bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of Lovastatin on Cerebral Circulation in Spontaneously Hypertensive Rats
Authors: Régrigny Olivier , Atkinson Jeffrey , Capdeville-Atkinson Christine , Limiñana Patrick , Chillon Jean-Marc
Published: June 2012

Abstract
—Statins, which are often given to hypertensive patients, reduce the incidence of stroke. However, their effects on the cerebral circulation have been scarcely studied, although lovastatin has been reported to reduce hypertension-induced renal arteriolar hypertrophy. We examined the structure and mechanics of cerebral arterioles and the lower limit of cerebral blood flow (CBF) autoregulation in spontaneously hypertensive rats (SHR) that were untreated (n=9) or treated for 1 month with lovastatin (n=12; 20 mg · kg
−1
· d
−1
) and in untreated Wistar-Kyoto rats (WKY; n=8). We studied the lower limit of CBF autoregulation by repeated measurement of CBF (arbitrary units; laser Doppler) and internal arteriolar diameter (μm; cranial window) at baseline and during stepwise hypotension. Stress-strain relationships were calculated from repeated measurement of internal arteriolar diameter during stepwise hypotension and cross-sectional area (CSA) of the vessel wall in maximally dilated cerebral arterioles (EDTA, 67 mmol/L). Lovastatin slightly reduced mean arterial pressure (treated, 153±3 versus untreated, 171±5 mm Hg,
P
<0.05; WKY, 106±3 mm Hg) and normalized CSA (treated, 826±52 versus untreated, 1099±16 μm
2
,
P
<0.05; WKY, 774±28 μm
2
). Stress-strain curves show that lovastatin also attenuated the increase in passive distensibility. Lovastatin had no effect on the external diameter of cerebral arterioles or the lower limit of CBF autoregulation. Our results show that although lovastatin has substantial effects on arteriolar mechanics and wall CSA, it has little effect on internal diameter. This phenomenon may explain its lack of effect on CBF autoregulation.
Atrial Natriuretic Peptide Modifies Arterial Blood Pressure Through Nitric Oxide Pathway in Rats
Authors: Costa María de los Angeles , Bosc Laura V. González , Majowicz Mónica P. , Vidal Norberto A. , Balaszczuk Ana M. , Arranz Cristina T.
Published: June 2012

Abstract
—The aim of the present study was to determine the relationship between the hypotensive effect of the atrial natriuretic peptide (ANP) and the nitric oxide (NO) pathway. N
G
-nitro-
l
-arginine methyl ester bolus (L-NAME, 1 mg/kg) reverted the decrease in mean arterial pressure induced by ANP administration (5 μg/kg bolus and 0.2 μg · kg
−1
· min
−1
infusion), and the injection of L-NAME before peptide administration suppressed the ANP hypotensive response. To confirm these findings, a histochemical reaction was used to determine NADPH-diaphorase activity (a NO synthase marker) in the endothelium and smooth muscle of aorta and arterioles of the small and large intestine. ANP increased aorta and arteriole endothelium staining after both in vivo administration and in vitro tissue incubation. In both cases, L-NAME prevented the ANP effect on NADPH-diaphorase activity. Tissues incubated with 8-bromoguanosine 3′, 5′-cyclic monophosphate mimicked ANP action. In addition, ANP administration increased urinary excretion of NO
x
end products. These findings indicate that ANP increases NO synthesis capability and NO production and suggest that the cGMP pathway may be involved. In conclusion, the NO pathway could be an intercellular messenger in the ANP endothelium-dependent vasorelaxation mechanism.
Heritability of Angiotensin-Converting Enzyme and Angiotensinogen
Authors: Cooper Richard S. , Guo Xiuqing , Rotimi Charles N. , Luke Amy , Ward Ryk , Adeyemo Adebowale , Danilov Sergei M.
Published: June 2012

Abstract
—Angiotensinogen (AGT) and angiotensin I–converting enzyme (ACE) are heritable traits, but whether the environmental context influences heritability has not been examined. Known genetic factors explain only a portion of variation in AGT and ACE, and levels of both proteins are influenced by the environment. The African diaspora provides an opportunity to compare these traits in genetically related populations in contrasting environments. As part of a study of the genetics of hypertension, we examined families that included 1449 Nigerians and 1147 African Americans. Body mass index (weight [kg]/height [m]
2
) was 21 kg/m
2
in Nigeria and 29 kg/m
2
in the United States, which is consistent with a large environmental contrast. AGT was considerably higher among African Americans (1919 versus 1396,
P
<0.01), whereas ACE was higher in Nigerians (630 versus 517,
P
<0.01). A household effect was observed among the Nigerian families (spouse correlations 0.30 for AGT, 0.18 for ACE), and correlations among first-degree relatives were large (0.42 to 0.51 and 0.36 to 0.38 for AGT and ACE, respectively). Among African Americans, the familial aggregations of AGT and ACE were very limited, and the familial correlation for AGT was not different from zero. Heritability was 77% for AGT and 67% for ACE in Nigeria and 18% for AGT and ACE in the United States. The familial patterns of body mass index and blood pressure were similar among both family sets. In conclusion, less familial aggregation was observed for AGT and ACE in the United States than in Nigeria, most likely reflecting a greater random individual environmental effect on these traits. Variation in heritability of traits could influence the power of epidemiological studies to identify genetic effects.
Antihypertensive Effects of Fasidotril, a Dual Inhibitor of Neprilysin and Angiotensin-Converting Enzyme, in Rats and Humans
Authors: Laurent Stéphane , Boutouyrie Pierre , Azizi Michel , Marie Christine , Gros Claude , Schwartz Jean-Charles , Lecomte Jeanne-Marie , Bralet Jean
Published: June 2012

Abstract
—The aim of this study was to assess the antihypertensive activity of fasidotril, a dual inhibitor of neprilysin (NEP) and angiotensin I–converting enzyme (ACE), in various models of hypertension in rats (spontaneously hypertensive rats [SHR]; renovascular Goldblatt 2-kidney, 1-clip rats; and deoxycorticosterone acetate [DOCA]-salt hypertensive rats) and in patients with mild-to-moderate essential hypertension. Fasidotril treatment (100 mg/kg PO twice daily for 3 weeks) resulted in a progressive and sustained decrease in systolic blood pressure (−20 to −30 mm Hg) in SHR and Goldblatt rats compared with vehicle-treated rats and prevented the progressive rise in blood pressure in DOCA-salt hypertensive rats. After a 4-week placebo run-in period, 57 patients with essential hypertension were included in a randomized double-blind, placebo-controlled, parallel-group study and received orally either fasidotril (100 mg twice daily) or placebo for 6 weeks. Blood pressure was measured during the 6 hours after the first intake and then at trough (12 hours after the last intake) on days 7, 28, and 42. The first dose of fasidotril had no significant effect on blood pressure. After 42 days, compared with placebo, fasidotril lowered supine systolic and diastolic blood pressures by 7.4/5.4 mm Hg and standing blood pressure by 7.6/6.8 mm Hg. Fasidotril, a dual NEP/ACE inhibitor, was an effective oral antihypertensive agent during chronic treatment in high-renin renovascular rats, normal-renin SHR, and low-renin DOCA-salt hypertensive rats and in patients with essential hypertension.
Enhanced Adrenomedullin Production by Mechanical Stretching in Cultured Rat Cardiomyocytes
Authors: Tsuruda Toshihiro , Kato Johji , Kitamura Kazuo , Imamura Takuroh , Koiwaya Yasushi , Kangawa Kenji , Komuro Issei , Yazaki Yoshio , Eto Tanenao
Published: June 2012

Abstract
—Adrenomedullin (AM) is secreted from cultured cardiac myocytes. In this study, we examined whether mechanical stretching stimulates AM production in cardiac myocytes, and if so, whether angiotensin II (Ang II) is involved in that mechanism. Neonatal rat cardiac myocytes cultured in serum-free medium were stretched 10% or 20% on flexible silicone rubber culture dishes, and AM mRNA expression was examined by quantitative polymerase chain reaction. The AM mRNA levels in the myocytes stretched 10% and 20% for 24 hours significantly increased by 56% (
P
<0.05) and 88% (
P
<0.01), respectively, when compared with the levels in nonstretched cells. AM secretion into the medium after the myocytes were stretched 10% and 20% increased by 22% (
P
<0.05) and 45% (
P
<0.01), respectively. In nonstretched myocytes incubated with 10
−6
mol/L Ang II for 24 hours, AM mRNA and secretion increased by 86% (
P
<0.05) and 36% (
P
<0.01), respectively. These effects of Ang II were abolished by 10
−6
mol/L CV-11974, an Ang II type I (AT
1
) receptor antagonist, but not by 10
−6
mol/L PD-123319, an Ang II type II antagonist. Stretch-induced increases of AM gene expression and secretion were significantly inhibited (
P
<0.05) in the presence of 10
−6
mol/L CV-11974 by 46% and 52%, respectively; however, they were not affected by 10
−6
mol/L PD-123319. These findings indicate that AM production from cardiac myocytes is augmented by mechanical stretching, partially through the AT
1
receptors, which suggests a local interaction between AM and the renin-angiotensin system in stretched cardiac myocytes.
Aging Increases PGHS-2–Dependent Vasoconstriction in Rat Mesenteric Arteries
Authors: Stewart Ken G. , Zhang Yunlong , Davidge Sandra T.
Published: June 2012

Abstract
—During aging, the vascular endothelium changes functionally and morphologically. Although previous studies have shown that endothelium-derived eicosanoids increase vessel tone in aging, the precise mechanism(s) has not been fully determined. We hypothesized that aging would increase prostaglandin H synthase (PGHS)-dependent vasoconstriction as well as decrease nitric oxide–dependent relaxation. Mesenteric arteries from 3-month-old (n=9) and 12-month-old (n=14) female Sprague-Dawley rats were studied in a myograph system. Aging significantly blunted the endothelium-dependent relaxation response to methacholine compared with young rats (EC
50
=7.77×10
−8
versus 2.68×10
−8
mol/L,
P
<0.05). Nitric oxide synthase inhibition reduced methacholine-induced relaxation in the young (
P
<0.05) but had no effect in the aging group. Specific inhibition of the PGHS-1 isoform did not significantly affect methacholine-mediated relaxation in the young or aged groups. However, PGHS-2 inhibition greatly enhanced relaxation to methacholine (1.59×10
−8
versus 7.77×10
−8
mol/L,
P
<0.01) in the aged group only, restoring vessel function to that of the young. In the aged group, inhibition of the prostaglandin H
2
/thromboxane A
2
receptor enhanced methacholine-dependent relaxation similar to that of PGHS-2 inhibition. Moreover, arterial expression of PGHS-2 protein increased with age. In summary, nitric oxide–dependent modulation of vessel function decreased with age, PGHS-1 did not significantly affect vessel tone in either the young or aging group, and PGHS-2 greatly increased vasoconstriction in aging. Thus, we have identified enhanced PGHS-2–mediated vasoconstriction in aging and therefore suggest that inhibition of this isoform is potentially a new target for therapeutic intervention to improve vascular function.
Prevalence and Risk Factors of Silent Cerebral Infarction in Apparently Normal Adults
Authors: Lee Sang-Chol , Park Sang-Joon , Ki Hyun-Kyun , Gwon Hyeon-Cheol , Chung Chin-Sang , Byun Hong Sik , Shin Kyung-Ja , Shin Myung-Hee , Lee Won Ro
Published: June 2012

Abstract
—Cerebrovascular disease is a major cause of death and disability in adults. Silent cerebral infarction (SCI) portends more severe cerebral infarctions or may lead to insidious progressive brain damage resulting in vascular dementia. This study was designed to evaluate the prevalence and risk factors of SCI in an apparently normal adult population. Nine hundred ninety-four consecutive symptom-free adults (mean age 49.0±7.7; men:women 830:164) who underwent brain magnetic resonance imaging at the Center for Health Promotion at Samsung Medical Center were assessed. All were neurologically normal in history and physical examination. A total of 121 SCI lesions was observed in 58 subjects. The lesion prevalence adjusted for patient age was 5.1%. There was no gender difference in prevalence. Ninety-nine lesions were <1 cm in diameter, 15 were between 1 and 2 cm, 3 were between 2 and 3 cm, and 4 were >3 cm in diameter. The most frequent site of the SCI lesion was basal ganglia, after which the periventricular white matter, cerebral cortex, and thalamus were the most frequent sites. Old age, hypertension, a history of coronary artery disease, evidence of cardiomegaly in chest radiographs, and high fasting glucose/hemoglobin A1c levels were associated with SCI on univariate analysis. Multivariate analysis demonstrated old age and hypertension to be independent risk factors for SCI, and mild alcohol consumption was revealed as an independent protective factor against SCI.
Dopamine D1 Receptor Gene Polymorphism Is Associated With Essential Hypertension
Authors: Sato Mikano , Soma Masayoshi , Nakayama Tomohiro , Kanmatsuse Katsuo
Published: June 2012

Abstract
—Dopamine has been shown to influence renal sodium excretion through a direct interaction with the dopamine receptor (DR). The dopamine D1 receptor (DRD1) has been localized to the proximal tubules and is known to increase sodium excretion by inhibiting Na-H exchanger and Na,K-ATPase activity. Defective renal dopamine production and/or DR function have been reported in essential hypertension (EH) as well as in genetic models of animal hypertension. With a restriction fragment length polymorphism of the DRD1 gene, we performed an association study in patients with EH. One hundred thirty-one subjects with EH and 136 age-matched normotensive (NT) controls were studied. Polymerase chain reaction was used to amplify the A-48G polymorphic site in the DRD1 gene, and restriction analysis of the polymerase chain reaction product was used to score the A and G alleles. The allele frequencies in the EH group and NT group were then compared. The G allele was observed more frequently in the EH group than in the NT group, and the allele frequencies in the 2 groups differed significantly (χ
2
=6.5,
P
=0.01). Multiple logistic linear regression analysis revealed that the genotype frequencies of
A/A
,
A/G
, and
G/G
differed significantly (odds ratio=2.1; 95% CI=1.19 to 3.66) between the EH and NT groups. EH patients who possess the
G
allele had a higher diastolic blood pressure than those lacking the
G
allele (
P
<0.01). Thus, the alleles detected by this restriction fragment length polymorphism in the DRD1 gene are associated with EH, and they appear to influence the diastolic blood pressure of Japanese EH patients.
CA-Repeat Polymorphism in Intron 1 of HSD11B2
Authors: Agarwal Anil K. , Giacchetti Gilberta , Lavery Gareth , Nikkila Heli , Palermo Mario , Ricketts Marie , McTernan Claire , Bianchi Giuseppe , Manunta Paolo , Strazzullo Pasquale , Mantero Franco , White Perrin C. , Stewart Paul M.
Published: June 2012

Abstract
—Mutations in the HSD11B2 gene encoding the kidney (11-HSD2) isozyme of 11β-hydroxysteroid dehydrogenase cause apparent mineralocorticoid excess, a form of familial hypertension. Because the hypertension associated with AME is of the salt-sensitive type, it seemed possible that decreases in 11-HSD2 activity might be associated with salt sensitivity. To examine this, Italians with mild hypertension underwent a protocol consisting of a rapid intravenous saline infusion and subsequent furosemide diuresis. To determine whether there were genetic associations between HSD11B2 and salt sensitivity, 198 Italians were genotyped for a CA repeat polymorphism (11 alleles) in the first intron. Increased differences in mean arterial pressure between the sodium loaded and depleted states were correlated with shorter CA repeat length (R=0.214,
P
=0.0025). The effect behaved as a recessive trait. This suggested that decreased HSD11B2 expression was associated with shorter CA repeat length. Furthermore, activity of renal 11-HSD2 as measured by an increase in the ratio of urinary-free cortisol/urinary-free cortisone was lower in 33 salt-sensitive subjects (urinary-free cortisol/urinary-free cortisone 0.89±0.04 [mean±SE]) compared with 34 salt-resistant subjects (0.71±0.04,
P
<0.001). However, when minigenes containing either 14 or 23 CA repeats were transfected into rabbit or human kidney cortical collecting duct cells, the construct with 14 repeats was instead expressed at levels 50% higher than those of the construct with 23 repeats, as determined by reverse transcription–polymerase chain reaction. We conclude that polymorphisms in HSD11B2 and decreased 11-HSD2 activity are associated with sensitivity to sodium loading, but a functional explanation for these associations remains to be elucidated.
Can Serum Carnitine Levels Distinguish Hypertrophic Cardiomyopathy From Hypertensive Hearts?
Authors: Nakamura Tomoki , Sugihara Hiroki , Kinoshita Noriyuki , Yoneyama Satoshi , Azuma Akihiro , Nakagawa Masao
Published: June 2012

Abstract
—Although echocardiography is a useful diagnostic tool in hypertrophic cardiomyopathy (HCM), it is sometimes difficult to differentiate it from hypertensive heart disease (HHD): some patients with HCM show symmetrical hypertrophy, whereas patients with HHD sometimes show asymmetrical septal hypertrophy. We used a radioiodinated long-chain fatty acid tracer to visualize the altered myocardial fatty acid metabolism of HCM and HHD. Carnitine is the essential substance for the β-oxidation of long-chain fatty acids. We recently reported that serum free carnitine levels in HCM were elevated and that they were significantly correlated with the severity of myocardial fatty acid metabolic disorder. Therefore, we investigated serum carnitine levels in patients with HCM and HHD, which can contribute to the differentiation of each other. We studied 56 patients with HCM and 20 patients with essential hypertension. Serum free carnitine levels were significantly higher in patients with HCM than those with HHD (HCM 52.5±9.5 nmol/mL, HHD 46.6±6.4 nmol/mL,
P
<0.01), but they showed no statistical difference between patients with HHD and normal subjects. Serum acylcarnitine levels were significantly lower in patients with HCM than those with HHD (HCM 10.1±4.0 nmol/mL, HHD 14.5±4.9 nmol/mL,
P
<0.0005), although they did not differ between patients with HHD and normal subjects. Scintigraphic analyses with a long-chain fatty acid analog revealed that myocardial tracer uptake was much reduced in patients with HCM compared with that in patients with HHD (quantitative analysis: HCM 2.11±0.12, HHD 2.22±0.17,
P
<0.05; semiquantitative analysis: HCM 13.6±6.3, HHD 2.0±1.5,
P
<0.0001). In conclusion, the differences in serum carnitine levels between HCM and HHD reflect altered myocardial fatty acid metabolic impairment, and the levels can help to distinguish these 2 diseases.
Effect of Antihypertensive Therapy on Renal Injury in Type 2 Diabetic Rats With Hypertension
Authors: Reddi Alluru S. , Nimmagadda Venkata R. , Lefkowitz Aza , Kuo Hon-Reen , Bollineni Jaya S.
Published: June 2012

Abstract
—In a previous study, we demonstrated that doxazocin (DZN), an α
1
-adrenergic blocker, prevented proteinuria in streptozotocin diabetic rats. In this study, we investigated whether DZN would lower established proteinuria by improving glomerular sclerosis in spontaneously hypertensive corpulent rats with type 2 diabetes mellitus. DZN treatment was compared with treatment with angiotensin-converting enzyme inhibitor, lisinopril (LIS) alone, and DZN in combination with LIS. Combination therapy was used to examine any additive effect of either drug alone in the reduction of proteinuria and glomerular sclerosis. Both male and female rats age 6 months with established proteinuria were used. The rats were allocated randomly to 1 of 4 groups: untreated, DZN treated, LIS treated, or a combination of DZN and LIS treatment. Drug treatment was continued for 16 weeks. The results show that (1) either drug alone or in combination significantly lowered systolic blood pressure; (2) DZN, LIS, or combination therapy reduced albuminuria at 16 weeks of treatment from baseline by 38.61±5.77%, 30.70±4.21%, and 42.17±4.77% (mean±SE), respectively. No difference in albuminuria was observed among the 3 groups of rats; (3) the fractional mesangial area, which was 20.55±3.77% in untreated rats, was significantly reduced to 11.18±1.32% in DZN-treated rats, with a further reduction to 8.72±0.64% in LIS-treated rats and to 3.48±0.35% in rats treated with DZN+LIS; and (4) DZN but not LIS significantly improved plasma glucose levels in spontaneously hypertensive corpulent rats (untreated 21.06±0.97 mmol/L versus DZN treated 15.81±0.93 mmol/L or DZN+LIS treated 17.38±1.10 mmol/L;
P
<0.025 to 0.005). Thus, the data suggest that 16-week treatment with either DZN or LIS improves established proteinuria and glomerular sclerosis, but combination therapy is superior to either DZN or LIS alone in preventing glomerular sclerosis in type 2 diabetic rats with hypertension.
Effects of Angiotensin-Converting Enzyme Inhibitors on Glucose Uptake
Authors: Kudoh Akira , Matsuki Akitomo
Published: June 2012

Abstract
—We investigated the effect of angiotensin-converting enzyme inhibitors on glucose uptake regulation as well as the effect of bradykinin (BK) on glucose uptake and its regulation by using inhibitors of phospholipase C, BK B2 receptor, protein kinase C, phosphatidylinositol 3-kinase, tyrosine kinase, and intracellular Ca
2+
. We measured 2-deoxyglucose uptake by using L
6
skeletal muscle cells. In the presence of 1 nmol/L of insulin, 1 μmol/L of enalaprilat enhanced insulin-induced glucose uptake from 89.2±8.1 to 138.0±13.6 pmol/h per mg protein. The stimulation of glucose uptake with enalaprilat was blocked to 92.7±7.8 pmol/h per mg protein by 10 μmol/L HOE 140 (a BK B2 receptor antagonist). In the presence of 1 nmol/L of insulin, exposure to 10 μmol/L BK stimulated glucose uptake from 89.2±8.1 to 171.6±10.1 pmol/h per mg protein. However, in the absence of insulin, BK could not enhance glucose uptake. One hundred nanomoles per liter of tyrphostin A-23 and genistein, which are tyrosine kinase inhibitors, significantly decreased the BK-induced glucose uptake from 142.0±8.4 to 87.6±6.4 and 85.2±7.3 pmol/h per mg protein, respectively. BK-induced glucose uptake was inhibited significantly by 10 μmol/L U73122 (a phospholipase C antagonist) from 142.0±8.4 to 95.7±9.5 pmol/h per mg protein. One and 20 μmol/L of TMB-8 (an intracellular calcium antagonist) significantly decreased BK-induced glucose uptake from 142.0±8.4 to 108.0±9.6 and 100.8±11.4 pmol/h per mg protein. Angiotensin-converting enzyme inhibitors enhanced insulin-induced glucose uptake via the BK B2 receptor. BK-stimulated glucose uptake is related to phospholipase C, tyrosine kinase, and an increase in intracellular calcium.
Cardiac Fibroblasts Express the cAMP-Adenosine Pathway
Authors: Dubey Raghvendra K. , Gillespie Delbert G. , Mi Zaichuan , Jackson Edwin K.
Published: June 2012

Abstract
—The extracellular “cAMP-adenosine pathway” refers to the local production of adenosine mediated by cAMP egress into the extracellular space, conversion of cAMP to AMP by ectophosphodiesterase, and the metabolism of AMP to adenosine by ecto-5′-nucleotidase. The goal of this study was to assess whether the cAMP-adenosine pathway limits cardiac fibroblast growth. Studies were conducted in ventricular cardiac fibroblasts maintained in 3-dimensional cultures. Addition of exogenous cAMP to cardiac fibroblasts increased extracellular levels of AMP, adenosine, and inosine in a concentration-dependent and time-dependent manner. This effect was attenuated by blockade of total phosphodiesterase activity (3-isobutyl-1-methylxanthine), ectophosphodiesterase activity (high concentration of 1,3-dipropyl-8-
p
-sulfophenylxanthine), or ecto-5′-nucleotidase (α, β-methylene-adenosine-5′-diphosphate). Treatment with exogenous cAMP inhibited cell growth as assessed by DNA synthesis (
3
H-thymidine incorporation), cell proliferation (cell counts), and protein synthesis (
3
H-leucine incorporation). Antagonism of A
2
(KF17837) or A
1
/A
2
(low concentration of 1,3-dipropyl-8-
p
-sulfophenylxanthine), but not A
1
(8-cyclopentyl-1,3-dipropylxanthine), adenosine receptors blocked the growth-inhibitory effects of exogenous cAMP, but not the growth inhibitory effects of 8-bromo-cAMP (stable cAMP analogue). The growth-inhibitory effects of exogenous cAMP were enhanced by the combined inhibition of adenosine deaminase [erythro-9-(2-hydroxy-3-nonyl) adenine] and adenosine kinase (iodotubercidin). In conclusion, the extracellular cAMP-adenosine pathway exists in cardiac fibroblasts and attenuates cell growth. Pharmacological augmentation of this pathway could abate pathological cardiac remodeling in heart disease.
Interaction of Carbon Dioxide and Sympathetic Nervous System Activity in the Regulation of Cerebral Perfusion in Humans
Authors: Jordan Jens , Shannon John R. , Diedrich Andre , Black Bonnie , Costa Fernando , Robertson David , Biaggioni Italo
Published: June 2012

Abstract
—Recent studies suggest that activation of the sympathetic nervous system either directly or indirectly influences cerebrovascular tone in humans even within the autoregulatory range. In 6 healthy subjects (aged 29±4 years), we used transcranial Doppler sonography to determine cerebral blood flow velocity during sympathetic activation elicited through head-up tilt (HUT) and sympathetic deactivation through ganglionic blockade. Pa
co
2
was manipulated through hyperventilation and CO
2
breathing (5%). With subjects in the supine position and during HUT, mean arterial pressure was not influenced by Pa
co
2
. During ganglionic blockade, mean arterial pressure decreased markedly with hyperventilation (−13±1.9 mm Hg). Manipulation of sympathetic tone elicited only mild changes in cerebral blood flow (64±5.8 cm/s supine, 58±4.9 cm/s upright, and 66±6.2 cm/s during ganglionic blockade;
P
=0.07 by ANOVA). The slope of the regression between Pa
co
2
and mean velocity was 1.6±0.18 cm/(s · mm Hg) supine, 1.3±0.14 cm/(s · mm Hg) during HUT, and 2.3±0.36 cm/(s · mm Hg) during ganglionic blockade (
P
<0.05). Spontaneous Pa
co
2
and ventilatory response to hypercapnia were also modulated by the level of sympathetic activity. Changes in sympathetic tone have a limited effect on cerebral blood flow at normal Pa
co
2
levels. However, the sympathetic nervous system seems to attenuate the CO
2
-induced increase in cerebral blood flow. This phenomenon may indicate a moderate direct effect of the sympathetic nervous system on the cerebral vasculature. Furthermore, sympathetic activation tends to increase ventilation and thus can indirectly increase cerebrovascular tone.
Possible Locus on Chromosome 18q Influencing Postural Systolic Blood Pressure Changes
Authors: Pankow James S. , Rose Kathryn M. , Oberman Albert , Hunt Steven C. , Atwood Larry D. , Djoussé Luc , Province Michael A. , Rao D. C.
Published: June 2012

Abstract
—We conducted a genome-wide scan for quantitative trait loci influencing the systolic blood pressure, diastolic blood pressure, and pulse responses to a postural challenge in 498 white sibling-pairs from the Hypertension Genetic Epidemiology Network, a multicenter study of the genetic susceptibility to hypertension. All participants were hypertensive (systolic blood pressure ≥140 mm Hg, diastolic blood pressure ≥90 mm Hg, or on antihypertensive medications) with diagnosis before age 60. Blood pressure and pulse were measured by an oscillometric method after a 5-minute rest in a supine position and again immediately on standing. The genome scan included a total of 387 autosomal short-tandem-repeat polymorphisms typed by the National Heart, Lung, and Blood Institute Mammalian Genotyping Service at Marshfield. We used multipoint variance-components linkage analysis to identify possible quantitative trait loci influencing postural change phenotypes after adjusting for sex, age, and use of antihypertensive medications. There was suggestive evidence for linkage on chromosome 18q for the postural systolic blood pressure response (maximum logarithm of the odds score=2.6 at 80 centiMorgans). We also observed a maximum logarithm of the odds score of 1.9 for the systolic blood pressure response and 1.7 for the diastolic blood pressure response on chromosome 6p. The marker that demonstrated the strongest evidence for linkage for the systolic blood pressure response (D18S858) lies within 20 centiMorgans of a marker previously linked to rare familial orthostatic hypotensive syndrome. Our findings indicate that there may be 1 or more genes on chromosome 18q that regulate systolic blood pressure during the physiological recovery period after a postural stressor.
Leptin Attenuates Cardiac Contraction in Rat Ventricular Myocytes
Authors: Nickola Marvie W. , Wold Loren E. , Colligan Peter B. , Wang Guei-Jane , Samson Willis K. , Ren Jun
Published: June 2012

Abstract
—Obesity is commonly associated with impaired myocardial contractile function. However, a direct link between these 2 states has not yet been established. There has been an indication that leptin, the product of the human obesity gene, may play a role in obesity-related metabolic and cardiovascular dysfunctions. The purpose of this study was to determine whether leptin exerts any direct cardiac contractile action that may contribute to altered myocardial function. Ventricular myocytes were isolated from adult male Sprague-Dawley rats. Contractile responses were evaluated by use of video-based edge detection. Contractile properties analyzed in cells electrically stimulated at 0.5 Hz included peak shortening, time to 90% peak shortening, time to 90% relengthening, and fluorescence intensity change. Leptin exhibited a dose-dependent inhibition in myocyte shortening and intracellular Ca
2+
change, with maximal inhibitions of 22.4% and 26.2%, respectively. Pretreatment with the NO synthase inhibitor
N
ω
-nitro-
l
-arginine methyl ester (L-NAME, 100 μmol/L) blocked leptin-induced inhibition of both peak shortening and fluorescence intensity change. Leptin also stimulated NO synthase activity in a time- and concentration-dependent manner, as reflected in the dose-related increase in NO accumulation in these cells. Addition of an NO donor (
S
-nitroso-
N
-acetyl-penicillamine [SNAP]) to the medium mimicked the effects of leptin administration. In summary, this study demonstrated a direct action of leptin on cardiomyocyte contraction, possibly through an increased NO production. These data suggest that leptin may play a role in obesity-related cardiac contractile dysfunction.
Effect of Angiotensin II Blockade on Renal Injury in Mineralocorticoid-Salt Hypertension
Authors: Sorooshian Mitra , Olson Jean L. , Meyer Timothy W.
Published: June 2012

Abstract
—Kidney function and structure were compared in control rats (group 1) and in 3 groups of rats made hypertensive by administration of aldosterone and saline for 8 weeks (groups 2, 3, and 4). Group 2 rats received only aldosterone and saline, while group 3 also received losartan and group 4 also received enalapril. Rats in all groups were subjected to uninephrectomy before beginning the experiment. Hypertension and proteinuria in rats given aldosterone and saline were not affected by losartan or enalapril (8-week values for blood pressure in mm Hg: 135±3 group 1, 193±4 group 2, 189±4 group 3, 189±5 group 4;
P
<0.05 groups 2, 3, and 4 versus 1; 8-week values for proteinuria in mg/d: 44±8 group 1, 278±34 group 2, 267±37 group 3, 289±36 group 4;
P
<0.05 groups 2, 3, and 4 versus 1). Vascular, glomerular, and tubulointerstitial injury accompanied hypertension and proteinuria at 8 weeks. Losartan and enalapril did not prevent vascular injury, which was characterized by thickening of arterial and arteriolar walls and by fibrinoid necrosis and thrombotic microangiopathy. Likewise, losartan and enalapril did not reduce the prevalence of glomerular segmental sclerosis (1±1% group 1, 10±2% group 2, 11±2% group 3, 13±2% group 4;
P
<0.05 groups 2, 3, and 4 versus 1) or limit tubulointerstitial injury as reflected by the volume fraction of the cortical interstitium (15±1% group 1, 20±1% group 2, 21±1% group 3, 21±1% group 4;
P
<0.05 groups 2, 3, and 4 versus 1). These findings suggest that local angiotensin II activity does not contribute to the development of renal injury in mineralocorticoid-salt hypertension.
Trends in Antihypertensive Drug Therapy of Ambulatory Patients by US Office-Based Physicians
Authors: Nelson Cheryl R. , Knapp Dee A.
Published: June 2012

Abstract
—This study assessed trends from 1980 to 1995 in ambulatory patients’ antihypertensive drug therapy by US office-based physicians for visits in which hypertension was the principal diagnosis and compared these trends with the respective guidelines given in 5 Joint National Committee (JNC) Reports on Detection, Evaluation, and Treatment of High Blood Pressure published around the same time period. Data from the National Center for Health Statistics’ National Ambulatory Medical Care Surveys for 1980, 1985, 1990, and 1995 were used. From 1980 to 1995, there was no significant trend in the percentage of hypertension visits that did not mention any antihypertensive drug (20% to 27%). Further analyses focused on those hypertension visits in which at least 1 antihypertensive drug was used. Across the years, antihypertensive drug visits mentioning calcium channel blockers or ACE inhibitors significantly increased; those noting diuretics significantly decreased. However, in 1995, antihypertensive drug visits that included a diuretic and/or a β-adrenergic blocker equalled 53%; these are the antihypertensive drug classes preferred by the JNC V. Physician antihypertensive drug prescribing was generally consistent with the basic antihypertensive drug guidelines of the JNC reports.
Angiotensin II Stimulates Extracellular Signal–Regulated Kinase Activity in Intact Pressurized Rat Mesenteric Resistance Arteries
Authors: Matrougui K. , Eskildsen-Helmond Y. E. G. , Fiebeler A. , Henrion D. , Levy B. I. , Tedgui A. , Mulvany M. J.
Published: June 2012

Abstract
—The activation of extracellular signal–regulated kinases 1/2 (ERK1/2) was assessed in isolated rat mesenteric resistance arteries (200-μm diameter) in a pressure myograph and stimulated for 5 minutes by angiotensin II (Ang II, 0.1 μmol/L) with a pressure of 70 mm Hg. ERK1/2 activity was measured by using an in-gel assay, and ERK1/2 phosphorylation was measured by Western blot analysis with use of a phospho-specific ERK1/2 antibody. Ang II (0.1 μmol/L) induced contraction (28% of phenylephrine contraction, 10 μmol/L). ERK kinase inhibitor PD98059 (10 μmol/L) attenuated this contraction by 36% but not that to phenylephrine or K
+
(60 mmol/L). In unpressurized arteries, Ang II increased ERK1/2 activity by 26%, and pressure (70 mm Hg) itself increased ERK1/2 activity by 72%. Ang II and pressure together acted synergistically, increasing ERK1/2 activity by 264%. Thus, in pressurized vessels, Ang II (0.1 μmol/L) increased ERK1/2 activity by 112%, calculated as [(364/172)−1]×100, which was confirmed by a measured 72% increase in ERK1/2 phosphorylation. Ang II type 1 receptor blockade by candesartan (10 μmol/L) abolished the Ang II–induced increase in ERK1/2 activity, but Ang II type 2 receptor blockade (PD123319, 10 μmol/L) did not. The Ang II–induced increase in ERK1/2 activity was inhibited by protein kinase C inhibitors Ro-31-8220 (1 μmol/L) and Go-6976 (300 nmol/L) and tyrosine kinase inhibitors genistein (1 μmol/L, general) and herbimycin A (1 μmol/L, c-Src family). The present findings show for the first time in intact resistance arteries that ERK1/2 activation is rapidly regulated by Ang II, is synergistic with pressure, and is involved in contraction. The ERK1/2 signaling pathway apparently includes upstream protein kinase C and c-Src.
Improvement in Midwall Myocardial Shortening With Regression of Left Ventricular Hypertrophy
Authors: Mayet Jamil , Ariff Ben , Wasan Balvinder , Chapman Neil , Shahi Manjit , Poulter Neil R. , Sever Peter S. , Foale Rodney A. , Thom Simon A. McG.
Published: June 2012

Abstract
—Despite normal indices of left ventricular (LV) chamber function, patients with LV hypertrophy (LVH) due to hypertension are thought to have depressed midwall systolic shortening compared with normotensives. The aims of the present study were (1) to confirm this observation and (2) to assess the effects of antihypertensive therapy that cause regression of LVH on LV systolic function assessed at both the midwall and endocardium. Thirty-eight previously untreated hypertensive subjects with LVH underwent echocardiography and were compared with 38 normotensive control subjects. Comparisons between the group with LVH and the control group revealed no significant differences in cardiac output (4.32±0.23 versus 4.55±0.21 L/min), ejection fraction (62.5±2% versus 66.4±1.07%), or endocardial fractional shortening (34.5±1.45% versus 37.0±0.82%), but shortening assessed at the midwall was significantly less in the group with LVH (17.9±1.11% versus 21.6±0.63%,
P
<0.01). Subsequently, 32 patients with uncontrolled hypertension (24 previously untreated and 8 on existing antihypertensive therapy) underwent treatment with ramipril, with the addition of felodipine and bendrofluazide if required, to reduce blood pressure to <140/90 mm Hg. These 32 patients underwent echocardiography at baseline, after blood pressure control, and after an additional 6 months of tight blood pressure control. Good blood pressure control was achieved after 6 months compared with baseline (143/86±2.8/1.4 versus 174/103±4.1/1.9 mm Hg;
P
<0.01) with significant regression of LV mass index (124±3.4 versus 145±3.8 g/m
2
,
P
<0.01). LV fractional shortening assessed at the midwall improved with regression of LVH (21.9±0.84 and 18.7±1.19%,
P
<0.05), with posttreatment midwall shortening being similar to that of the normal control subjects evaluated in the first study. Hypertensive patients with LVH have depressed midwall systolic shortening despite normal indices of LV chamber function. Regression of LVH after good blood pressure control improved midwall shortening to normal levels.
Hypertension and Its Treatment in Postmenopausal Women
Authors: Wassertheil-Smoller Sylvia , Anderson Garnet , Psaty Bruce M. , Black Henry R. , Manson JoAnn , Wong Nathan , Francis Jon , Grimm Richard , Kotchen Theodore , Langer Robert , Lasser Norman
Published: June 2012

Abstract
—Little is known about the patterns of treatment and adequacy of blood pressure control in older women. The Women’s Health Initiative, a 40-center national study of risk factors and prevention of heart disease, breast and colorectal cancer, and osteoporosis in postmenopausal women, provides a unique opportunity to examine these issues in the largest, multiethnic, best-characterized such cohort. Baseline data from the initial 98 705 women, aged 50 to 79 years, enrolled were analyzed to relate prevalence, treatment, and control of hypertension to demographic, clinical, and risk-factor covariates, and logistic regression analyses were performed to estimate odds ratios after adjusting for multiple potential confounders. Overall, 37.8% of the women had hypertension, which is defined as systolic blood pressure ≥140 mm Hg and/or diastolic blood pressure ≥90 mm Hg or being on medication for high blood pressure; 64.3% were treated with drugs, and blood pressure was controlled in only 36.1% of the hypertensive women, with lower rates of control in the oldest group. After adjustment for multiple covariates, current hormone users had higher prevalence than did nonusers (odds ratio 1.25). Hypertensive women had more comorbid conditions than did nonhypertensive women, and women with comorbidities were more likely to be treated pharmacologically. Diuretics were used by 44.3% of hypertensives either as monotherapy or in combination with other drug classes. As monotherapy, calcium channel blockers were used in 16%, angiotensin-converting enzyme inhibitors in 14%, β-blockers in 9%, and diuretics in 14% of the hypertensive women. Diuretics as monotherapy were associated with better blood pressure control than any of the other drug classes as monotherapy. In conclusion, hypertension in older women is not being treated aggressively enough because a large proportion, especially those most at risk for stroke and heart disease by virtue of age, does not have sufficient blood pressure control.
Heterozygous Knock-Out of ET
B
Receptors Induces BQ-123–Sensitive Hypertension in the Mouse
Authors: Berthiaume Nathalie , Yanagisawa Masashi , Labonté Julie , D’Orléans-Juste Pedro
Published: June 2012

Abstract
—Homozygous knock-out of ET
A
or ET
B
receptor genes results in lethal developmental phenotypes in the mouse. Such deleterious phenotypes do not occur in heterozygous littermates. However, it remains to be determined whether mice partially defective in ET
A
or ET
B
receptors display significant alterations in their responses to exogenous or endogenous endothelin-1 (ET-1). Furthermore, the anesthetized ET
B
(+/−) knock-out mice showed a significantly higher mean arterial blood pressure than the ET
A
(+/−) knock-out or their wild-type littermates. The pressor response to ET-1 but not to a selective ET
B
agonist, IRL-1620, was significantly reduced in the ET
A
(+/−) knock-out mice. In ET
B
(+/−) knock-out mice, the pressor effect of IRL-1620 was more markedly altered than those induced by ET-1. In wild-type mice, both ET
A
and ET
B
receptors were found to be involved in the pressor effect of ET-1, as confirmed by the significant and specific antagonism induced by either BQ-123 (ET
A
antagonist) or BQ-788 (ET
B
antagonist). Also, ET
A
-selective or mixed ET
A
/ET
B
- but not ET
B
-selective antagonists reversed the hypertensive state of the ET
B
(+/−) knock-out mice to the level of wild-type littermates. Finally, radiolabeled ET-1 plasmatic clearance was altered in ET
B
(+/−) but not ET
A
(+/−) knock-out mice when compared with wild-type animals. Thus, heterozygous knock-out of ET
B
receptors results in a hypertensive state, suggesting an important physiological role for that particular receptorial entity in opposing the endogenous ET-1–dependent pressor effects in the mouse.
Application of Supercritical Fluid Chromatography to Characterize a Labile Digitalis-Like Factor
Authors: Graves Steven W. , Markides Karen E. , Hollenberg Norman K.
Published: June 2012

Abstract
—A sodium pump inhibitor (digitalis-like factor), isolated from the peritoneal dialysate of volume-expanded, hypertensive patients with kidney failure who were treated with this dialysis modality, was further purified and characterized by means of supercritical fluid chromatography, a separation technique whose application to very-low-concentration biomolecules is new. Previous studies suggested that after high-performance liquid chromatography (HPLC) purification, this inhibitor was the only factor correlated with volume status and blood pressure in these patients. When this same HPLC fraction was furthered purified on 2-dimensional supercritical fluid chromatography, a single peak coeluted with [Na,K]ATPase inhibitory activity. When split specimens were used, there was a strict correlation between the peak area, measured by flame ionization detection, and activity (n=10,
R
=0.98,
P
=0.00001). Inhibitory activity after supercritical fluid chromatography was still correlated with the degree of volume expansion of donor patients (
P
=0.01). After HPLC purification, this volume-sensitive inhibitor was chemically labile. With further purification on supercritical fluid chromatography, the active peak was still labile with comparable half-life. Supercritical fluid chromatography coupled with flame ionization detection provided an estimate of the amount of the inhibitor present. Again using split specimens, we determined that the labile digitalis-like factor was ≈30-fold more effective than ouabain in inhibiting renal [Na,K]ATPase activity and ≥500 times more effective than ouabain in causing vascular smooth muscle contraction. The data suggest that we have purified to homogeneity a labile digitalis-like factor that is readily distinguished from ouabain or bufalin, based on chromatographic characteristics, chemical lability, and a much lower effective concentration for its biological activity.
Effect of Enalapril on Exhaled Nitric Oxide in Normotensive and Hypertensive Subjects
Authors: Sumino Hiroyuki , Nakamura Tetsuya , Kanda Tsugiyasu , Sato Kunio , Sakamaki Tetsuo , Takahashi Takashi , Saito Yuichiro , Hoshino Jin , Kurashina Toshiaki , Nagai Ryozo
Published: June 2012

Abstract
—We investigated whether an angiotensin-converting enzyme (ACE) inhibitor increases the production of nitric oxide (NO) in exhaled air in normotensive and hypertensive subjects. In study 1, 8 normotensive male subjects received a single oral dose of enalapril (5 mg) or nitrendipine (10 mg) in a crossover manner. Exhaled air was collected at baseline, and at 2, 4, and 8 hours after administration of the drug. In study 2, 10 normotensive subjects (6 men and 4 women) and 10 hypertensive subjects (6 men and 4 women) received a single oral dose of enalapril (5 mg). Exhaled air was collected at baseline and at 2 and 4 hours after administration of the drug. In study 1, enalapril significantly increased the NO release rate from the lung in normotensive subjects (36.9±5.1 pmol/s at baseline versus 58.3±7.3 pmol/s at 4 hours,
P
<0.01). Nitrendipine did not change the NO release rate. In study 2, enalapril significantly increased the release of NO from the lung in normotensive subjects (40.4±6.0 pmol/s at baseline versus 70.3±11.4 pmol/s at 4 hours,
P
<0.01) but not in hypertensive subjects. ACE inhibition increased NO production from the lung in normotensive subjects but not in hypertensive patients. The reduction of angiotensin II production and/or the accumulation of bradykinin in the pulmonary tissue may be responsible for increased NO production in components of the lung, such as the pulmonary vascular endothelium, bronchial epithelial cells, macrophages, nasopharyngeal cells, and neurons. However, the effects of ACE inhibition on NO production from the lung differ between hypertensive subjects and normotensive subjects.