bluuebunny/crossref_metadata_2025 huggingface dataset:
Nifedipine Increases Cytochrome P4502C Expression and Endothelium-Derived Hyperpolarizing Factor–Mediated Responses in Coronary Arteries
Authors: Fisslthaler Beate , Hinsch Nora , Chataigneau Thierry , Popp Rüdiger , Kiss Ladislau , Busse Rudi , Fleming Ingrid
Published: June 2012

Abstract
—In addition to NO and prostacyclin, endothelial cells release a factor that elicits vasodilatation by hyperpolarizing the underlying vascular smooth muscle cells. In some vascular beds, this so-called endothelium-derived hyperpolarizing factor (EDHF) displays the characteristics of a cytochrome P450 (CYP)-derived arachidonic acid metabolite, such as an epoxyeicosatrienoic acid. Native porcine and cultured human coronary artery endothelial cells were screened for CYP epoxygenases, and CYP2B, CYP2C, and CYP2J were detected with reverse transcription–polymerase chain reaction. The CYP inducer β-naphthoflavone and the Ca
2+
antagonist nifedipine significantly increased CYP2C mRNA but did not change the expression of CYP2J or CYP2B. To determine the relationship between CYP2C expression and EDHF production in native endothelial cells, we incubated porcine coronary arteries with nifedipine. Nifedipine enhanced endothelial CYP2C protein expression, as well as the generation of 11,12-epoxyeicosatrienoic acid. In organ bath experiments, pretreatment with nifedipine enhanced bradykinin-induced, EDHF-mediated relaxations as well as the concomitant hyperpolarization of smooth muscle cells. The specific CYP2C9 inhibitor sulfaphenazole, on the other hand, significantly attenuated EDHF-mediated hyperpolarization and relaxation. These results demonstrate that in porcine coronary arteries, the elevated expression of a CYP epoxygenase, homologous to CYP2C8/9, is associated with enhanced EDHF-mediated hyperpolarization in response to bradykinin. Therefore, we propose that an isozyme of CYP2C is the most likely candidate for the CYP-dependent EDHF synthase in porcine coronary arteries.
Coronary Vasodilator Capacity and Epicardial Vessel Remodeling in Physiological and Hypertensive Hypertrophy
Authors: Kozàkovà Michaela , Galetta Fabio , Gregorini Luisa , Bigalli Giovanni , Franzoni Ferdinando , Giusti Costantino , Palombo Carlo
Published: June 2012

Abstract
—The aim of this study was to compare resting coronary flow velocity, determinants of myocardial oxygen demand, and coronary vasodilator capacity in subjects with physiological, exercise-induced, and hypertensive left ventricular hypertrophy. Sixteen healthy sedentary men, 16 endurance athletes, and 16 hypertensive subjects (mean±SEM for left ventricular mass index: 94.9±5.5, 184.6±8.4, 154.4±9.5 g/m
2
, respectively) were studied by transesophageal and transthoracic Doppler echocardiography. Coronary flow velocity in left anterior descending artery and cross-sectional area of left main artery were assessed at rest and during dipyridamole-induced vasodilation. Myocardial oxygen demand was estimated through rate-pressure product, left ventricular wall stress, and inotropic function. Coronary flow reserve and minimum coronary resistance were comparable to those of sedentary men in athletes (mean±SEM: 3.23±0.16 versus 3.60±0.18 and 0.96±0.06 versus 1.04±0.04 mm Hg · s · cm
−
1
), while in hypertensive subjects they were decreased and increased, respectively (mean±SEM: 2.31±0.08 and 1.21±0.10 mm Hg · s · cm
−
1
;
P
<0.05 for both). Resting flow velocity was directly related to rate-pressure product in sedentary men and athletes and also to wall stress in athletes, while these correlations were absent in hypertensives. Dilation of left main artery after dipyridamole was significantly higher in athletes than in sedentary men and hypertensive subjects (mean±SEM for area change: 32.9±3.7% versus 12.8±2.5% and 6.4±3.3%;
P
<0.05 and 0.01). These data indicate that vasodilator capacity of coronary microcirculation is not impaired in athletes with physiological hypertrophy, in contrast to hypertensive patients. The relationship between resting flow velocity and determinants of oxygen demand is preserved in physiological hypertrophy but missing in hypertensive hypertrophy. Furthermore, the vasodilator capacity of coronary macrocirculation is also enhanced in exercise-trained subjects.
Enhanced NO Inactivation and Hypertension Induced by a High-Fat, Refined-Carbohydrate Diet
Authors: Roberts Christian K. , Vaziri Nosratola D. , Wang Xiu Q. , Barnard R. James
Published: June 2012

Abstract
—We have recently demonstrated that long-term consumption of a high-fat, refined-carbohydrate (HFS) diet induces hypertension (HTN) in normal rats compared with a low-fat, complex-carbohydrate (LFCC) diet. Limited evidence suggests that high-fat or high-sugar diets cause enhanced generation of reactive oxygen species (ROS). We therefore hypothesized that by inducing oxidative stress, the HFS diet may promote nitric oxide (NO) inactivation and HTN. To test this hypothesis, female Fischer rats were placed on either the HFS or the LFCC diet starting at 2 months of age. Blood pressure, urinary NO metabolites (NO
x
), and total renal NO synthase activity were monitored, and the tissue abundance of nitrotyrosine (NT), which is the stable “footprint” of NO oxidation by ROS, was determined. The HFS diet group exhibited a gradual rise in arterial blood pressure and were hypertensive by 18 months. This trend was accompanied by a marked accumulation of NT in all tested tissues, an initial rise and a subsequent fall in NO synthase activity, and a fall in urinary NO
x
excretion. The HFS diet–fed animals had a blunted blood pressure response to the NO synthase inhibitor
N
ω
-nitro-
l
-arginine methyl ester (
l
-NAME) compared with the LFCC diet group, which showed a marked hypertensive response to
l
-NAME.
l
-NAME–induced HTN was reversible with
l
-arginine in the LFCC diet group; however, HTN was not corrected by
l
-arginine supplementation in the HFS diet group. These findings point to enhanced ROS-mediated inactivation and sequestration of NO, which may contribute to the reduction of bioactive NO and HTN in the HFS diet–fed animals.
Effect of Indomethacin on Blood Pressure Lowering by Captopril and Losartan in Hypertensive Patients
Authors: Conlin Paul R. , Moore Thomas J. , Swartz Stephen L. , Barr Eliav , Gazdick Lisa , Fletcher Charlena , DeLucca Paul , Demopoulos Laura
Published: June 2012

Abstract
—NSAIDs are known to attenuate the effects of some antihypertensive medications. It is not known whether the new class of angiotensin II receptor antagonists is similarly affected. We conducted a multicenter study assessing the effect of indomethacin on the antihypertensive effects of losartan and captopril. After 4 weeks of placebo washout, hypertensive patients received 6 weeks of active antihypertensive therapy with either 50 mg losartan once daily (n=111) or 25 mg captopril twice daily for 1 week, which was increased to 50 mg twice daily for 5 weeks (n=105). This was followed by 1 week of concomitant therapy with indomethacin (75 mg daily). The primary outcome measure was the change in mean 24-hour ambulatory diastolic blood pressure after the addition of indomethacin. Both captopril and losartan significantly lowered ambulatory diastolic blood pressure (losartan −5.3 mm Hg,
P
<0.001; captopril −5.6 mm Hg,
P
<0.001) after 6 weeks of therapy. Indomethacin significantly attenuated the 24-hour ambulatory diastolic blood pressure for both losartan (2.2 mm Hg,
P
<0.05) and captopril (2.7 mm Hg,
P
<0.001) and also attenuated the effect of captopril on trough sitting diastolic blood pressure. Changes in daytime diastolic blood pressure (7:00
am
to 11:00
pm
) were similar to the 24-hour response in both groups. Nighttime diastolic blood pressure (11:01
pm
to 6:59
am
) was significantly attenuated in captopril-treated patients (2.0 mm Hg,
P
<0.05), but losartan was unaffected (0.4 mm Hg). Thus, concurrent treatment with indomethacin similarly attenuates the 24-hour antihypertensive response to losartan and captopril.
Impact of Arterial Stiffening on Left Ventricular Structure
Authors: Roman Mary J. , Ganau Antonello , Saba Pier Sergio , Pini Riccardo , Pickering Thomas G. , Devereux Richard B.
Published: June 2012

Abstract
—Aging of the vasculature results in arterial stiffening and an increase in systolic and pulse pressures. Although pressure load is a stimulus for left ventricular hypertrophy, the extent to which vascular stiffening per se, independent of blood pressure, influences left ventricular structure is uncertain. Two hundred seventy-six subjects (79 normotensive and 197 otherwise healthy hypertensive individuals) underwent echocardiography to assess left ventricular structure. Arterial stiffness was estimated by the pressure-independent stiffness index, β, and the pressure-dependent elastic modulus derived from simultaneous carotid ultrasound and applanation tonometry. Systemic arterial compliance (the inverse of stiffness) was estimated by the arterial compliance index. In multivariate analysis, β was related to age (
P
<0.001) and smoking history (
P
<0.01) but not mean pressure, whereas elastic modulus was related to age and mean pressure (both
P
<0.001). The arterial compliance index was only related to age. Whereas systolic and diastolic pressures and the elastic modulus were positively associated with left ventricular mass (all
P
<0.001), primarily because of increases in wall thicknesses, β and the arterial compliance index bore no relation to left ventricular mass. β was inversely related to chamber diameter and directly related to left ventricular relative wall thickness, the ratio of wall thickness to chamber radius. Younger and older hypertensive subjects had comparable left ventricular mass, despite higher systolic and pulse pressures in the older group, whereas older hypertensives had higher mean relative wall thickness, associated with a significant increase in arterial stiffness (β, 7.06 versus 5.17; elastic modulus, 595 versus 437 dyne/cm
2
×10
−
6
) and reduction in the arterial compliance index (0.87 versus 1.05 mL/mm Hg per square meter) (all
P
<0.001). Thus, the extent to which arterial stiffness relates to left ventricular hypertrophy is dependent on the method by which arterial stiffness is estimated. Pressure-dependent methods show an association with left ventricular hypertrophy, whereas the pressure-independent stiffness index, β, and the arterial compliance index are most strongly associated with aging and left ventricular concentric remodeling but not hypertrophy.
Cardiac Aldosterone Production in Genetically Hypertensive Rats
Authors: Takeda Yoshiyu , Yoneda Takashi , Demura Masashi , Miyamori Isamu , Mabuchi Hiroshi
Published: June 2012

Abstract
—Aldosterone is synthesized in extra-adrenal tissues, both blood vessels and brain. We undertook the present study to determine whether the rat heart produces aldosterone and to investigate the effects of adrenalectomy, ACE inhibition, and angiotensin II on aldosterone synthesis in the heart. To clarify the pathophysiological role of cardiac aldosterone in the hypertensive heart, we compared the synthesis of aldosterone in the hearts of stroke-prone spontaneously hypertensive rats (SHRSP) with that in Wistar-Kyoto rats. The effects of the aldosterone antagonist spironolactone on myocardial hypertrophy in adrenalectomized SHRSP were also studied. Isolated rat hearts were perfused for 2 hours, and the perfusate was analyzed with HPLC and mass spectrometry. The activity of aldosterone synthase was estimated on the basis of the conversion of [
14
C]deoxycorticosterone to [
14
C]aldosterone. The levels of aldosterone synthase gene (CYP11B2) mRNA were determined with competitive polymerase chain reaction. Aldosterone production, the activity of aldosterone synthase, and the expression of CYP11B2 mRNA were increased in hearts from adrenalectomized rats and rats treated with angiotensin II. ACE inhibitors decreased cardiac aldosterone synthesis. Cardiac aldosterone, aldosterone synthase activity, and CYP11B2 mRNA levels in hearts from 2- and 4-week-old SHRSP were significantly greater than those of age-matched Wistar-Kyoto rats. Spironolactone prevented cardiac hypertrophy in adrenalectomized SHRSP. These results suggest that the rat heart produces aldosterone and that endogenous cardiac aldosterone may affect cardiac function and hypertrophy in hypertension in rats.
Genetic Mapping of Blood Pressure Quantitative Trait Loci in Milan Hypertensive Rats
Authors: Zagato Laura , Modica Rossana , Florio Monica , Torielli Lucia , Bihoreau Marie-Thérèse , Bianchi Giuseppe , Tripodi Grazia
Published: June 2012

Abstract
—In a previous study, by using a candidate gene approach, we detected in both Milan hypertensive rats and humans a polymorphism in the α-adducin gene (ADD1) that was associated with blood pressure and renal sodium handling. In the present study, a genomewide search with 264 informative markers was undertaken in 251 (Milan hypertensive strain × Milan normotensive strain) F2 rats to further investigate the contribution of the adducin gene family (
Add1
,
Add2
, and
Add3
) and to identify novel quantitative trait loci (QTLs) that affect blood pressure. The influence of 2 different methods of blood pressure measurement, the intracarotid catheter and the tail-cuff method, was also evaluated. We found evidence that QTLs affected systolic blood pressure (SBP) measured at the carotid (direct SBP) on rat chromosome 1 with a logarithm of the odds (LOD) score peak of 3.3 on D1Rat121 and on rat chromosome 14 on
Add1
locus (LOD=3.2). A QTL for SBP measured at the tail (indirect SBP) was found on rat chromosome 10 around D10Rat33 (LOD=5.0). All of these QTLs identified chromosomal regions not detected in other rat studies and harbor genes (Na
+
/H
+
exchanger A3; α-adducin; α
1B
-adrenergic receptor) that may be involved in blood pressure regulation. Therefore, these findings may be relevant to human hypertension, also in consideration of the biochemical and pathophysiological similarities between MHS and a subgroup of patients of primary hypertension, which led to the identification of α-adducin as a candidate gene in both species.
Genetic and Environmental Influences on Left Ventricular Mass
Authors: Garner Chad , Lecomte Edith , Visvikis Sophie , Abergel Eric , Lathrop Mark , Soubrier Florent
Published: June 2012

Abstract
—The relations between left ventricular mass (LVM) with age, gender, body size, and blood pressure were investigated in healthy adults and children from 149 nuclear families. LVM was strongly correlated with overall weight, especially in the children. Genetic analysis indicated that the segregation of LVM was compatible with an additive polygenic model, with a heritability estimate of 34% before adjustment for weight and 28% after adjustment for weight. Genetic and/or familial environmental factors played a strong role in the correlation of LVM and weight; they accounted for all of the correlation between the 2 traits in adults and 59% of the correlation in children. Spouses exhibited a strong correlation in their weight, which suggested that common family environment may contribute to the family correlations and to the observed heritability of the trait. LVM was strongly correlated with blood pressure before adjustment for weight, but this correlation could be attributed to nonfamilial environment rather than genetic factors. After adjustment for weight, the intertrait correlations between LVM and blood pressure were nonsignificant. Thus, adjustment for weight accounts for all common determinants of LVM and blood pressure.
Systolic and Diastolic Blood Pressure, Pulse Pressure, and Mean Arterial Pressure as Predictors of Cardiovascular Disease Risk in Men
Authors: Sesso Howard D. , Stampfer Meir J. , Rosner Bernard , Hennekens Charles H. , Gaziano J. Michael , Manson JoAnn E. , Glynn Robert J.
Published: June 2012

Abstract
—We compared systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse pressure (PP), and mean arterial pressure (MAP) in predicting the risk of cardiovascular disease (CVD), stratifying results at age 60 years, when DBP decreases while SBP continues to increase. We prospectively followed 11 150 male physicians with no history of CVD or antihypertensive treatment through the 2-year questionnaire, after which follow-up began. Reported blood pressure was averaged from both the baseline and 2-year questionnaires. During a median follow-up of 10.8 years, there were 905 cases of incident CVD. For men aged <60 years (n=8743), those in the highest versus lowest quartiles of average SBP (≥130 versus <116 mm Hg), DBP (≥81 versus <73 mm Hg), and MAP (≥97 versus <88 mm Hg) had relative risks (RRs) of CVD of 2.16, 2.23, and 2.52, respectively. Models with average MAP and PP did not add information compared with models with MAP alone (
P
>0.05). For men aged ≥60 years (n=2407), those in the highest versus lowest quartiles of average SBP (≥135 versus <120 mm Hg), PP (≥55 versus <44 mm Hg), and MAP (≥99 versus <91 mm Hg) had RRs of CVD of 1.69, 1.83, and 1.43, respectively. The addition of other blood pressure measures did not add information compared with average SBP or PP alone (all
P
>0.05). These data suggest that average SBP, DBP, and MAP strongly predict CVD among younger men, whereas either average SBP or PP predicts CVD among older men. More research should distinguish whether MAP, highly correlated with SBP and DBP, better predicts CVD.
Renal Hemodynamic and Hormonal Responses to the Angiotensin II Antagonist Candesartan
Authors: Lansang M. Cecilia , Osei Suzette Y. , Price Deborah A. , Fisher Naomi D. L. , Hollenberg Norman K.
Published: June 2012

Abstract
—The development of very specific blockers for the angiotensin II type 1 (AT
1
) receptor made it possible to examine the contribution of angiotensin II to normal control mechanisms and disease with a specificity beyond what ACE inhibitors could provide. In the present study, we explored the contribution of angiotensin II to 2 renal mechanisms: renal hemodynamics and the short feedback loop, in which angiotensin II acts as a determinant of renin release. To make that comparison, we studied healthy volunteers in balance on a 10-mmol sodium intake to activate the renin system. Our goal was to compare the relation between the dose of candesartan, an AT
1
receptor blocker, and the renal hemodynamic and hormonal responses. A second goal was to ascertain the relation between time after candesartan administration and the peak response. Twelve healthy subjects (mean age 33±2.3 years) in low-sodium balance were administered candesartan in 4-, 8-, 16-, and 32-mg doses. Candesartan produced a dose-related increase in renal plasma flow, with the maximum vasodilator response at 16 mg (142±13 mL · min
−1
· 1.73 m
−2
) occurring during the first 4 hours after the dose. Likewise, candesartan caused a dose-related rise in plasma renin activity, with 32 mg as the dose producing the greatest response at 4 and 24 hours after administration. The peak plasma renin activity achieved in this study (15.3±1.6 ng · L
−1
· s
−1
; 55.0±5.6 ng angiotensin I · mL
−1
· h
−1
) was found at the 4- to 8-hour interval after dosing in a subset of subjects (n=5) who received the 16-mg dose 4 hours earlier than the other subjects. On the basis of the difference in the relation between dose and response and the relationship between time after drug administration and response, the determinants of the renal hemodynamic and hormonal response can be said to differ. The remarkable rise in plasma renin activity after candesartan is substantially larger than that in earlier studies with ACE inhibition, providing additional evidence for non–ACE-dependent angiotensin II generation in the kidney.
Angiotensin II Infused Intrarenally Causes Preglomerular Vascular Changes and Hypertension
Authors: Stevenson Kathleen M. , Edgley Amanda J. , Bergström Göran , Worthy Katrina , Kett Michelle M. , Anderson Warwick P.
Published: June 2012

Abstract
—The effects on the renal vasculature and on arterial blood pressure of chronic infusion of low doses of angiotensin II (Ang II) into the renal artery were studied. Sprague Dawley rats were infused continuously with Ang II (0.5, 1.5, or 4.5 ng · kg
−1
· min
−1
) or vehicle into the right renal artery (contralateral nephrectomy). Intrarenal Ang II infusion for 25 days produced dose-dependent rises (
P
<0.001) in awake mean arterial pressure (111±1, 119±5, and 130±3 mm Hg in rats receiving 0.5, 1.5, and 4.5 ng · kg
−1
· min
−1
Ang II, respectively) compared with 105±1 mm Hg (vehicle). Renal vessel lumen characteristics were assessed with an established, maximally dilated, isosmotic perfused kidney preparation. This revealed a small dose-dependent right shift in the pressure-flow relation (
P
=0.05), as well as a dose-dependent right shift and a dose-dependent reduction in the slope of the pressure–glomerular filtration rate relation (
P
=0.04 and 0.03, respectively). The effects of Ang II infusion on arterial pressure were not affected by the timing of the contralateral nephrectomy but were reduced when the contralateral kidney remained in situ. Acute losartan administration (10 mg/kg IV bolus) produced similar effects on arterial pressure in rats infused with vehicle or Ang II (4.5 ng · kg
−1
· min
−1
) for 14 days,
P
=0.89), indicating the lack of systemic spillover of Ang II. Intraperitoneal Ang II (0.5, 1.5, or 4.5 ng · kg
−1
· min
−1
for 25 days) had no effect on arterial pressure. Thus, chronic intrarenal infusion of low doses of Ang II resulted in changes in the renal vasculature compatible with dose-related structural reductions in the lumen diameter of preglomerular vessels and produced dose-related increases in arterial pressure.
Angiotensin II Type 2 Receptors Stimulate Collagen Synthesis in Cultured Vascular Smooth Muscle Cells
Authors: Mifune Mizuo , Sasamura Hiroyuki , Shimizu-Hirota Ryoko , Miyazaki Hitoshi , Saruta Takao
Published: June 2012

Abstract
—Previously, we and others have shown that angiotensin II enhances vascular smooth muscle cell extracellular matrix synthesis via stimulation of the angiotensin II type 1 (AT
1
) receptor. Recently, expression of the type 2 (AT
2
) receptor has been confirmed in the adult vasculature, but its role has not yet been fully defined. The aim of the present study was to examine the effects of stimulation of AT
2
receptors on collagen synthesis in vascular smooth muscle cells. Retroviral gene transfer was used to supplement adult vascular smooth muscle cells with AT
2
receptors to mimic the vasculature in vivo. The treatment of these cells with the AT
2
receptor agonist CGP42212A (10
−7
mol/L) alone did not cause a significant change in p42/p44 MAP kinase activity but caused a modest (30% to 50%) decrease in protein tyrosine phosphatase activity. Treatment with CGP42112A also caused a dose- and time-dependent increase in both cell-associated and secretory collagen synthesis (148±17% of control at 48 hours,
P
<0.05), which was completely inhibited by the AT
2
receptor antagonist PD123319, unaffected by the AT
1
receptor antagonist losartan, and attenuated by treatment with pertussis toxin or G
α
i
antisense oligonucleotides. Interestingly, studies in other cell lines demonstrated that CGP42112A caused similar results in transfected mesangial cells but had essentially opposite effects in fibroblasts (NIH-3T3-AT
2
). These results suggest that AT
2
receptor stimulation can increase collagen synthesis in vascular smooth muscle cells via a G
α
i
-mediated mechanism and provide evidence for heterogeneity in the effects of AT
2
receptor stimulation in different tissues.
Relation Between Serum Uric Acid and Risk of Cardiovascular Disease in Essential Hypertension
Authors: Verdecchia Paolo , Schillaci Giuseppe , Reboldi GianPaolo , Santeusanio Fausto , Porcellati Carlo , Brunetti Paolo
Published: June 2012

Abstract
—The question of serum uric acid as an independent risk factor in subjects with essential hypertension remains controversial. For up to 12 years (mean, 4.0) we followed 1720 subjects with essential hypertension. At entry, all subjects were untreated and all were carefully screened for absence of cardiovascular disease, renal disease, cancer, and other important disease. Outcome measures included total cardiovascular events, fatal cardiovascular events, and all-cause mortality. During 6841 person-years of follow-up there were 184 cardiovascular events (42 fatal) and 80 deaths from all causes. In the 4 quartiles of serum uric acid (division points: 0.268, 0.309, and 0.369 mmol/L [4.5, 5.2, and 6.2 mg/dL] in men; 0.190, 0.232, and 0.274 mmol/L [3.2, 3.9, and 4.6 mg/dL] in women), the rate (per 100 person-years) of cardiovascular events was 2.51, 1.48, 2.66, and 4.27, that of fatal cardiovascular events was 0.41, 0.33, 0.38, and 1.23, and that of all-cause deaths was 1.01, 0.55, 0.93, and 2.01, respectively. The relation between uric acid and event rate was J-shaped in both genders. After adjustment for age, gender, diabetes, total cholesterol/HDL cholesterol ratio, serum creatinine, left ventricular hypertrophy, ambulatory blood pressure, and use of diuretics during follow-up, uric acid levels in the highest quartile were associated with increased risk for cardiovascular events (relative risk, 1.73; 95% CI, 1.01 to 3.00), fatal cardiovascular events (relative risk, 1.96; 95% CI, 1.02 to 3.79), and all-cause mortality (relative risk, 1.63; 95% CI, 1.02 to 2.57) in relation to the second quartile. In untreated subjects with essential hypertension, raised uric acid is a powerful risk marker for subsequent cardiovascular disease and all-cause mortality.
Capacity for Purinergic Control of Renin Promoter via P2Y
11
Receptor and cAMP Pathways
Authors: van der Weyden Louise , Adams David J. , Morris Brian J.
Published: June 2012

Abstract
—Renin secretion can be stimulated by ATP via purinergic P2Y receptors. ATP is a cotransmitter with norepinephrine and is released from the cytosol during cell damage. Such release could account for the de novo renin expression seen in the proximal tubule in renal disease and in myocardial infarct borders. Whereas most P2Y purinoceptor subtypes utilize phosphoinositide signal-transduction pathways, the effector mechanisms of the subtype P2Y
11
also involve increases in cAMP, a well-known renin secretagogue and stimulus to renin production. The present study tested the effect of ATP on human renin gene (
REN
) promoter activity and the role of P2Y
11
. By means of reverse transcriptase–polymerase chain reaction, we found that renin-expressing Calu-6 cells express P2Y
11
mRNA. Expression was also detected in the brain, kidney, testis, muscle, liver, and spleen. We made a novel cell line (Calu-6/P2Y11) in which P2Y
11
cDNA, under the control of a strong promoter, was stably integrated into genomic DNA. These cells produced P2Y
11
mRNA during culture. Treatment of Calu-6/P2Y11 cells with 1 mmol/L ATP caused a 3-fold increase in renin mRNA and protein over 36 hours. Transient transfection of Calu-6/P2Y11 cells with constructs containing 896 bp of human
REN
5′-flanking DNA linked to the luciferase reporter gene led to a 5.8±0.6-fold increase (mean±SEM) in reporter activity in response to ATP (
P
=0.0015). In contrast, UTP produced only a 1.4±0.1-fold increase (
P
=0.016). For ADP, it was 1.7±0.1-fold (
P
=0.011). The response profile was ATP>ADP>AMP=adenosine=0, consistent with a P2Y
11
effect. Mutation of the cAMP response element (CRE) located at –222 in the
REN
promoter DNA abolished the effect of ATP. Furthermore, ATP induced a rapid, time-dependent increase in the phosphorylation of CRE binding protein (CREB) and activating transcription factor-1. These data implicate a cAMP pathway in mediation of the P2Y
11
effect. In conclusion, we have made a novel cell line that overexpresses the P2Y
11
purinoceptor. Stimulation of these cells by ATP activates a cAMP signal-transduction pathway that phosphorylates CREB and stimulates renin promoter activity via the CRE at –222. The data raise the possibility of a contribution of ATP/P2Y
11
effects to sympathetic stimulation of renin, as well as to responses in renin seen after tissue damage, such as in kidney disease and myocardial infarction.
Fluvastatin Upregulates Inducible Nitric Oxide Synthase Expression in Cytokine-Stimulated Vascular Smooth Muscle Cells
Authors: Chen Hong , Ikeda Uichi , Shimpo Masahisa , Ikeda Michiyo , Minota Seiji , Shimada Kazuyuki
Published: June 2012

Abstract
—Nitric oxide (NO) production by inducible NO synthase (iNOS) may play an important role in the pathogenesis of atherosclerosis. Although fluvastatin has been shown to reduce progression of atherosclerosis, it is not known whether it regulates iNOS expression. We investigated the effects of fluvastatin on iNOS expression and subsequent NO synthesis in vascular smooth muscle cells (VSMCs) and the mechanism by which fluvastatin exerts its effects. Fluvastatin significantly increased interleukin-1β (IL-1β)–induced nitrite production by VSMCs in a time-dependent (0 to 24 hours) and dose-dependent (10
−
8
to 10
−
5
mol/L) manner. Increased nitrite production by fluvastatin was accompanied by increased iNOS mRNA and protein accumulation. IL-1β induced nuclear factor-κB activation in VSMCs, which was not affected by fluvastatin. Exogenous mevalonate significantly prevented the stimulatory effect of fluvastatin on nitrite production. Cotreatment with geranylgeranyl-pyrophosphate also reversed the effect of fluvastatin. Furthermore, both Rho inhibitor C3 exoenzyme and Rho kinase inhibitor Y-27632 significantly increased IL-1β–induced nitrite accumulation in VSMCs. These results demonstrated that fluvastatin upregulates iNOS expression and subsequent NO formation in rat VSMCs through inhibition of Rho.
Noninvasive Assessment of the Digital Volume Pulse
Authors: Millasseau Sandrine C. , Guigui Franck G. , Kelly Ronan P. , Prasad Krishna , Cockcroft John R. , Ritter James M. , Chowienczyk Philip J.
Published: June 2012

Abstract
—The digital volume pulse can be recorded simply and noninvasively by photoplethysmography. The objective of the present study was to determine whether a generalized transfer function can be used to relate the digital volume pulse to the peripheral pressure pulse and, hence, to determine whether both volume and pressure pulse waveforms are influenced by the same mechanism. The digital volume pulse was recorded by photoplethysmography in 60 subjects (10 women, aged 24 to 80 years), including 20 subjects with previously diagnosed hypertension. Simultaneous recordings of the peripheral radial pulse and digital artery pulse were obtained by applanation tonometry and a servocontrolled pressure cuff (Finapres), respectively. In 20 normotensive subjects, measurements were obtained after the administration of nitroglycerin (NTG, 500 μg sublingually). Transfer functions obtained by Fourier analysis of the waveforms were similar in normotensive and hypertensive subjects. In normotensive subjects, transfer functions were similar before and after NTG. By use of a single generalized transfer function for all subjects, the radial and digital artery pressure waveforms could be predicted from the volume pulse with an average root mean square error of 4.4±2.0 and 4.3±1.9 mm Hg (mean±SD) for radial and digital artery waveforms, respectively, similar to the error between the 2 pressure waveforms (4.4±1.4 mm Hg). The peripheral pressure pulse is related to the digital volume pulse by a transfer function, which is not influenced by effects of hypertension or NTG. Effects of NTG on the volume pulse and pressure pulse are likely to be determined by a similar mechanism.
Relationship of Fibrinogen Levels and Hemostatic Abnormalities With Organ Damage in Hypertension
Authors: Sechi Leonardo A. , Zingaro Laura , Catena Cristiana , Casaccio Daniele , De Marchi Sergio
Published: June 2012

Abstract
—Elevated plasma levels of fibrinogen and activated coagulation pathways are risk factors of cardiovascular disease in the general population. In a cross-sectional study of a case series, we investigated the relationship between fibrinogen and hemostatic markers with target-organ damage (TOD) in patients with arterial hypertension. Prothrombin time, partial thromboplastin time, fibrinogen, fibrin D-dimer, prothrombin fragment 1+2 (F1+2), and antithrombin III were measured in 352 untreated patients with mild to moderate essential hypertension and 92 normotensive controls. Staging of TOD was assessed according to W.H.O. guidelines by clinical evaluation and laboratory tests including measurements of creatinine clearance, proteinuria, ophthalmoscopy, electrocardiography, echocardiography, and ultrasound examination of major arteries. F1+2 concentrations were significantly greater in hypertensive patients than normotensive controls and were positively correlated with blood pressure. Age, blood pressure levels, duration of hypertension, smoking, HDL-cholesterol, triglycerides, and plasma fibrinogen, fibrin D-dimer, and F1+2 levels were significantly related to the presence and severity of TOD in univariate analysis. Plasma fibrinogen and D-dimer levels were related to organ damage independent of age, blood pressure, duration of hypertension, and smoking status. Separate analysis indicated significant association of fibrinogen and D-dimer levels with cardiac, cerebrovascular, peripheral vascular, and renal damage. In conclusion, elevated plasma levels of fibrinogen and a prothrombotic state are associated with the presence and severity of TOD in patients with essential hypertension and may contribute to the development of atherosclerotic disease in these patients.
Baseline Characteristics and Early Blood Pressure Control in the CONVINCE Trial
Authors: Black Henry R. , Elliott William J. , Neaton James D. , Grandits Gregory , Grambsch Patricia , Grimm Richard H. , Hansson Lennart , Lacoucière Yves , Muller James , Sleight Peter , Weber Michael A. , White William B. , Williams Gordon , Wittes Janet , Zanchetti Alberto , Fakouhi T. Daniel , Anders Robert J.
Published: June 2012

Abstract
—Blood pressure (BP) control rates around the world are suboptimal. Part 2 of the National Health and Nutrition Educational Survey (NHANES) III indicates that only 27.4% of hypertensive Americans aged 18 to 74 years have a BP of <140/90 mm Hg. We wanted to assess BP control during the first 2 years and to describe the baseline characteristics of patients enrolled in the Controlled ONset Verapamil INvestigation of Cardiovascular Endpoints (CONVINCE) Study, an international clinical trial that compares outcomes in hypertensive patients randomized to initial treatment with either controlled-onset extended-release verapamil or the investigator’s choice of atenolol or hydrochlorothiazide. At randomization, BP was <140/90 mm Hg in only 20.3% of the 16 602 subjects (average±SD age 65.6±7.4 years; 56% women, 84% white/7% black/7% Hispanic). The average BP at enrollment was 148/85 mm Hg for patients taking BP medications (n=13 879) and 161/94 mm Hg for previously untreated patients (n=2723). After medication titration, with a transtelephonic computer that recommended an increase in the dose or number of antihypertensive agents whenever the BP was 140/90 mm Hg, 84.8% of the subjects attained the goal BP. During 2 years of treatment, BP control was maintained in 67% to 69% of the subjects (69% to 71% for systolic BP of <140 mm Hg and 90% for diastolic BP of <90 mm Hg). These data suggest that the control of systolic BP is more difficult than the control of diastolic BP. The US national goal of having 50% of hypertensives with a BP of <140/90 mm Hg may be achievable if a forced titration strategy is used. Interested investigators, free care and medications, and well-educated subjects may make the attainment of such a goal easier in the CONVINCE study than in the general population.
Expression of Ca
2+
Transport Genes in Platelets and Endothelial Cells in Hypertension
Authors: Mountian Irina , Baba-Aïssa Fawzia , Jonas Jean-Christophe , Humbert De Smedt  , Wuytack Frank , Parys Jan B.
Published: June 2012

Abstract
—Altered Ca
2+
handling is observed in different cells in essential hypertension. We investigated the expression of sarco(endo)plasmic reticulum Ca
2+
-ATPase (SERCA) and inositol 1,4,5-trisphosphate receptor (IP
3
R) isoforms in platelets and aortic endothelial cells (EC) isolated from spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats by ratio reverse-transcriptase—polymerase chain reaction (RT-PCR) analysis and Western blotting. SERCA2b and SERCA3 were assessed at mRNA (EC and platelets) and at protein level (platelets). IP
3
R1, IP
3
R2, and IP
3
R3 mRNAs were demonstrated in both cell types, but only IP
3
R1 and IP
3
R2 proteins were detected in platelets. Compared with WKY, SHR EC and platelets showed higher SERCA3 and IP
3
R2 expression and lower IP
3
R1 expression. We then investigated the effect of lisinopril (20 mg · kg
−
1
· d
−
1
; 10-week treatment of 4-week-old rats or 2-week treatment of adult rats) and captopril (100 mg · kg
−
1
· d
−
1
; 2-week treatment of adult rats). Consequently, expression patterns of SERCAs and IP
3
Rs were significantly modified. Except for SERCAs mRNA in platelets, all differences between SHR and WKY disappeared. However, SERCA3 remained the predominant isoform. Both EC and platelets demonstrated a high equal expression of IP
3
R2 mRNA. IP
3
R1 was the predominant platelet protein isoform, as it was in untreated WKY. mRNA was also isolated from pancreatic islets of WKY and SHR, but no effect of either rat strain or of lisinopril treatment was observed on the expression of the studied genes. We hypothesize that the identical expression pattern of SERCAs and IP
3
Rs after treatment with ACE inhibitors represents a different nonhypertensive configuration, which, through changes in intracellular Ca
2+
handling, improves endothelial and platelet dysfunction in SHR but has no effect in WKY.
Vasopeptidase Inhibition Prevents Endothelial Dysfunction of Resistance Arteries in Salt-Sensitive Hypertension in Comparison With Single ACE Inhibition
Authors: d’Uscio Livius V. , Quaschning Thomas , Burnett John C. , Lüscher Thomas F.
Published: June 2012

Abstract
—To determine whether natriuretic peptides in addition to the renin-angiotensin system are involved in functional and structural vascular changes in salt-sensitive hypertension, we compared equipotent hypotensive treatment with the dual neutral endopeptidase/ACE inhibitor omapatrilat (35 mg · kg
−1
· d
−1
) or the ACE inhibitor captopril (100 mg · kg
−1
· d
−1
). The reactivity and geometry of mesenteric resistance arteries from Dahl salt-sensitive rats were studied in vitro under perfused and pressurized conditions. Chronic salt administration increased systolic blood pressure by 57±4 mm Hg, whereas concentrations of atrial natriuretic peptide were reduced in heart and in plasma (
P
<0.05). In addition, the medial cross-sectional area of small mesenteric arteries was increased and endothelium-dependent relaxation in response to acetylcholine and contraction in response to endothelin-1 were impaired in the mesenteric arteries of salt-sensitive rats on a high-salt diet (
P
<0.05). Concomitant treatment with either omapatrilat or captopril reduced the increase in systolic blood pressure and hypertrophic remodeling to a similar degree (
P
<0.05) but affected plasma and cardiac atrial natriuretic peptide levels differently (
P
<0.05). In addition, omapatrilat normalized endothelium-dependent relaxations to a greater extent than captopril (
P
<0.05). Furthermore, vasopeptidase inhibition increased cGMP levels compared with captopril (
P
<0.05). Contractions to endothelin-1 were normalized by either antihypertensive drug. These results suggest that in the Dahl rat, with similar reductions in systolic blood pressure, omapatrilat is superior to captopril in preventing impaired endothelial function in small resistance arteries. Thus, vasopeptidase inhibition may have therapeutic advantages of the prevention of changes in vascular function and structure in salt-sensitive forms of hypertension.
Rat Coronary Endothelial Cell Membrane Potential Responses During Hypertension
Authors: Gauthier Kathryn M. , Rusch Nancy J.
Published: June 2012

Abstract
—The purpose of this study was to provide the first membrane potential profile in coronary endothelial cells from normotensive sham-operated control and 1-kidney, 1-clip renal hypertensive rats. Dilator responses were assessed in cannulated coronary arteries from control and 1-kidney, 1-clip rats, and the perforated patch-clamp method was used to compare membrane potential responses between the intact endothelial cells. Under these conditions, acetylcholine (100 pmol/L to 10 μmol/L) induced similar large dilations of coronary arteries from control and 1-kidney, 1-clip rats that were associated with endothelial cell hyperpolarizing responses of 16±3 and 18±2 mV, respectively. Substance P (10 fmol/L to 1 nmol/L) and bradykinin (100 fmol/L to 10 nmol/L) also substantially dilated coronary arteries from control rats but only induced small (2 to 4 mV) endothelial cell hyperpolarizing responses. These dilations, which appeared independent of membrane potential changes, were highly blunted or absent in arteries from 1-kidney, 1-clip rats. Thus, dilator responses to acetylcholine that are associated with large endothelial hyperpolarizing responses are normal in the small coronary arteries of 1-kidney, 1-clip rats. However, dilator response to substance P and bradykinin, which apparently are not heavily dependent on endothelial cell hyperpolarizations, are selectively targeted for impairment in the coronary arteries of this model of hypertension
Thyroid Hormone Stimulates Renin Gene Expression Through the Thyroid Hormone Response Element
Authors: Kobori Hiroyuki , Hayashi Matsuhiko , Saruta Takao
Published: June 2012

Abstract
—We previously reported that thyroid hormone stimulates renin synthesis in vivo and in vitro. Here, we analyzed the 5′-flanking sequence of the human renin gene for promoter activity responsive to thyroid hormone using Calu-6 cells, which secrete renin endogenously and express thyroid hormone receptor-β. The luciferase reporter gene was cloned together with 5′-flanking portions of the human renin gene of various lengths into the pGL3-Basic vector. Luciferase activity assays were performed using the Dual Luciferase Reporter Assay System. 3,3′,5-Triiodo-
l
-thyronine stimulated the promoter activity of pGL3-Basic−1111/+12 and pGL3-Basic−1298/+12 by 2.3±0.1- and 1.7±0.1-fold, respectively. Shorter constructs (pGL3-Basic−144/+12, pGL3-Basic−226/+12, pGL3-Basic−452/+12, and pGL3-Basic−953/+12) were not stimulated by thyroid hormone. These results suggest that there is a possible thyroid hormone response element (5′-AGG TCA GGT CAc aat GTT CCT-3′) between nucleotides −1111 and −953. In 3 constructs with site-directed mutations in this sequence, basal promoter activities were significantly increased, whereas promoter activation by thyroid hormone was abolished. Electrophoretic mobility shift assays showed that the −1111/−953 DNA fragment of the intact human renin gene was bound to nuclear proteins of Calu-6 cells; however, none of the 3 mutant probes were bound to any nuclear proteins. These results suggest that thyroid hormone stimulates the promoter activity of the human renin gene through thyroid hormone response element–dependent mechanisms in Calu-6 cells.
T+31C
Polymorphism of Angiotensinogen Gene and Essential Hypertension
Authors: Ishikawa Kazuhiko , Baba Shunroku , Katsuya Tomohiro , Iwai Naoharu , Asai Takashi , Fukuda Masayuki , Takiuchi Shin , Fu Yuxiao , Mannami Toshifumi , Ogata Jun , Higaki Jitsuo , Ogihara Toshio
Published: June 2012

A common variant at codon 235 of the angiotensinogen gene with methionine to threonine amino acid substitution (
AGT M235T
) has been reported as a genetic risk for essential hypertension. However, the frequency of
AGT T235
was heterogeneous among races, and a positive association between
AGT M235T
and hypertension was not settled. To examine the association in a general population of Japanese (n=4013), we introduced the TaqMan polymerase chain reaction method and examined the relation between hypertension and
T+31C
polymorphism, which was in absolute linkage disequilibrium with
AGT M235T.
The
C+31
allele of
AGT
was significantly associated with the positive family history of hypertension (FH) but not with the presence of hypertension or blood pressure. The subjects with CC tended to have hypertensive relatives, especially a hypertensive father or siblings, and its statistical significance was stronger in men. Adjustment of confounding factor did not alter the results of simple association study, suggesting that this positive association with FH is independent and significant. Our findings revealed that the TaqMan polymerase chain reaction method is a powerful tool for genetic association study with a large number of subjects and that
AGT T+31C
is significantly associated with paternal FH.
Increased Levels of 12(S)-HETE in Patients With Essential Hypertension
Authors: González-Núñez Daniel , Claria Joan , Rivera Francisca , Poch Esteban
Published: June 2012

The platelet-type 12-lipoxygenase (12-LO) catalyzes the transformation of arachidonic acid into 12-hydroperoxyeicosatetraenoic acid [12-(S)HPETE], which is reduced to 12-hydroxyeicosatetraenoic acid [12-(S)HETE]. These metabolites exhibit a variety of biological activities such as mediation of angiotensin II–induced intracellular calcium transients in cultured rat vascular smooth muscle cells. It has recently been reported that platelet 12(S)-HETE production is enhanced in the spontaneously hypertensive rat. The pronounced hypotensive effect of LO inhibition in SHR suggests that LO activity may play a role in this form of hypertension. The aim of this study was to determine the basal and thrombin-induced platelet 12(S)-HETE production and the urinary 12(S)-HETE excretion in essential hypertension. We studied 19 patients with this disease (57±2 years of age) and 9 normotensive control subjects (48±5 years of age) (
P
=0.074). 12(S)-HETE was measured in Sep-Pack–extracted samples with specific ELISA and high-performance liquid chromatography. The platelet basal level of 12(S)-HETE was significantly higher in patients than in control subjects (3.56±1.22 versus 0.64±0.13 ng/10
6
platelets,
P
<0.025). In contrast, there were no differences in thrombin-stimulated (1 U/mL) 12(S)-HETE generation: 7.66±2.14 in patients versus 4.87±1.46 in control subjects (
P
=0.61). Platelet 12-LO protein levels, measured by Western blotting with a polyclonal antibody, were higher in the patients than in the control subjects. The urinary excretion of 12(S)-HETE was higher in patients than in control subjects: 36.8±7.24 versus 17.1±3.14 ng/mg creatinine (
P
<0.01). These results indicate that 12(S)-HETE levels and 12-LO protein are increased in patients with essential hypertension, suggesting a role for this metabolite in human hypertension.