lod score for free fatty acid levels did not change. The chromosome 4 locus contains an attractive candidate gene, α-adducin, which has been associated with altered BP in animal studies and in some human populations. However, we found no evidence for an association between 2 intragenic α-adducin polymorphisms and systolic BP in this sample. We also observed suggestive evidence for linkage (lod=1.8) of diastolic BP to the lipoprotein lipase gene locus on chromosome 8p, supporting a finding previously observed in a separate insulin-resistant population. In addition, we also obtained suggestive evidence for linkage of systolic BP (lod=2.4) and plasma apolipoprotein B levels (lod=2.0) to a locus on proximal chromosome 19p. In conclusion, our genome scan results support the existence of multiple genetic factors that can influence both BP and plasma lipid parameters.
A Novel Form of Platelet-Type 12-Lipoxygenase mRNA in Human Vascular Smooth Muscle Cells
Authors: Limor Rona , Weisinger Gary , Gilad Suzan , Knoll Esther , Sharon Orly , Jaffe Anat , Kohen Fortuna , Berger Esther , Lifschizt-Mercer Beatriz , Stern Naftali
Published: September 2007

The lipoxygenase pathway has been implicated in the growth, migration, and contraction of vascular smooth muscle cells (VSMCs). However, the precise type of lipoxygenase present in the vascular wall has not been characterized. In this study, we used a specific reverse-transcriptase polymerase chain reaction method with 2 sets of specific primers on total RNA and polyA (+)RNA of normal human VSMCs prepared from umbilical artery. Two forms of platelet-type 12-lipoxygenase mRNA were present in human VSMCs: the already published form cloned from human erythroleukemia cells and a variant form of platelet-type 12-lipoxygenase, which includes 2 additional sequences consistent with the 2 introns (D and E). This novel form of 12-lipoxygenase poly A (+)RNA was downregulated by lipopolysaccharide (10 μg/mL) and upregulated by epidermal growth factor (100 ng/mL) but was not affected by angiotensin II (10
−7
mol/L). We developed a rabbit anti-human platelet-type 12-lipoxygenase polyclonal antibody directed against a 24-amino acid peptide encoded within exon 4. Western immunoblotting of protein extracted from VSMCs and umbilical artery and platelet extract with this antibody showed a coordinate 110-kDa protein and the already-described 70-kDa band detected in platelets and cord homogenate. Another 120-kDa protein was consistently detected in cord extracts but not in platelet or VSMC homogenates. The immunohistochemistry study performed with the same antibody showed extensive cytoplasmic staining of VSMCs. The specific role of these different forms of platelet-type 12-lipoxygenase is subject to further investigation.
Cardiovascular Risk Assessment Using Pulse Pressure in the First National Health and Nutrition Examination Survey (NHANES I)
Authors: Domanski Michael , Norman James , Wolz Michael , Mitchell Gary , Pfeffer Marc
Published: September 2007

Increased stiffness of the conduit arteries has been associated with increased risk of death and cardiovascular death in a number of populations. None of these populations, however, are fully representative of the US population. The cohort examined in the First National Health and Nutrition Examination Survey (NHANES I) that was free of overt cardiovascular disease was selected to be representative of the US population. We assessed and quantified the increased risk of death associated with elevated pulse pressure in this population. A cohort of 5771 subjects from NHANES I was used to determine the value of adding pulse pressure to standard cardiovascular disease risk factors for assessment of the risk of death during a mean follow-up period of 16.5 years. Analyses were performed by use of the SUDAAN statistical package for performing Cox proportional regression, logistic regression, and other standard methods in complex, weighted samples. Pulse pressure increased with increasing age, body mass index, cholesterol level, and mean arterial pressure. With increasing pulse pressure, the percentage of cigarette smokers decreased and the percentage of diabetics increased. Despite these associations with known risk factors, pulse pressure was independently predictive of an increased risk of death from cardiovascular disease, coronary heart disease, and all-cause mortality. It provides independent prognostic information beyond that provided by known risk factors that were evaluated in this study, including the Sixth Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure hypertension classification. A 10 mm Hg increase in pulse pressure in persons 25 to 45 of age was associated with a 26% increase in risk of cardiovascular death (95% confidence interval [CI], 5 to 50) and with an 10% increase (95% CI, 2 to 19) in persons 46 to 77 years of age. In a cohort designed to be representative of the US population, elevated pulse pressure has been shown to provide independent prognostic information. This variable may be a marker for the extent of vascular disease and may contribute to the occurrence of clinical events.
Pulse Pressure Changes With Six Classes of Antihypertensive Agents in a Randomized, Controlled Trial
Authors: Cushman William C. , Materson Barry J. , Williams David W. , Reda Domenic J. ,   for the Veterans Affairs Cooperative Study Group on Antihypertensive Agents
Published: September 2007

Pulse pressure has been more strongly associated with cardiovascular outcomes, especially myocardial infarction and heart failure, than has systolic, diastolic, or mean arterial pressure in a variety of populations. Little is known, however, of the comparative effects of various classes of antihypertensive agents on pulse pressure. In retrospective analyses of the Veterans Affairs Single-Drug Therapy for Hypertension Study, we compared changes in pulse pressure with 6 classes of antihypertensive agents: 1292 men with diastolic blood pressure of 95 to 109 mm Hg on placebo were randomized to receive hydrochlorothiazide, atenolol, captopril, clonidine, diltiazem, prazosin, or placebo. Drug doses were titrated to achieve a goal diastolic blood pressure of <90 mm Hg during a 4- to 8-week medication titration phase. Pulse pressure change (placebo subtracted) was assessed from baseline to the end of the 3-month titration and 1-year maintenance. Mean baseline systolic, diastolic, and pulse pressures were 152, 99, and 53 mm Hg, respectively. Reductions in pulse pressure during titration were greater (
P
<0.001) with clonidine (6.7 mm Hg) and hydrochlorothiazide (6.2 mm Hg) than with captopril (2.5 mm Hg), diltiazem (1.6 mm Hg), and atenolol (1.4 mm Hg); reduction with prazosin (3.9 mm Hg) was similar to all but clonidine. After 1 year, pulse pressure was reduced significantly more (
P
<0.001) with hydrochlorothiazide (8.6 mm Hg) than with captopril and atenolol (4.1 mm Hg with both); clonidine (6.3 mm Hg), diltiazem (5.5 mm Hg), and prazosin (5.0 mm Hg) were intermediate. These data show that classes of antihypertensive agents differ in their ability to reduce pulse pressure. Whether these differences affect rates of cardiovascular events remains to be determined.
Progress in Hypertension Research
Authors: Genest Jacques
Published: September 2007

The author reviews the various factors (sodium, aldosterone, renin-angiotensin system, and norepinephrine; each of these factors being influenced by others) involved in the mechanism of human hypertension. A coherent picture is emerging, with the final pathway of these mechanisms converging on the renin-angiotensin system in the presence of a positive sodium balance and responsible for arteriolar resistance and responsiveness to pressor agents. This would correspond to the labile phase of hypertension, which leads with time to arteriolar restructuring and the increased media/lumen ratio, as demonstrated by Schiffrin and coworkers, and which can revert to normal structure with the administration of antihypertensive drugs such as converting-enzyme inhibitors, calcium-blocking drugs, and antagonists of the angiotensin II type 1 receptor. The author also presents the experience obtained in the Hypertension Clinic of the Clinical Research Institute of Montréal, which has been in existence since 1953; this experience is based on the observation of senior observers (clinical scientists, clinicians, and nurses) that the blood pressure of hypertensive patients can be controlled to normal levels in almost all cases for years and decades with a proper combination of the present antihypertensive drugs.
Study of Plasma Factors Associated With Neutrophil Activation and Lipid Peroxidation in Preeclampsia
Authors: Barden Anne , Ritchie Jackie , Walters Barry , Michael Constantine , Rivera Jennifer , Mori Trevor , Croft Kevin , Beilin Lawrie
Published: September 2007

Neutrophil activation occurs in women with preeclampsia and is resolved after delivery. The present study examined whether circulating factors in plasma of women with preeclampsia caused neutrophil activation and lipid peroxidation. Twenty-one women with proteinuric preeclampsia were matched for age and gestational age with 19 normal pregnant women. Plasma was collected from all subjects before delivery and at 6 weeks postpartum and incubated with autologous white-cell buffy coat collected at the postpartum visit. Neutrophil activation was assessed by level of CD11b and CD18 expression after incubation with autologous antepartum or postpartum plasma. Lipid peroxidation was assessed by measurement of F
2
-isoprostanes in plasma, plasma–white cell incubates, and urine. Neutrophil CD11b and CD18 expression was not differentially altered by incubation with plasma from either women with preeclampsia or normal pregnant women and was similar between groups when incubation was performed with plasma collected after delivery. In preeclampsia, plasma F
2
-isoprostanes were significantly increased before and after delivery compared with controls. Plasma F
2
-isoprostanes were increased 2-fold after incubation of plasma with buffy coat, but preeclamptic women had higher levels compared with those of controls when either pregnant or postpartum plasma was used. In pregnant preeclamptics, plasma F
2
-isoprostanes were positively correlated with lymphocyte count. Six weeks after delivery, plasma F
2
-isoprostanes in the preeclamptic women were significantly positively associated with lymphocyte count and cholesterol and negatively associated with albumin. In conclusion, the present study does not suggest that a stable circulating factor causes neutrophil activation in preeclampsia. However, lipid peroxidation is elevated before and after delivery in women with preeclampsia, which suggests that these women may have an underlying predisposition to increased oxidative stress that may be driven by or contribute to a persistent low-grade inflammatory response.
Lipoprotein Lipase Gene Mutations and the Genetic Susceptibility of Preeclampsia
Authors: Kim Young J. , Williamson Roger A. , Chen K. , Smith Jennifer L. , Murray Jeffrey C. , Merrill David C.
Published: September 2007

In the pathogenesis of preeclampsia, endothelial cell activation or dysfunction is a central theme, and marked dyslipidemia may contribute to endothelial cell dysfunction. The objective of this study was to evaluate the association between preeclampsia and mutations within the lipoprotein lipase (LPL) gene. DNA was extracted from whole blood or cheek swabs of 250 preeclamptic patients, 265 control subjects, and 106 offspring of preeclamptic patients (all white). Control subjects were women who had undergone ≥2 term pregnancies unaffected by preeclampsia. All samples were genotyped for 3 LPL polymorphisms with the use of polymerase chain reaction of known allelic variants. The 3 mutations studied were the following: (1) Asp9Asn substitution in exon 2, (2) T-to-G substitution at position −93 of the proximal promotor region (−93T/G), and (3) Asn291Ser substitution in exon 6. Results were analyzed with an χ
2
contingency table. The prevalences of the Asp9Asn mutation, −93T/G promotor mutation, and Asn291Ser mutation were not significantly different among the preeclamptic patients and control subjects (Asp9Asn: patients, 2.8%; control subjects, 4.0%; −93T/G: patients, 4.5%; control subjects, 5.5%; Asn291Ser: patients, 4.0%; control subject, 3.0%). In addition, there was no difference in the frequency of any of the mutations in the offspring of preeclamptic women compared with that observed in the control population. Between a small group of patients with nulliparous HELLP syndrome (a variant of severe preeclampsia: hemolysis, elevated liver enzyme, low platelets) patients (n=12) and control subjects, there was a significant difference in the prevalence of the Asn291Ser mutation (16.7% versus 3.0%,
P
=0.01). In this large white population, the Asp9Asn mutation, −93T/G promotor mutation, and Asn291Ser mutation were not associated with an increased risk for preeclampsia. In a small subgroup of patients, the Asn291Ser mutation was associated with an increased risk for nulliparous HELLP syndrome.
Blood Pressure Responses to Small Doses of Amiloride and Spironolactone in Normotensive Subjects
Authors: Pratt J. Howard , Eckert George J. , Newman Shirley , Ambrosius Walter T.
Published: September 2007

The epithelial sodium channel (ENaC) is a principal site for sodium reabsorption and as such may participate importantly in blood pressure (BP) regulation. Amiloride, a direct inhibitor of ENaC, characteristically has mild antihypertensive properties, consistent with ENaC having more minor influences on BP regulation. Counter-regulatory influences may, however, prevent amiloride from effectively lowering BP. Aldosterone secretion is known to increase in response to the reduced sodium reabsorption that follows amiloride inhibition of ENaC, and because aldosterone upregulates ENaC function, we considered the possibility that secondary hyperaldosteronism mitigates the ability of amiloride to reduce BP. In the present study, the BP responses to amiloride (5 mg per day), spironolactone (25 mg per day), the combination of the 2 drugs, and placebo were studied in healthy normotensive subjects. Over 4 weeks of treatment, the combination of amiloride and spironolactone lowered systolic BP by 4.6±1.6 (mean±SEM) mm Hg (
P
=0.022) and diastolic BP by 2.2±1.2 mm Hg (
P
=0.30), whereas either drug alone had no significant effect on BP. The findings suggest that the 2 drugs with different modes of action—amiloride, a direct inhibitor of ENaC, and spironolactone, a mineralocorticoid receptor antagonist—may compliment each other’s ability to inhibit ENaC and thereby reduce sodium reabsorption to a point at which BP decreases. On the other hand, we cannot rule out that the BP response resulted from the greater dose of total drug. The lowering of BP with small doses of inhibitors of ENaC serves as additional evidence for the importance of ENaC to the tonic maintenance of BP.
Different Alcohol Drinking and Blood Pressure Relationships in France and Northern Ireland
Authors: Marques-Vidal Pedro , Arveiler Dominique , Evans Alun , Amouyel Philippe , Ferrières Jean , Ducimetière Pierre
Published: September 2007

To assess the effect of alcoholic beverages consumed on blood pressure levels by day of the week, baseline data from the Prospective Epidemiological Study of Myocardial Infarction (PRIME), including 6523 male subjects who drank at least once a week (5156 in France and 1367 in Northern Ireland), were analyzed. In France, alcohol consumption was rather homogeneous throughout the week, with a slight increase during weekends, whereas in Northern Ireland, Fridays and Saturdays accounted for 66% of total alcohol consumption. After adjustment for age, body mass index, heart rate, tobacco smoking, educational level, marital status, and professional activity, blood pressure levels were higher in Northern Irish drinkers on Monday and decreased until Thursday, whereas blood pressure levels were constant throughout the week for French drinkers (day×country interactions,
P
<0.05). Conversely, no between-day differences were found regarding teetotalers in both countries. In drinkers, between-day differences and day×country interactions were suppressed after adjustment for the average alcohol consumption of the third day before measurement. We conclude that the binge-drinking pattern observed among Northern Irish drinkers leads to physiologically disadvantageous consequences regarding blood pressure levels, whereas no such fluctuations in blood pressure levels are found for regular consumption.
Supplemention With Tetrahydrobiopterin Suppresses the Development of Hypertension in Spontaneously Hypertensive Rats
Authors: Hong Hong-Jye , Hsiao George , Cheng Tzu-Hurng , Yen Mao-Hsiung
Published: September 2007

It has been suggested that tetrahydrobiopterin (H
4
B), a cofactor of NO synthase, can reverse endothelial dysfunction caused by cardiovascular diseases, including atherosclerosis, coronary artery disease, and hypertension. Moreover, an impairment of H
4
B biosynthesis in spontaneously hypertensive rats (SHR) was observed. Thus, we hypothesized that the defect of the H
4
B synthesis system may play an important role in the development of hypertension in SHR. In the present study H
4
B (10 mg/kg per day IP) was used to treat SHR and Wistar-Kyoto rats (WKY) from the age of 5 through 16 weeks. Results demonstrated that chronic treatment with H
4
B significantly improved the impaired vascular responses to acetylcholine and suppressed the development of hypertension in SHR but did not affect WKY. The increase of inducible NO synthase expression, nitrotyrosine immunostaining, NO production, and superoxide anion formation in adult SHR were also significantly suppressed by chronic treatment with H
4
B. In contrast, H
4
B had no effect on WKY. In conclusion, this study demonstrated that H
4
B significantly attenuated the development of hypertension in SHR. The antihypertensive effect of H
4
B might be mediated through its direct antioxidant activity and/or decreasing oxygen free radical production from NO synthase, thereby reducing inducible NO synthase expression and peroxynitrite formation. Thus, the present study proposed that supplementation with H
4
B might be beneficial in preventing pathological conditions such as essential hypertension.
Candesartan Inhibits Carotid Intimal Thickening and Ameliorates Insulin Resistance in Balloon-Injured Diabetic Rats
Authors: Igarashi Masahiko , Hirata Akihiko , Yamaguchi Hiroshi , Tsuchiya Hiromi , Ohnuma Hiroshi , Tominaga Makoto , Daimon Makoto , Kato Takeo
Published: September 2007

This study investigates the effects of candesartan, an angiotensin II type 1 receptor blockade, on carotid arterial intimal thickening and glucose tolerance in balloon-injured male Wistar fatty rats and their littermates (Wistar lean rats). Candesartan was orally administered to 12-week-old rats for 21 days, and age-matched rats without the agent were used as the respective controls. Balloon catheterization in the left common carotid artery was performed on day 7, and the artery was removed on day 14 for histological analysis. Compared with the area ratios of the neointima/media in fatty rats without treatment, the ratios in fatty rats treated with candesartan at 1 mg · kg
−1
· d
−1
and lean rats without treatment were significantly decreased to 65%; on the other hand, the ratios of fatty rats treated with candesartan at 10 mg · kg
−1
· d
−1
and lean rats treated with 1 mg · kg
−1
· d
−1
were reduced to 35%, and those of lean rats treated with 10 mg · kg
−1
· d
−1
were reduced to 28%. The administration of candesartan also decreased the level of plasma glucose time- and dose-dependently in fatty rats. In an intragastric glucose load, the levels of both glucose and insulin at 30 and 60 minutes were significantly decreased when fatty rats were treated with candesartan at 10 mg · kg
−1
· d
−1
. In cultured vascular smooth muscle cells from fatty rats, insulin-stimulated Akt (New England Biolabs) phosphorylation and 2-deoxy-
d
-glucose uptake were inhibited to 59% and 68%, respectively, by angiotensin II, but the effects were ameliorated by the addition of 10
−7
mol/L candesartan. We conclude that candesartan could be effective for the suppression of vascular smooth muscle cell growth dose-dependently in Wistar fatty and lean rats. Furthermore, the agent could improve insulin resistance in Wistar fatty rats.
Local Effects of Atherosclerotic Plaque on Arterial Distensibility
Authors: Giannattasio Cristina , Failla Monica , Emanuelli Guglielmo , Grappiolo Alessandra , Boffi Lucia , Corsi Davide , Mancia Giuseppe
Published: September 2007

Hypertension, diabetes, and hypercholesterolemia are characterized by a reduction in arterial distensibility and by accelerated atherosclerosis. Whether arterial stiffening is an inherent feature of these conditions or just the consequence of the atherosclerotic clinical or subclinical lesions is not known, however. Our aim was to obtain information on this issue by directly measuring, in humans, arterial distensibility both at the site of an atherosclerotic lesion and at the proximal normal site. In 10 patients (8 men; mean±SEM age, 65.2±3.4 years) affected by monolateral hemodynamic significant internal carotid artery stenosis, we measured arterial distensibility (Wall Track System; PIE Medical) bilaterally, both at the internal carotid artery and at the common carotid artery level. In the common carotid artery, measurements were made 3 cm below the bifurcation. In the affected internal carotid artery, measurements were made at the plaque shoulder (wall thickness of 2 mm). Measurements were made in the contralateral internal carotid artery at a symmetrical level. Arterial wall thickness was measured in the same site of arterial distensibility. Arterial distensibility was less in the internal than in the common carotid artery, with a marked reduction at the plaque internal carotid artery level compared with the corresponding contralateral site (−45%,
P
<0.01). It was also less, however, in the common carotid artery branching into the atherosclerotic internal carotid artery than in the contralateral common carotid artery (−25%,
P
<0.05). Wall thickness was similar in the 2 common carotid arteries and obviously greater in the affected internal carotid artery than in the contralateral artery. Arterial distensibility was markedly less in the internal carotid artery where there was a plaque compared with the intact contralateral internal carotid artery; it was also less, however, in the common carotid artery of the affected side in comparison with the contralateral common carotid artery. This provides evidence that the effect of a plaque on arterial mechanical properties is not limited to the actual plaque site but rather extends to a considerable degree in a proximal direction.
Differential Role of Kinases in Brain Stem of Hypertensive and Normotensive Rats
Authors: Seyedabadi Maryam , Goodchild Ann K. , Pilowsky Paul M.
Published: September 2007

Spontaneously hypertensive rats (SHR) are characterized by extreme elevations of blood pressure. The genetic factors underlying this are yet to be identified. Here we demonstrate, in vivo, that in SHR and normotensive Wistar-Kyoto rats (WKY), injection of the mitogen-activated protein kinase inhibitor PD 098,059 bilaterally into the rostral ventrolateral medulla (RVLM) dramatically lowers arterial pressure. PD 098,059 does not alter the responses evoked by microinjection of glutamate into the RVLM or brief apnea. Wortmannin (phosphatidylinositol-3 kinase inhibitor) bilaterally into the RVLM causes a 35±4% fall in arterial pressure in SHR but has no effect in WKY. Furthermore, wortmannin reduces the pressor response evoked by microinjection of angiotensin (Ang) II in the RVLM of SHR compared with WKY. The response to Ang II microinjection into the RVLM of WKY was unaffected by wortmannin. Simultaneous bilateral injections of PD 098,059 and wortmannin into the RVLM abolished the response to exogenous Ang II in the RVLM but did not affect the response evoked by glutamate in either SHR or WKY. Thus, it appears that PD 098,059– and/or wortmannin-sensitive mechanisms are not involved in the responses evoked by glutamate in the RVLM and that these kinase inhibitors are not neurotoxic. We conclude that a PD 098,059–sensitive pathway in the RVLM of SHR and WKY tonically regulates arterial pressure and that a wortmannin-sensitive pathway in the RVLM is important in the maintenance of hypertension in SHR. This may be related to a phosphatidylinositol-3 kinase–dependent mechanism involved in the action of Ang II on the Ang II type 1 receptor.
Receptor-Based Differences in Human Aortic Smooth Muscle Cell Membrane Stiffness
Authors: Huang Hayden , Kamm Roger D. , So Peter T.C. , Lee Richard T.
Published: September 2007

Cells respond to mechanical stimuli with diverse molecular responses. The nature of the sensory mechanism involved in mechanotransduction is not known, but integrins may play an important role. The integrins are linked to both the cytoskeleton and extracellular matrix, suggesting that probing cells via integrins should yield different mechanical properties than probing cells via non–cytoskeleton-associated receptors. To test the hypothesis that the mechanical properties of a cell are dependent on the receptor on which the stress is applied, human aortic smooth muscle cells were plated, and magnetic beads, targeted either to the integrins via fibronectin or to the transferrin receptor by use of an IgG antibody, were attached to the cell surface. The resistance of the cell to deformation (“stiffness”) was estimated by oscillating the magnetic beads at 1 Hz by use of single-pole magnetic tweezers at 2 different magnitudes. The ratio of bead displacements at different magnitudes was used to explore the mechanical properties of the cells. Cells stressed via the integrins required ≈10-fold more force to obtain the same bead displacements as the cells stressed via the transferrin receptors. Cells stressed via integrins showed stiffening behavior as the force was increased, whereas this stiffening was significantly less for cells stressed via the transferrin receptor (
P
<0.001). Mechanical characteristics of vascular smooth muscle cells depend on the receptor by which the stress is applied, with integrin-based linkages demonstrating cell-stiffening behavior.
Genes Encoding Fibrinogen and Cardiovascular Risk
Authors: Iacoviello Licia , Vischetti Michela , Zito Francesco , Benedetta Donati Maria
Published: September 2007

The role of fibrinogen in cardiovascular disease has been extensively studied, and meta-analyses have definitively confirmed that high levels of fibrinogen are associated with an increased risk of the disease. In recent years, several polymorphisms have been identified in the fibrinogen chain genes that contribute to determine the levels of fibrinogen in the general population. The fibrinogen β-chain gene has been more extensively studied because the β-chain synthesis is the limiting step in the production of mature fibrinogen. Overall, the studies show an association between β-fibrinogen chain polymorphisms and the levels of fibrinogen. In contrast, the majority of the studies did not find any relation with the risk of cardiovascular disease. The individual responses to gender or to environmental stimuli such as smoking, physical exercise, or infections may be genetically determined, and genetic variability underlies changes in biological reactions that contribute to differences in cardiovascular risk. In the future, gene-environment interactions should be considered in evaluating the relevance of genetic variations on the risk of cardiovascular disease.
Hyperhomocysteinemia in Liver Cirrhosis
Authors: García-Tevijano Elena Ruiz , Berasain Carmen , Rodríguez José Antonio , Corrales Fernando José , Arias Roberto , Martín-Duce Antonio , Caballería Juan , Mato José María , Avila Matías Antonio
Published: September 2007

Numerous clinical and epidemiological studies have identified elevated homocysteine levels in plasma as a risk factor for atherosclerotic vascular disease and thromboembolism. Hyperhomocysteinemia may develop as a consequence of defects in homocysteine-metabolizing genes; nutritional conditions leading to vitamin B
6
, B
12
, or folate deficiencies; or chronic alcohol consumption. Homocysteine is an intermediate in methionine metabolism, which takes place mainly in the liver. Impaired liver function leads to altered methionine and homocysteine metabolism; however, the molecular basis for such alterations is not completely understood. In addition, the mechanisms behind homocysteine-induced cellular toxicity are not fully defined. In the present work, we have examined the expression of the main enzymes involved in methionine and homocysteine metabolism, along with the plasma levels of methionine and homocysteine, in the liver of 26 cirrhotic patients and 10 control subjects. To gain more insight into the cellular effects of elevated homocysteine levels, we have searched for changes in gene expression induced by this amino acid in cultured human vascular smooth muscle cells. We have observed a marked reduction in the expression of the main genes involved in homocysteine metabolism in liver cirrhosis. In addition, we have identified the tissue inhibitor of metalloproteinases-1 and α1(I)procollagen to be upregulated in vascular smooth muscle cells and liver stellate cells exposed to pathological concentrations of homocysteine. Taken together, our observations suggest (1) impaired liver function could be a novel determinant in the development of hyperhomocysteinemia and (2) a role for elevated homocysteine levels in the development of liver fibrosis.
Long-Lasting Cardiovascular Effects of Liposome-Entrapped Angiotensin-(1-7) at the Rostral Ventrolateral Medulla
Authors: Silva-Barcellos Neila M. , Frézard Frédéric , Caligiorne Sordaini , Santos Robson A.S.
Published: September 2007

The aim of this work was to evaluate the potential of liposomes as a tool for the sustained release of the short half-life peptides of the renin-angiotensin system in a specific site of the brain. Angiotensin (Ang)-(1-7) was selected for this study because of its known cardiovascular effects at the level of the rostral ventrolateral medulla (RVLM) and because of the considerable interests in elucidating its physiopathological role as a neuromodulator. Ang-(1-7)–containing liposomes (LAng) were microinjected unilaterally in the RVLM of Wistar rats, and the effects on blood pressure (MAP) and heart rate were evaluated by telemetry. Empty liposomes (Lemp) were used as control. LAng elicited a significant pressor effect during daytime and bradycardia during nighttime that lasted for 5 and 3 days, respectively. These cardiovascular effects resulted in a significant attenuation of the circadian variations of MAP and heart rate. In the case of MAP, a significant inversion of the circadian rhythm was observed on day 2 after LAng microinjection. None of these effects were observed following microinjection of Lemp. Using this novel technique, it was possible to establish, in chronic conditions, the pressor effect of Ang-(1-7) at the RVLM. Moreover, our data unmasks a new physiological role for Ang-(1-7) at the level of the RVLM: modulation of the circadian rhythms of MAP and heart rate.